Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC r6yrxDmBYVqrfyPPjK5DBtc S0066-782X2020001200690 abc.20200151 10.36660/abc.20200151 Artigo de Revisão Farmacogenômica e Doença Cardiovascular: Onde Estamos e Para Onde Vamos 0000-0003-2357-5176 Stein Ricardo 1 2 Beuren Thaís 1 2 0000-0002-3266-0121 Cela Luis Ramudo 3 0000-0001-6929-8392 Ferrari Filipe 1 2 Universidade Federal do Rio Grande do Sul Porto Alegre RS Brasil Universidade Federal do Rio Grande do Sul, Porto Alegre, RS - Brasil Universidade Federal do Rio Grande do Sul Hospital de Clínicas de Porto Alegre Programa em Pós-Graduação em Cardiologia e Ciências Cardiovasculares Porto Alegre RS Brasil Programa em Pós-Graduação em Cardiologia e Ciências Cardiovasculares - Universidade Federal do Rio Grande do Sul - Hospital de Clínicas de Porto Alegre, Porto Alegre, RS - Brasil Universidade da Corunha Corunha Galicia Espanha Universidade da Corunha, Corunha, Galicia - Espanha Correspondência: Ricardo Stein • Universidade Federal do Rio Grande do Sul - Rua Ramiro Barcelos, 2350 - Serviço de Fisiatria/Térreo. CEP 90035-903, Porto Alegre, RS – Brasil. E-mail: kuqui.r@gmail.com

Contribuição dos Autores

Concepção e desenho da pesquisa: Stein R; Obtenção de dados e Redação do manuscrito: Stein R, Beuren T, Cela LR, Ferrari F; Análise e interpretação dos dados e Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Stein R, Beuren T, Ferrari F.

Potencial Conflito de Interesses

Declaro não haver conflito de interesses pertinentes.

 23 10 2020 10 2020 115 4 690 700 04 03 2020 02 04 2020 10 06 2020 This is an open-access article distributed under the terms of the Creative Commons Attribution License Resumo

A farmacogenômica (FGx) investiga a interação entre genes e medicamentos. Através da análise de regiões específicas do DNA, informações sobre o perfil de metabolização do paciente para um determinado fármaco podem ser descritas, assim como o perfil esperado de resposta ao tratamento. Objetivamente, esse tipo de teste pode ter impacto no tratamento de pacientes que não estão respondendo adequadamente a um determinado medicamento, seja pela ausência dos efeitos esperados ou em virtude do aparecimento de efeitos adversos. Neste cenário, o objetivo desta revisão é o de informar o cardiologista clínico sobre esta importante área do conhecimento e atualizá-lo sobre o tema, procurando preencher as lacunas no que diz respeito à relação custo-benefício da aplicação da FGx nas doenças cardiovasculares, além de fornecer informações para a implementação da terapia guiada pela FGx na prática clínica.

 Palavras-chave Doenças Cardiovasculares Genes Hereditariedade Genoma Perfil Genético Farmacogenética Biotransformação Tratamento Farmacológico/eventos adversos Saúde Pública Introdução, DNA e os Genes

A farmacogenômica (FGx) é a ciência que estuda a interação entre genes e medicamentos. A partir da análise de regiões específicas do DNA, é possível obter informações sobre, por exemplo, o perfil de metabolização do paciente para um determinado fármaco, bem como o perfil esperado de resposta ao tratamento. A FGx também visa diminuir a ocorrência de eventos adversos aos medicamentos (EAM).1,2 As inúmeras pesquisas nesta área têm focado na identificação de genes que predispõem às doenças, modulam respostas aos fármacos, e afetam a concentração e a ação desses medicamentos, além de se associarem a reações adversas.3 É frustrante saber que a eficácia de alguns tratamentos medicamentosos varia entre 25% a 80%, sendo que somente um terço dos pacientes expostos ao uso de diferentes tipos de fármacos obtém os benefícios terapêuticos desejados.4

Entre as causas da variação na resposta individual à mesma posologia de um fármaco, pode-se destacar a idade, os fatores genéticos e imunológicos, as enfermidades e a ocorrência de interações entre princípios ativos.5 A variabilidade genética pode alterar tanto a farmacodinâmica, ou seja, a relação entre a dose administrada e os efeitos produzidos, quanto a farmacocinética, que relaciona os eventos de absorção, distribuição, metabolismo e excreção da substância à sua concentração sistêmica.1

A ocorrência de EAM constitui um problema de saúde pública no mundo todo, pois aumenta significativamente o tempo de hospitalização, além de ter sido considerada como a quarta dentre as seis causas mais frequentes de morte nos Estados Unidos nos últimos 20 anos.6,7 Lá, por exemplo, mais de dois milhões de pessoas são hospitalizadas8 e pelo menos 55.000 morrem por ano em decorrência da não resposta ao tratamento ou de EAM.9 No Brasil, os dados ainda são escassos, e a FGx pode ser uma ferramenta de auxílio tanto no tratamento do paciente quanto na otimização dos gastos financeiros. Foi evidenciado que no Hospital de Clínicas de Porto Alegre, Brasil, 14% dos pacientes procuraram a emergência por EAM, e as classes de medicamentos mais envolvidas foram os antirretrovirais, os anticoagulantes, e os anti-hipertensivos. Daqueles que procuraram a emergência uma primeira vez, 20-30% retornaram. Os pesquisadores evidenciaram que o custo médio para tratar um paciente por EAM durante um ano foi de R$ 2200,00, sendo o custo total de 18 milhões de reais.10

Em uma publicação recente, foi realizada uma estimativa nacional de casos de morbimortalidade relacionados ao uso de medicamentos no Sistema Único de Saúde (SUS), utilizando dados do Datasus.11 A estimativa foi de que dos 150 milhões de brasileiros que vão ao médico pelo menos uma vez ao ano, 86% saem com prescrição de algum medicamento. Os danos causados por medicamentos, além de graves do ponto de vista clínico, custam bilhões ao ano para o SUS: a cada real investido no fornecimento de medicamentos, o governo gasta cinco reais para tratar as morbidades relacionadas a eles. As mais onerosas são as causadas por reações adversas (39,3% dos gastos), a não adesão ao tratamento (36,9%) e o uso de doses que não são as habitualmente recomendadas (16,9%). Metade dos casos poderia ser evitado com uma supervisão mais cuidadosa e efetiva dos diferentes tratamentos. Por fim, 60 bilhões por ano foi a estimativa de gastos no sistema de saúde público brasileiro com a morbimortalidade relacionada ao uso de medicamentos (30% do orçamento inicial do SUS).11

A doença cardiovascular (DCV) é a principal causa de morte no mundo, contribuindo significativamente para o crescente ônus econômico na área da saúde. Em 2016, 31% de todas as mortes no mundo (17,9 milhões) foram causadas por DCVs; aproximadamente 555 bilhões de dólares foram gastos nos Estados Unidos, e as previsões informam que esses custos aumentem para US$ 1,1 trilhão no ano 2035.12

Por essas razões, os exames de FGx, os quais são mais difundidos em países como Estados Unidos, Espanha e Canadá, vêm ganhando espaço no Brasil, tendo potencial de modificar para melhor a relação medicamento-médico-paciente. Com o auxílio da FGx, o médico poderá ter mais segurança e assertividade ao prescrever o medicamento adequado e a dose correta, já que possuirá informações importantes sobre o perfil genético do paciente, sem deixar de levar em conta outros fatores importantes relacionados ao indivíduo que está sendo tratado.13 Assim, a DCV está na vanguarda da terapia guiada por FGx, sendo interessante que os cardiologistas estejam atentos para as informações relativas a essa área do conhecimento.

Sabemos que existem várias classes de medicamentos para reduzir o risco de DCV, como também existe uma variação significativa na resposta ao tratamento.14 Além da variação que pode ser atribuída a diversas características sociodemográficas, há determinantes genéticos da droga, assim como respostas que podem afetar a maneira como as drogas são metabolizadas, absorvidas e distribuídas.1,14-16 Portanto, dados genéticos podem ser usados para identificação e avaliação das respostas a doses de drogas, controle de efeitos colaterais e também para previsão de resultados.17-19 Nos últimos anos, devido ao desenvolvimento na clonagem de genes, na genotipagem e no sequenciamento de DNA, a FGx emerge como um componente útil. O conhecimento atual pode ser aplicado em um gene individual, em uma área terapêutica ou em medicamento específico: a) uso de testes FGx para prever a dose individual de medicamento; b) uso de testes FGx para prever a ausência de resposta a um medicamento; e c) uso de testes FGx para prever indivíduos com sério risco de toxicidade se um medicamento for prescrito ou administrado.

Várias diretrizes clínicas nessa área do conhecimento estão disponíveis, sendo as principais delas: o Clinical Pharmacogenetics Implementation Consortium (CPIC),20 o Dutch Pharmacogenetics Working Group (DPWG),21 o Canadian Pharmacogenomics Network for Drug Safety (CPNDS),22 o Groupe de Pharmacologie Clinique Oncologique (GPCO/Unicancer),23 o Réseau National de Pharmacogénétique Hospitalière (RNPGx),24 e o American College of Rheumatology (ACR).25

Um Pouco de História

Umas das primeiras terapias baseadas em uma mutação específica, que mudaram significativamente o prognóstico de doenças, são o trastuzumab no câncer de mama HER-2 positivo e o imatinibe na leucemia mieloide crônica.26,27 Desde então, a oncologia aposta progressivamente na utilização da informação genética, e atualmente esta serve para pautar a decisão terapêutica, tendo incluído o teste genômico em 39% dos ensaios clínicos de oncologia em 2018.28 Além da oncologia, inúmeras outras áreas identificaram ou aprimoraram tratamentos baseados em variações genéticas. Para a fibrose cística já foram identificadas mais de 100 mutações causadoras, o que, apesar de dificultar o desenvolvimento de tratamento específico para cada variante, possibilitou o agrupamento dos seus subtipos que parecem responder a tratamentos semelhantes.29

Os avanços da medicina genômica não se limitam apenas a drogas que agem a nível proteico. Técnicas como o CRISPR (clustered regularly interspaced short palindromic repeats) – uma região especializada do DNA – são usadas para silenciar genes e evitar o desenvolvimento de doenças em embriões e/ou modificar genes relacionados à doença em adultos.30 Essas técnicas são parte do que se conhece como terapia genética e, apesar de estarem em fase embrionária, são esperadas como alternativas potencialmente revolucionárias.

 Metabolização de Medicamentos

As principais diretrizes de FGx usam termos de consenso que visam facilitar a aplicação clínica dos resultados genéticos e harmonizar o relatório entre os diferentes laboratórios.31 Essa classificação é distinta para diferentes tipos de genes, e leva em consideração a combinação de variantes detectadas no mesmo gene e sua “zigosidade”. Um exemplo é a classificação consensual do citocromo P450 2D6 (CYP2D6), uma das principais enzimas do metabolismo de medicamentos, que está envolvida no metabolismo de aproximadamente 25% dos medicamentos comercializados. Os pacientes podem ser classificados em quatro fenótipos em relação ao seu perfil de metabolização dos medicamentos: a) metabolizadores lentos, b) metabolizadores intermediários, c) metabolizador rápidos, e d) metabolizadores ultrarrápidos, detalhados a seguir:

• Metabolizadores Lentos

Os pacientes apresentam uma quebra muito lenta dos medicamentos, tornando os efeitos colaterais mais pronunciados. Os indivíduos deste grupo geralmente são portadores de dois alelos com variantes que provocam redução, ou mesmo inatividade da enzima. Ainda, as doses padrão de certos medicamentos podem não funcionar como esperado. Até 15% da população se encaixa neste subgrupo.32

 • Metabolizadores intermediários

Os metabolizadores intermediários podem de alguma forma afetar a quebra dos medicamentos, causando efeitos semelhantes aos metabolizadores lentos, mas não de forma tão pronunciada.33

 • Metabolizadores rápidos

Estes indivíduos possuem uma taxa do metabolismo tida como “normal”. A medicação provavelmente funcionará conforme o planejado, e essas pessoas utilizarão as doses recomendadas na bula dos remédios.34

 • Metabolizadores ultrarrápidos

Os pacientes desse grupo metabolizam os medicamentos muito rapidamente, pois possuem alelos que produzem enzimas com elevada atividade ou apresentam cópias extras de alelos (ex.: duplicações ou triplicações do gene).35

O gene CYP2D6, especificamente, é responsável pelo metabolismo em cerca de 25% dos medicamentos prescritos,36 e possui alelos que podem causar os quatro tipos de metabolismo descritos anteriormente.37 Estes alelos têm uma prevalência que varia de acordo com a etnia. Por exemplo, um dos principais alelos não funcionais conhecidos, o CYP2D6*4, tem prevalência estimada de 25% em indivíduos caucasianos; já o alelo CYP2D6*10 e CYP2D6*17 (ambos de função reduzida) são mais comuns em africanos e asiáticos, com uma frequência alélica de aproximadamente 40%.38

 Ensaios Clínicos Randomizados

Diversos estudos vêm sendo realizados nos últimos anos para testar o papel da FGx na prática clínica. Em um ensaio clínico randomizado (ECR),39 1.956 pacientes infectados pelo vírus da imunodeficiência humana (HIV) foram divididos em dois grupos. O primeiro foi rastreado prospectivamente quanto à presença do alelo HLA-B*5701 e, aqueles positivos, não receberam o antiviral abacavir. O outro grupo recebeu tratamento padrão com abacavir sem rastreamento prospectivo quanto à presença de HLA-B*5701 (grupo controle). A incidência de hipersensibilidade ao medicamento foi menor no grupo que passou pelo rastreamento genético (3,4%) em comparação ao grupo controle (7,8%). Este resultado levou a Food and Drug Administration (FDA) dos Estados Unidos a incluir a exigência do teste FGx na bula do medicamento.39 Mais recentemente, o estudo de Smith et al.40 evidenciou redução de 30% na intensidade de dor em usuários crônicos de opioide quando a terapia era guiada pela presença da variante no gene CYP2D6.40 Uma meta-análise, incluindo cinco ECRs, encontrou 1,71 mais chance de remissão de sintomas em pacientes recebendo terapia guiada por genotipagem quando comparada à terapia usual.41

Focando na área de DCVs, os estudos mais numerosos são relacionados aos antiagregantes plaquetários e aos anticoagulantes. Após observações retrospectivas de que a presença de variantes genéticas classificadas como perda de função apresentava impacto nos efeitos do clopidogrel, iniciativas surgiram para avaliar o benefício de incluir o teste de forma rotineira. Investigadores da Implementing Genomics in Practice (IGNITE) evidenciaram em um grupo de 1.815 pacientes, maior taxa de eventos cardiovasculares naqueles com variantes de perda de função do gene CYP2C19 e em uso de clopidogrel, comparado com antiplaquetários alternativos, como o prasugrel ou o ticagrelor (hazard ratio [HR] 2,26, intervalo de confiança [IC] 95% 1,18-4,32; p=0,013).42 Outro ECR mostrou diminuição importante nos eventos coronarianos tardios com a implementação da estratégia FGx para uso do clopidogrel.43

Já em relação à varfarina, a maioria dos estudos avaliou variantes genéticas ligadas ao seu metabolismo nos genes CYP2C9 e VKORC1. O European Pharmacogenetics of anticoagulant therapy (EU-PACT) mostrou que, guiando a terapia pelo teste genético, houve aumento significativo no tempo em que os pacientes mantinham-se com um INR (International Normalized Ratio) dentro da faixa terapêutica (2,0-3,0).44 Mais recentemente, o estudo Genetics Informatics Trial of Warfarin to Prevent Deep Vein Thrombosis (GIFT) mostrou diminuição de sangramentos significativos, tromboembolismo venoso e morte no período perioperatório em pacientes com terapia guiada por FGx para cirurgias eletivas de implante de próteses de quadril e de joelho.45 Ambos os estudos citados relacionados à varfarina incluíram uma população majoritariamente branca e, por isso, há a necessidade de se incluir variantes do CYP2C9 mais comuns em populações de ascendência africana para obtenção de resultados mais acurados relacionados a esse grupo populacional. Por sua vez, o maior dos estudos da varfarina, o Clarification of Optimal Anticoagulation Through Genetics (COAG) mostrou-se diferente dos demais e relatou não haver diferença em se iniciar terapia com varfarina guiada por informação clínica ou guiada pela pesquisa de variantes do gene CYP2C9, as quais são muito mais comuns em população de ascendência europeia, em uma coorte composta apenas por 27% de afro-americanos.46 Por outro lado, e considerando o custo-benefício relacionado ao uso da varfarina e do clopidogrel, uma revisão sistemática recente que incluiu 31 ECRs mostrou que, comparado à terapia padrão, o teste FGx foi superior em 81% das vezes.13

Paralelamente aos estudos de medicamentos isolados, o conceito de teste preventivo vem crescendo e apresentando algumas evidências de benefício. Em 2012, Schildcrout et al.47 mostraram, em uma coorte de 52.942 pacientes em cuidado domiciliar, uma exposição de 64,8% a pelo menos um medicamento de mecanismo influenciado por variantes genéticas. Os autores estimaram em 398 o número de eventos adversos potenciais que poderiam ter sido evitados com a genotipagem preventiva. Já o estudo do genótipo de 44.000 participantes do biobanco da Estônia mostrou que 99,8% desses indivíduos tinham genótipo associado a um risco aumentado a pelo menos uma medicação.48 Com resultados concordantes, o protocolo RIGHT (‘Right Drug, Right Dose, Right Tim eUsing Genomic Data to Individualize Treatment’) criado pela clínica Mayo/iniciativa eMERGE, sequenciou painel incluindo os genes SLCO1B1 (membro da família do transportador de ânions orgânicos transportadores de soluto 1B1), CYP2C19, CYP2C9, VKORC1 e CYP2D6. Eles identificaram em 99% dos 1.013 indivíduos pelo menos uma variante de risco para uso de algum medicamento.49

Nos Estados Unidos, medicamentos com recomendações relacionadas à FGx perfazem 18% de todas as prescrições50 e 30% dos medicamentos com alto risco FGx mais prescritos representam 738 milhões de prescrições por ano.51 Tais informações vão à direção de que parece existir um impacto positivo do teste FGx preventivo, não apenas pelo aumento da eficácia terapêutica e custo-benefício, mas também pelo seu potencial de evitar EAMs. Além dos dados já mencionados, um estudo holandês também mostrou benefício pela redução de 73% para 28% no risco de na taxa de intoxicação por fluoropirimidinas em pacientes com dose guiada por genotipagem, além da redução das mortes induzidas pelo medicamento de 10% para 0%.52

 Importância da Farmacogenômica

Nos últimos anos a FGx surgiu como uma área de grande interesse e entusiasmo, pois lida fundamentalmente com a chamada “medicina personalizada”, levando em consideração a influência da variação genômica dos pacientes sobre suas respostas às medicações.53

Diferentes são os benefícios que podem ser alcançados com o advento da FGx, a citar:

Aumento no poder da terapia e redução na probabilidade de intoxicação;

Tratamentos iniciados no momento mais apropriado.

Além disso, a FGx pode contribuir para redução geral no custo dos cuidados de saúde, conforme apresentado na Figura 1. É importante mencionar que quase 200 mil mortes/ano na Europa são relacionadas aos EAM, com um custo de aproximadamente 80 bilhões de euros.54

Vantagens da Farmacogenômica e Possível Redução nos Custos à Saúde. *Através da possibilidade de uma detecção mais precoce.

Estima-se que uma boa parcela dos pacientes não apresenta respostas consideradas satisfatórias aos medicamentos.55,56 Nesse sentido, a FDA recomenda, por exemplo, que testes FGx sejam realizados antes da quimioterapia com a droga mercaptopurina – utilizada comumente para pacientes com alguns tipos de leucemia aguda.57 Tal recomendação baseia-se no fato de que, como esta droga pode causar efeitos colaterais graves e aumentar o risco de infecção a depender da variante genética do indivíduo, a terapia pode não surtir o efeito desejado.

O Genomics and Targeted Therapy Group, um braço do departamento de Farmacologia Clínica da FDA, tem como objetivo garantir a aplicação apropriada das estratégias FGx por meio das suas funções de revisão regulatória, pesquisa, desenvolvimento de diretrizes e educação profissional. Parte desse trabalho incluiu a criação de uma tabela agrupando as orientações farmacológicas das 161 drogas, que até o momento contém informações genômicas em seus rótulos. Sua última atualização traz números expressivos de biomarcadores associados a drogas em diversas áreas da medicina, inúmeras delas amplamente utilizadas na prática clínica58 (Tabela 1).

Relação do número de biomarcadores genômicos descritos no rótulo de medicações em diversas especialidades médicas com base na tabela fornecida pelo <italic>Food and Drug Administration</italic>
Área Biomarcadores
Oncologia 167
Infectologia 35
Psiquiatria 34
Neurologia 29
Hematologia 25
Anestesiologia 23
Cardiologia 22
Gastroenterologia 17
Reumatologia 11
Pneumologia 10
Endocrinologia 7
Erros inatos do metabolismo 7
Urologia 5
Dermatologia 4
Toxicologia 2
Transplante 1

Por fim, espera-se que, em breve, a FGx seja mais acessível e que a sua utilização consciente possa contribuir para que os médicos prescrevam as medicações com maior “acurácia” e os pacientes possam recebê-las com maior chance de sucesso terapêutico aliado ao menor risco de EAM.

 Associação entre Variantes Genéticas e Respostas aos Medicamentos na Doença Cardiovascular

É de amplo conhecimento que fatores como idade, comorbidades, peso, bem como aqueles demográficos, podem contribuir para diferenças significativas nas respostas a uma mesma terapia farmacológica, bem como ao desenvolvimento de EAM.59,60 Nesse contexto, a variação genética pode representar um pilar fundamental para esse desfecho. Acredita-se que muitas mortes ao redor do mundo poderiam ter sido evitadas se o médico tivesse conhecimento prévio do perfil FGx dos pacientes, e pudesse empregar a medicação em doses corretas para aquele indivíduo.61 Pacientes com um mesmo diagnóstico (por exemplo, infarto agudo do miocárdio) são normalmente tratados da mesma maneira, embora suas respostas à terapia medicamentosa possam ser distintas. A “terapia sob medida” pode reduzir os EAMs e aumentar as taxas de eficácia, conforme ilustrado na Figura 2. Por exemplo, há uma enorme variação na dose diária necessária de um dos anticoagulantes mais utilizados na prática clínica, a varfarina, podendo variar em até 20 vezes.62 Por sua vez, o propranolol (betabloqueador) pode ter a sua dose variando em até 40 vezes a depender de qual paciente esteja recebendo a droga.60 Alguns fármacos utilizados em larga escala na prática clínica do cardiologista, os quais podem ter importantes associações genéticas, são apresentados na Tabela 2.

Potenciais Aplicações Clínicas da Farmacogenômica. Adaptado de Johnson, 2003.<xref ref-type="bibr" rid="B99"><sup>99</sup></xref> Associação entre genes e medicamentos
Genes Medicamentos Classe Variante gênica associada Efeito associado ao alelo
CYP2C9, VKORC1 Varfarina Antagonista da vitamina K CYP2C9*2 (p.Arg144Cys; rs1799853) Depuração reduzida de medicamentos; necessidade de dose reduzida
CYP2C9*3 (p.Ile359Leu; rs1057910) Depuração reduzida de medicamentos; necessidade de dose reduzida
VKORC1 (-1639G>A; rs9923231) ↑ Sensibilidade a medicamentos; necessidade de dose reduzida
CYP2C19 Clopidogrel Inibidor do receptor P2Y12 CYP2C19*2 (c.681G>A; rs4244285) ↑ Risco de eventos cardiovasculares; perda de função; menor efeito antiplaquetário.
CYP2C19*17 (c.-806C>T; rs12248560) ↑ Sensibilidade à medicação; ganho de função; ↑ Risco de sangramento
SLCO1B1 Sinvastatina Inibidor da HMG-CoA redutase SLCO1B1*5 (p.Val174Ala; rs4149056) ↑ Risco de desenvolvimento miopatia ou rabdomiólise
ADRB1 Atenolol, metoprolol Betabloqueador ADRB1 (p.Ser49Gly; rs1801252) Melhor controle da PA; ↑ FEVE
ADRB1 (p.Arg389Gly; rs1801253)
CES1 Dabigatrana Anticoagulante de ação direta CES1 (G143E, rs71647871) ↓ Metabolismo do medicamento e seus metabólitos
ITGB3 Aspirina Antiagregante plaquetário ITGB3 (PlA1/A2 [T1565→C], rs5918) ↓ Efeito antiplaquetário

PA: Pressão arterial; FEVE: Fração de ejeção do ventrículo esquerdo; CYP2C9: Citocromo P450 2C9; VKORC1: Subunidade 1 do complexo Epóxido Redutase da Vitamina K; CYP2C19: P450 2C19; SLCO1B1: Membro da família do transportador de ânion orgânico transportador de soluto 1B1; CYP4F2: Citocromo P450, família 1, subfamília A, polipeptídeo 2; ADRB1: Adrenoceptor Beta 1; CYP11B2: Citocromo P450, família 11, subfamília B, polipeptídeo 2; FUT4: Fucosiltransferase 4; CES1: Carboxilesterase 1;ITGB3: Integrina beta-3.

 Varfarina

A varfarina é um fármaco pertencente à classe dos antagonistas da vitamina K, e vem sendo utilizada em grande escala na prevenção de eventos trombóticos.63 Evidências sugerem que a resposta do indivíduo à varfarina, bem como a outros antagonistas da vitamina K, pode ser influenciada de forma importante por variações genéticas na enzima hepática do citocromo P450 (CYP2C9) e na Subunidade 1 do complexo Epóxido Redutase da Vitamina K (VKORC1), alvo para estes fármacos,64,65 além de polimorfismos no membro 2 da subfamília F e família 4 do citocromo P450 4 (CYP4F2).66 Foi demonstrado que variações nos alelos CYP2C9*2 e CYP2C9*3 diminuíram a atividade enzimática da CYP2C9 e inibiram o metabolismo anticoagulante,67 enquanto o polimorfismo VKORC1- 1639G>A parece ter influência na resposta farmacodinâmica aos antagonistas da vitamina K.68 Devido a essas observações, a FDA apontou a necessidade de informações FGx na bula da varfarina.

Na prática, os portadores heterozigotos dos alelos de função reduzida CYP2C9*2 ou CYP2C9*3 podem necessitar de uma dose reduzida de varfarina em cerca de 30% e 47%, respectivamente, enquanto os portadores homozigotos CYP2C9*3 podem necessitar reduções ainda maiores (~80%).69-71 Por sua vez, a variante -1639 G>A do gene VKORC1 parece reduzir a expressão de proteínas, o que teoricamente representa uma dose menor de manutenção de varfarina em comparação com os não portadores desta variante.72 Da mesma forma, combinações de algumas variantes associadas a um metabolismo extremo tornam mais difícil a obtenção de um INR terapêutico de maneira sistemática nesses pacientes.73 Nesse cenário, as diretrizes do CPIC recomendam considerar um anticoagulante oral de ação direta (por exemplo, edoxabana).74

 Clopidogrel

Nos Estados Unidos, estima-se que mais de três milhões de indivíduos recebam anualmente prescrição de clopidogrel após a colocação de um stent.75 Ele é um fármaco tienopiridínico do grupo dos antiagregantes plaquetários.76 A resposta do indivíduo frente ao clopidogrel pode sofrer alteração, determinada pelo polimorfismo do CYP2C19.77

A variante de perda de função do CYP2C19*2 foi associada a um risco aumentado de eventos cardiovasculares adversos, incluindo trombose de stent durante o tratamento com clopidogrel.78 Mais especificamente, o alelo CYP2C19*2 (rs4244285) causa perda de função e foi associado à redução na atividade antiagregante do medicamento.79 Além disso, portadores do alelo CYP2C19 *3 (rs4986893) também têm respostas reduzidas ao clopidogrel e uma taxa mais alta de eventos cardiovasculares adversos recorrentes em comparação com não portadores.80,81 É importante mencionar que as frequências dos alelos CYP2C19 *2 e CYP2C19 *3 são mais altas nas populações asiáticas, sugerindo que estes indivíduos têm maior probabilidade de serem resistentes à terapia com esta droga.82 Em contraste, o alelo CYP2C19*17 (rs3758581) promove ganho de função e tem sido associado ao aumento da atividade enzimática e à melhor inibição das plaquetas. Os portadores da variante CYP2C19*17 foram denominados metabolizadores ultrarrápidos.83

A raça parece ser outro fator com papel importante nesse cenário. Cresci et al.84 compararam o efeito do polimorfismo do CYP2C19 sobre eventos CVs adversos entre pacientes com infarto agudo do miocárdio em caucasianos e afro-americanos tratados com clopidogrel. Foi observado que o alelo CYP2C19*2 teve associação significativa com aumento da taxa de mortalidade em um ano e a uma tendência no aumento na incidência de infarto do miocárdio recorrente em caucasianos. Já o alelo CYP2C19*17 foi associado a um aumento na mortalidade em um ano e a um risco aumentado de sangramento em afro-americanos. É importante mencionar que pacientes submetidos à intervenção coronária percutânea que possuem pelo menos um alelo CYP2C19*2 podem apresentar maior risco de trombose de stent. Em um ECR,85 aproximadamente 2.500 pacientes foram pré-tratados uniformemente com 600 mg de clopidogrel. Os portadores do alelo CYP2C19*2 apresentaram um aumento significativamente maior na incidência de trombose de stent em 30 dias, quando comparados com os portadores do alelo CYP2C19 de tipo selvagem.85 Nessa mesma linha, a meta-análise conduzida por Mega et al.,86 que arrolou estudos com pacientes mais complexos e em tratamento agressivo, encontrou um risco aumentado de trombose de stent quando o alelo *2 foi identificado pela FGx.

Apesar dessas evidências, uma revisão sistemática com meta-análise abrangendo 15 estudos não corroboraram com tais achados, não indicando uma influência clara dos polimorfismos do gene CYP2C19 na eficácia clínica do clopidogrel,87 sugerindo que o uso de regimes antiplaquetários individualizados guiados pelo genótipo CYP2C19 não devam ser realizados.

Na atualidade, o American College of Cardiology em conjunto com a American Heart Association também não recomenda testes de FGx de rotina para o CYP2C19.88 No entanto, outra meta-análise mais recente demonstrou que os pacientes que se beneficiam do estudo FGx são aqueles com doença arterial coronária que são submetidos a procedimentos de revascularização miocárdica percutânea.89 Nesse contexto, o CPIC recomenda formalmente que pacientes com síndrome coronária aguda, ou ainda, aqueles submetidos à intervenção coronária percutânea, sejam submetidos ao teste FGx. O CPIC enfatiza que aqueles que possuem uma ou duas cópias do alelo com perda de função devem receber agentes antiplaquetários alternativos (como prasugrel ou ticagrelor), a fim de reduzir o risco de eventos cardiovasculares adversos.90 Por outro lado, outras populações de pacientes (por exemplo, fibrilação atrial), nas quais o uso do clopidogrel é mais discutível, o painel FGx não está indicado.

Claassens et al.91 realizaram um ECR recente para avaliar os resultados da terapia antiplaquetária guiada pelo genótipo CYP2C19 em pacientes com infarto agudo do miocárdio com supradesnível do segmento ST. Os pacientes foram alocados para receberem tratamento guiado por genótipo – pacientes sem variantes de perda da função CYP2C19 receberam clopidogrel e pacientes com variantes receberem terapia padrão (prasugrel ou ticagrelor). Não foi observada nenhuma diferença entre os grupos quanto à incidência de eventos trombóticos. Dessa forma, uma estratégia guiada por FGx foi não inferior à abordagem descrita como padrão (prasugrel ou ticagrelor), a qual é muito mais cara e que apresentou maior incidência de sangramento.91

Recentemente, os resultados do ECR TAILOR PCI foram apresentados. Este estudo avaliou uma estratégia guiada por genótipo (n = 2.652) versus terapia padrão (n = 2.650) em pacientes com doença arterial coronariana estável ou instável submetidos à intervenção coronária percutânea com objetivo de orientar a terapia antiplaquetária. No grupo randomizado para estratégia guiada por genótipo, os pacientes submetidos à genotipagem receberam ticagrelor 90 mg duas vezes ao dia (portadores de um alelo CYP2C19 *2 ou *3) ou clopidogrel 75 mg diariamente. No grupo denominado terapia padrão, os sujeitos receberam 75 mg de clopidogrel diariamente e passaram por genotipagem somente após 12 meses. O desfecho primário era composto por morte cardiovascular, infarto do miocárdio, acidente vascular cerebral, trombose de stent ou isquemia recorrente em 12 meses. O desfecho primário e a incidência de sangramento não foram diferentes entre os grupos de tratamento. Entretanto, cabe ressaltar a redução de 34% nesses eventos em um ano, bem como uma redução significativa de 40% no número total de eventos por paciente no braço guiado por FGx. Por fim, uma análise post hoc encontrou uma redução de aproximadamente 80% na taxa de eventos adversos nos primeiros três meses de tratamento nos pacientes randomizados para terapia guiada por genótipo.92,93

 Betabloqueadores

Essa classe de drogas é amplamente utilizada para o tratamento de arritmias cardíacas, angina, infarto do miocárdio e hipertensão.94 Os genes associados à resposta inter individual do betabloqueador incluem o CYP2D6, o adrenoceptor beta 1 (ADBR1), o adrenoceptor beta 2 (ADBR2) e o receptor quinase 5 acoplado à proteína G (GRK5).95 Por exemplo, alguns betabloqueadores, incluindo propranolol e o metoprolol, são metabolizados pelo CYP2D6, e a perda de função desta variante é muito comum.34 Por sua vez, evidências sugeriram que pacientes hipertensos portadores do alelo Arg389 tipo selvagem homozigoto obtiveram três vezes maior redução da pressão arterial diastólica diurna com o uso do metoprolol quando comparados aos portadores do alelo Gly389.96 Embora com resultados ainda não tão consistentes, pacientes que são homozigotos do haplótipo Arg389 do ADBR1 parecem apresentar uma resposta mais satisfatória a toda a família dos betabloqueadores, apresentando melhor fração de ejeção do ventrículo esquerdo quando comparados aos portadores do alelo Gly389.97

Em relação à cor da pele, a frequência mais alta do alelo Gly389 em afroamericanos em comparação com os brancos pode ser uma explicação plausível para sua resposta reduzida aos betabloqueadores. Embora etnia e polimorfismos da ADRB1 tenham sido relatados como preditores independentes de resposta ao betabloqueador,98 outros estudos prospectivos elucidando os papéis dessas variantes genéticas na respostas étnico-específicas são justificados.

Assim, no cenário da insuficiência cardíaca, ainda não há recomendações para o uso de informações FGx que visem orientar o uso de betabloqueadores.

 Estatinas

As estatinas são uma classe de fármacos que têm como alvo a inibição da 3- hidroxi-3-methyl-glutaril-CoA redutase (HMG-CoA redutase). Elas visam reduzir os níveis sanguíneos de colesterol, especialmente o LDL.99 Em conjunto com mudanças no estilo de vida, as estatinas são consideradas como terapia de primeira linha para prevenção primária e, especialmente secundária, de DCVs. Esses fármacos, por outro lado, apresentam uma ampla variabilidade interindividual na extensão da redução do LDL, explicada, em parte, por fatores ambientais e genômicos.100 Dessa forma, para que haja uma resposta mais eficaz, pode ser necessário um ajuste de dosagem para cada indivíduo.

Recentemente, Licito et al.101 avaliaram o perfil FGx relativo à dor neuromuscular em 76 pacientes portadores de diabetes tipo 2 e DCV prévia que estivessem em uso de fármacos antidiabéticos e anticolesterolêmicos, como a estatina. Foram estudadas diferentes variantes, tais como: SLCO1B1, ABCB1, ABCC8 e biotransformadores de drogas da família citocromo P450 (CYP), incluindo CYP2C9*2, CYP2C9*3, CYP2C8*3 e CYP3A4*22. Dos 35 pacientes tratados com estatinas, aproximadamente 17% apresentaram dor neuromuscular. A análise FGx mostrou ausência de correlação entre polimorfismos de genes candidatos e toxicidade, exceto para o alelo SLCO1B1 T521C. Assim, quando disponível, sugere-se a análise da variante SLCO1B1 T521C, permitindo que os médicos otimizem o tratamento prescrito, visando minimizar a dor neuromuscular e maximizar os benefícios da estatina.

Ainda, a variante mais significativamente associada ao gene SLCO1B1, c.521T>C, leva à diminuição da função de transporte do SLCO1B1, a qual pode reduzir a depuração das estatinas e aumentar chance de toxicidade do músculo esquelético. Uma meta-análise de nove estudos de caso-controle, englobando quase 4.500 pacientes, mostrou que indivíduos com o alelo variante C eram significativamente mais propensos a sofrer miopatia relacionada à estatina (CT + CC versus TT: odds ratio = 2,09; IC95% = 1,27-3,43).102

 Possíveis Barreiras à Implementação da Farmacogenômica

Graças ao avanço da tecnologia e das técnicas de sequenciamento, o custo da avaliação FGx diminuiu significativamente nos últimos anos (Lei de Moore), facilitando seu uso na prática clínica; porém, o custo relativamente elevado ainda representa uma barreira para a implementação mais ampla dessa ferramenta. Além disso, uma possível falta de familiaridade dos profissionais da saúde, a ausência de uma plataforma padronizando a investigação e o pensamento acadêmico e, de uma forma geral, o fato de que o volume de estudos que demonstram os benefícios da FGx ainda é insuficiente, são fatores que contribuem para uma baixa aceitação por parte da comunidade científica da inclusão de testes FGx na prática clínica.

No entanto, esforços para contornar esses obstáculos ocorrem atualmente de forma global e contam com estudos de grandes proporções,103 tais como, o UK’s 100.000 Genomes Project104 e o PREemptive Pharmacogenomic testing for prevention of Adverse drug REactions (PREPARE),105 o qual conta com a participação de sete países na Europa. No outro lado do Atlântico Norte, nos Estados Unidos, o Electronic Medical Records and Genomics (eMERGE),106 o Network and the Implementation of Genomics in Practice (IGNITE),107 e o Clinical Sequencing Evidence Generating Research Consortium,108 são parte de uma série de projetos custeados pelo National Human Genome Research Institute, sendo estimado um investimento na pesquisa genética de pelo menos US$ 775 milhões no período de 2007-2022. Na Ásia, o programa South East Asian Pharmacogenomics Research Network (SEAPharm) inclui cinco países para conduzir estudos de FGx.109 De forma geral, estes estudos visam definir, gerar e analisar evidências sobre a utilidade clínica do sequenciamento genômico para guiar terapia, custo-eficácia e o valor de sua implementação de forma vasta na prática médica. Dos resultados já obtidos, uma revisão que incluiu 44 avaliações de custo-benefício, mostrou que 30% delas mostrou custo-efetividade e 27% evidenciou até redução de custos,110 o que contribui para uma perspectiva otimista para o futuro da FGx.

Entre inúmeras contribuições das iniciativas globais para a expansão da FGx na prática clínica, vale destacar um de seus aspectos cruciais: a educação e o treinamento dos profissionais de saúde e a promoção e estímulo ao investimento em tecnologia nos centros de pesquisa e assistência. Além da contribuição com a literatura, os projetos promovem o treinamento de pessoas para a prática adequada da medicina genômica, a qual exige a adoção de atitudes básicas que talvez sejam menos relevantes em outras especialidades. Exemplos são a inclusão da família do paciente no aconselhamento e no plano de tratamento, além da confidencialidade que assegura o uso de informações genéticas com propósitos exclusivamente assistenciais (evitando seu uso inapropriado para imposição da lei, seguros, marketing ou relação empregatícia). A educação e treinamento têm papel central para a aceitação da medicina genômica na prática clínica, e a aceitação por sua vez é ponto chave para sua implementação. O esforço para geração de dados contribui significativamente, mas a disposição e engajamento dos profissionais da área da saúde que almejam a excelência da assistência médica são indispensáveis. A dimensão e o progresso dos esforços e investimentos que ocorrem globalmente deixam clara a relevância e o potencial atribuídos à medicina genômica, que já pode ser considerada parte da prática médica de alta qualidade e um dos pilares da medicina de precisão.

 Considerações Finais

Áreas de consenso: o teste FGx pode ser útil para o uso otimizado de diversos medicamentos, permitindo uma maior segurança farmacológica;

Áreas de controvérsia: se os testes FGx devem ser aplicados mais amplamente, inclusive na prescrição de certos medicamentos em que o benefício geral é menos claro, permanece controverso;

Área de crescimento: cada vez mais, as informações pessoais sobre genótipos são disponibilizadas diretamente ao consumidor. Isso provavelmente aumentará a demanda por prescrição personalizada, significando que os prescritores precisam levar em consideração as informações FGx. Como exemplo, podemos citar o Projeto 100.000 genomas. Este impressionante projeto fornecerá sequências genômicas completas que podem fazer parte de um prontuário médico do paciente. Esta informação parece ser de grande valor na prescrição personalizada;

Áreas oportunas para o desenvolvimento de pesquisas: desenvolvimento de novos medicamentos visando fatores de risco genéticos específicos para doenças. Estes podem ser prescritos para aqueles com genótipo de risco. É provável que as informações FGx estejam disponíveis rotineiramente no futuro, especialmente em ambientes tecnologicamente avançados. Isso poderia influenciar a prescrição de uma variedade de medicamentos além daqueles para os quais, atualmente, são necessários testes antes da prescrição.

Fontes de Financiamento

O presente estudo não teve fontes de financiamento externas.

Vinculação Acadêmica

Este artigo é parte de tese de Doutorado de Filipe Ferrari e Thaís Beuren pela Universidade Federal do Rio Grande do Sul.

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Liu WN Fu KL Gao HY Shang YY Wang ZH Jiang GH β1 adrenergic receptor polymorphisms and heart failure: a meta-analysis on susceptibility, response to β-blocker therapy and prognosis PLoS One 2012 7 7 e37659 97. Liu WN, Fu KL, Gao HY, Shang YY, Wang ZH, Jiang GH, et al. β1 adrenergic receptor polymorphisms and heart failure: a meta-analysis on susceptibility, response to β-blocker therapy and prognosis. PLoS One. 2012;7(7):e37659. Kurnik D Li C Sofowora GG Friedman EA Muszkat M Xie HG Beta-1-adrenoceptor genetic variants and ethnicity independently affect response to beta-blockade Pharmacogenet Genom 2008 18 10 895 902 98. Kurnik D, Li C, Sofowora GG, Friedman EA, Muszkat M, Xie HG, et al. Beta-1-adrenoceptor genetic variants and ethnicity independently affect response to beta-blockade. Pharmacogenet Genom. 2008;18(10):895–902. Davies JT Delfino SF Feinberg CE Johnson MF Nappi VL Olinger JT Current and Emerging Uses of Statins in Clinical Therapeutics: A Review Lipid Insights 2016 9 4 13 29 99. Davies JT, Delfino SF, Feinberg CE, Johnson MF, Nappi VL, Olinger JT, et al. Current and Emerging Uses of Statins in Clinical Therapeutics: A Review. Lipid Insights. 2016;9(4):13-29. Kitzmiller JP Mikulik EB Dauki AM Murkherjee C Luzum JA Pharmacogenomics of statins: understanding susceptibility to adverse effects Pharmgenomics Pers Med 2016 9 97 106 100. Kitzmiller JP, Mikulik EB, Dauki AM, Murkherjee C, Luzum JA. Pharmacogenomics of statins: understanding susceptibility to adverse effects. Pharmgenomics Pers Med. 2016;9:97-106. Licito A Marotta G Battaglia M Benincasa G Mentone L Grillo MR Assessment of pharmacogenomic SLCO1B1 assay for prediction of neuromuscular pain in type 2 diabetes mellitus and cardiovascular patients: preliminary results Eur Rev Med Pharmacol Sci 2020 24 1 469 477 101. Licito A, Marotta G, Battaglia M, Benincasa G, Mentone L, Grillo MR, et al. Assessment of pharmacogenomic SLCO1B1 assay for prediction of neuromuscular pain in type 2 diabetes mellitus and cardiovascular patients: preliminary results. Eur Rev Med Pharmacol Sci. 2020;24(1):469-77. Hou Q Li S Li L Li Y Sun X Tian H Association Between SLCO1B1 Gene T521C Polymorphism and Statin-Related Myopathy Risk: A Meta-Analysis of Case-Control Studies Medicine (Baltimore) 2015 94 37 e1268 102. Hou Q, Li S, Li L, Li Y, Sun X, Tian H. Association Between SLCO1B1 Gene T521C Polymorphism and Statin-Related Myopathy Risk: A Meta-Analysis of Case-Control Studies. Medicine (Baltimore). 2015;94(37):e1268. Translating pharmacogenomics into clinical decisions: do not let the perfect be the enemy of the good Kristi Krebs Lili Milani Human Genomics 2019 103. Translating pharmacogenomics into clinical decisions: do not let the perfect be the enemy of the good Kristi Krebs. Lili Milani: Human Genomics; 2019. Turnbull C Scott RH Thomas E Jones L Murugaesu N Pretty FB The 100000 Genomes Project: bringing whole genome sequencing to the NHS BMJ 2018 361 k1687 k1687 104. Turnbull C, Scott RH, Thomas E, Jones L, Murugaesu N, Pretty FB, et al. The 100000 Genomes Project: bringing whole genome sequencing to the NHS. BMJ. 2018;361:k1687. van der Wouden CH Cambon-Thomsen A Cecchin E Cheung KC Dávila-Fajardo CL Deneer VH Implementing Pharmacogenomics in Europe: Design and Implementation Strategy of the Ubiquitous Pharmacogenomics Consortium Clin Pharmacol Ther 2017 101 3 341 358 105. van der Wouden CH, Cambon-Thomsen A, Cecchin E, Cheung KC, Dávila-Fajardo CL, Deneer VH, et al. Implementing Pharmacogenomics in Europe: Design and Implementation Strategy of the Ubiquitous Pharmacogenomics Consortium. Clin Pharmacol Ther. 2017;101(3):341-58. Fullerton SM Wolf WA Brothers KB Return of individual research results from genome-wide association studies: experience of the Electronic Medical Records and Genomics (eMERGE) Network Genet Med 2012 14 4 424 431 106. Fullerton SM, Wolf WA, Brothers KB, et al. Return of individual research results from genome-wide association studies: experience of the Electronic Medical Records and Genomics (eMERGE) Network. Genet Med. 2012;14(4):424–31. Owusu Obeng A Fei K Levy KD Elsey AR Pollin TI Ramirez AH Physician-reported benefits and barriers to clinical implementation of genomic medicine: a multi-site IGNITE-network survey J Pers Med 2018 8 3 E24 107. Owusu Obeng A, Fei K, Levy KD, Elsey AR, Pollin TI, Ramirez AH, et al. Physician-reported benefits and barriers to clinical implementation of genomic medicine: a multi-site IGNITE-network survey. J Pers Med 2018;8(3):E24. Clinical Sequencing Evidence-Generating Research (CSER) 2020 Cited in 2020 Feb 15 Available from: https://www.genome.gov/Funded-Programs-Projects/Clinical-Sequencing-Evidence-Generating-Research-CSER2 108. Clinical Sequencing Evidence-Generating Research (CSER). 2020. [Cited in 2020 Feb 15] Available from: < https://www.genome.gov/Funded-Programs-Projects/Clinical-Sequencing-Evidence-Generating-Research-CSER2>. South East Asian Pharmacogenomics Research Networ (SEAPHARM) Cited in 2020 Jan 20 Available from: https://www.ims.riken.jp/english/projects/pj09.php 109. South East Asian Pharmacogenomics Research Networ (SEAPHARM). [Online]. [Cited in 2020 Jan 20] Available from: <https://www.ims.riken.jp/english/projects/pj09.php>. Verbelen M Weale ME Lewis CM Cost-effectiveness of pharmacogenetic guided treatment: are we there yet? Pharmacogenomics J 2017 17 5 395 402 110. Verbelen M, Weale ME, Lewis CM. Cost-effectiveness of pharmacogenetic guided treatment: are we there yet? Pharmacogenomics J. 2017;17(5):395–402. Review Article Pharmacogenomics and Cardiovascular Disease: Where are We and Where do We go from Here? 0000-0003-2357-5176 Stein Ricardo 1 2 Beuren Thaís 1 2 0000-0002-3266-0121 Cela Luis Ramudo 3 0000-0001-6929-8392 Ferrari Filipe 1 2 Porto Alegre RS Brazil Universidade Federal do Rio Grande do Sul, Porto Alegre, RS - Brazil Porto Alegre RS Brazil Graduate Program in Cardiology and Cardiovascular Sciences - Universidade Federal do Rio Grande do Sul - Hospital de Clínicas de Porto Alegre, Porto Alegre, RS - Brazil La Coruña Galícia Spain Universidad de Coruña, La Coruña, Galícia - Spain Mailing Address: Ricardo Stein • Universidade Federal do Rio Grande do Sul - Rua Ramiro Barcelos, 2350 - Serviço de Fisiatria/Térreo. Postal Code 90035-903, Porto Alegre, RS – Brazil. E-mail: kuqui.r@gmail.com

Author Contributions

Conception and design of the research: Stein R; Acquisition of data and Writing of the manuscript: Stein R, Beuren T, Cela LR, Ferrari F; Analysis and interpretation of the data and Critical revision of the manuscript for intellectual content: Stein R, Beuren T, Ferrari F.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

 Keywords: Cardiovascular Diseases Genes Heredity Genome Genetic Profile Pharmacogenetics Biotransformation Drug Therapy/adverse effects Public Health Introduction, the DNA and the Genes

Pharmacogenomics (PGx) is the science of understanding the interaction between genes and drugs. The analysis of specific areas of the DNA provides information about a certain drug metabolism and about the expected response to a certain treatment. PGx also aims to reduce the incidence of adverse drug events (ADEs).1,2 Many studies in this area have focused on the identification of genes that predispose to diseases, modulate drug response, affect drug concentration and correlate with adverse effects of patients exposed to different types of drugs, so the desired therapeutic benefit is achieved.4

The causes of individual responses to a same drug dosage include age, genetic and immunological factors, comorbidities and interaction between active principles.5 Genetic variability may influence not only pharmacodynamics, but also pharmacokinetics, which studies the relationship of the absorption, metabolism and excretion of the drug to its systemic concentration.1

ADEs are a public health problem in the world, as they significantly increase the length of hospital stay, and are considered the fourth of the six main causes of death in the United States in the last 20 years.6,7 Also, in the United States, more than two million people are hospitalized8 and at least 55,000 people die each year from abscence of treatment response or from ADE per se. In Brazil, data is still scarce and PGx could be a useful tool in the treatment of patients and optimization of financial expenses.10 The most common drug classes were antiretrovirals, anticoagulants and antihypertensives. In this study,10 the mean cost to treat a patient for ADE was BRL2,200, with a total cost of 18 million Brazilian reals.

In a recent publication, a national estimate of drug-related morbidity and mortality was conducted by the Brazilian Unified Health System (SUS) using data from the Datasus database.11 The estimate showed that of 150 million Brazilians that go to the doctor at least once a year, 86% leave the doctor with a drug prescription. The adverse events caused by the drugs are severe, not only from a clinical point of view, but also from an economical perspective – for every Brazilian real spent on drug provision, five Brazilian reals are spent on the treatment of drug-related comorbidities. The most expensive events are those caused by adverse reactions (39.3% of the expenses), non-adherence to treatment (36.9% of the expenses) and unusual dose regimens (16.9% of the expenses). Half of the cases could be prevented by a more careful and effective supervision of different therapies. Finally, it was estimated that 60 billion Brazilian reals were spent annually on drug-related morbidity and mortality by the SUS, corresponding to 30% of its initial budget.11

Cardiovascular disease (CVD) is the main cause of death in the world, significantly contributing to the increasing economic burden of health costs. In 2016, 31% of all deaths in the world (17.9 million) were caused by CVDs. These diseases cost the United States approximately $555 billion in that year, and estimates say that this cost will reach $1.1 trillion in 2035.12

For this reason, the use of PGx tests, which is more widespread in countries like the United States, Spain and Canada, has gained importance in Brazil, with the potential to improve the drug-physician-patient relationship. With the aid of PGx, the physician could prescribe, in a safer and more assertive way, the most appropriate drug at the correct dose, since, in addition to other important factors, information about patient’s genetic profile would be now available.13 Thus, CVDs are at the forefront of PGx-guided therapy, and cardiologists should be alert to this area of knowledge.

Several classes of drugs are known to reduce the risk of CVDs, but it is also known that there is a significant individual variation in treatment response.14 In addition to variations attributable to sociodemographic characteristics, there are genetic determinants of drug and responses that may affect how the drugs are metabolized, absorbed and distributed.1,14-16 Therefore, genetic data can be used in the identification and evaluation of drug response, control of side effects, and prediction of results.17-19 With recent advances in gene cloning, genotyping and DNA sequencing, PGx has emerged as a useful component. Current knowledge may be applied at an individual gene level, to a therapeutic area or to specific drug: (a) PGx tests to predict an individual dose of the drug; (b) PGx tests to predict individual risk of drug toxicity in response to a drug prescribed or administered.

There are many clinical guidelines available in this area of knowledge, and the most relevant ones are: the Clinical Pharmacogenetics Implementation Consortium (CPIC),20 the Dutch Pharmacogenetics Working Group (DPWG),21 the Canadian PGxs Network for Drug Safety (CPNDS),22 the Groupe de Pharmacologie Clinique Oncologique (GPCO/Unicancer),23 the Réseau National de Pharmacogénétique Hospitalière (RNPGx),24 and the American College of Rheumatology (ACR).25

A Little of History

Some of the main therapies based on a specific mutation, that changed significantly the prognosis of diseases, are trastuzumab therapy against HER2-positive breast cancer and imatinib in chronic myeloid therapy.26,27 Since then, Oncology has bet on the use of genetic information and today it serves to guide the therapeutic decision making, having included the genomic test in 39% of the clinical trials in the field in 2018.28 In addition to oncology, other areas have identified and improved therapies based on genetic variations. For cystic fibrosis, more than 100 causative mutations have been identified, that, even though make the development of a specific treatment for each variant difficult, enables the grouping of subtypes that seem to respond to similar treatments.29

Advances in genomic medicine are not limited to drugs that act at the protein level. Techniques like the clustered regularly interspaced short palindromic repeats (CRISPR) system, which refers to a specialized DNA region, have been used to silence genes and prevent the development of diseases in embryos and/or modify disease-related genes in adults.30 These techniques are part of what is known as genetic therapy and, although at embryonic stage, they are expected as potentially revolutionary alternatives.

 Drug Metabolization

The main PGx guidelines have adopted terms that aim to facilitate clinical application of genetic results and harmonize reports from different laboratories.31 This classification varies with different types of genes, and takes into account the combination of variants identified in the same gene and its zygosity. One example is the consensual classification of cytochrome P450 2D6 (CYP2D6), one of the main enzymes of drug metabolism, which is involved in the metabolism of approximately 25% of the commercialized drugs. Patients may be classified into one of four phenotypes regarding the type of drug metabolizers: poor metabolizers, intermediate metabolizers, extensive metabolizers and ultrarapid metabolizers, as detailed below:

• Slow Metabolizers

Patients experience a very slow breakdown of medications, making side effects more pronounced. Patients of this group have two alleles with variants that cause a reduction, or even inactivity of the enzyme. Also, standard doses of certain drugs may not work as expected. Up to 15% of the population are in this group.32

 • Intermediate Metabolizers

Intermediate metabolizers may somehow affect the breakdown of medications, causing effects similar to those in poor metabolizers, but not as pronounced.33

 • Extensive Metabolizers

The rate of metabolism of these patients is considered “normal”. Medication is likely to work as planned, and these individuals will take the dose recommended in the package insert of the medication;34

 • Ultrarapid Metabolizers

Patients in this group metabolize medications very quickly, due to the presence of two alleles that produce highly active enzymes or of extra copies of the alleles (e.g. gene duplication or triplication).35

The CYP2D6 gene, responsible for the metabolism of nearly 25% of the medications prescribed,36 has the alleles that generate the four metabolizer types, previously described.37 The prevalence of these alleles varies with ethnicity. For example, one of the main known nonfunctional alleles, the CYP2D6*4, has an estimated prevalence of 25% among Caucasians, whereas the CYP2D6*10 and the CYP2D6*17 (both with reduced function) are more common in African and Asian populations, with an allele frequency of about 40%.38

 Randomized Clinical Trials

Over the last years, several studies have been conducted to test the role of PGx in clinical practice. A randomized clinical trial (RCT)39 involving 1,956 patients infected with human immunodeficiency virus were randomly assigned to one of two groups – to undergo prospective HLA-B*5701 screening, with exclusion of HLA-B*5701-positive patients from abacavir treatment, or to undergo a standard-of-care approach of abacavir use without prospective HLA-B*5701 screening (control group). The incidence of hypersensitivity reaction was lower in the prospective-screening group (3.4%) than in the control group (7.8%). This result made the US Food and Drug Administration (FDA) require the inclusion of PGx test in the package insert of the medication.39 More recently, Smith et al.40 reported a reduction by 30% in pain intensity in chronic opioid users when the therapy was guided by the presence of CYP2D6. A meta-analysis including five RCTs found that individuals receiving genotyping-guided therapy were 1.71 times more likely to achieve symptom remission compared with individuals who received standard treatment.41

Regarding studies on CVDs, most are related to antiplatelet and anticoagulation agents. After retrospective observations that the presence of genetic variants classified as loss of function had an impact on the effects of clopidogrel, initiatives have emerged to evaluate the benefits of including PGx tests as a routine approach. The Implementing Genomics in Practice (IGNITE) investigators observed, in a group of 1,815 patients, higher rates of cardiovascular events in patients with a CYP2C19 loss-of-function allele prescribed clopidogrel compared with alternative antiplatelet therapy, including prasugrel or ticagrelor (hazard ratio [HR] 2.26, 95% confidence interval [CI] 1.18-4.32; p=0.013).42 Another RCT showed an important decrease in late coronary events with implementation of PGx strategy for clopidogrel prescription.43

Regarding warfarin, most studies evaluated genetic variants related to its metabolization in CYP2C9 and VKORC1 genes. The European Pharmacogenetics of anticoagulant therapy (EU-PACT) showed that a genotype-guided therapy significantly increased the percentage of time in the therapeutic range of 2.0 to 3.0 for the international normalized ratio (INR).44 More recently, the Genetics Informatics Trial of Warfarin to Prevent Deep Vein Thrombosis (GIFT) study showed a significant reduction in major bleeding, venous thromboembolism and death in patients on genotype-guided therapy with warfarin during the perioperative period of elective surgeries of hip or knee arthroplasty.45 These two studies involving warfarin included a predominantly white populations and therefore, further studies including CYP2C9 variants that are more common African-descendant populations are needed to obtain in accurate results related to these groups. Interestingly, the largest study on warfarin, the Clarification of Optimal Anticoagulation Through Genetics (COAG) study, showed contrasting results, reporting no difference in initiating warfarin therapy based on clinical information and initiating warfarin therapy based on individual’s genotype (search for CYP2C9 variants, which are far more common in European-descendant populations, in a cohort composed of 27% of African-Americans).46 On the other hand, considering the cost-benefit of the use of warfarin and clopidogrel, a recent systematic review including 31 RCTs showed that, the PGx test was superior to standard therapy in 81% of the times.13

Parallel to studies on one type of medication, the concept of preventive test has gained importance and shown evidence of benefit. In 2012, Schildcrout et al.47 estimated that 64.8% of 52,942 medical home individuals were exposed to at least one medication with a mechanism influenced by genetic variants. The authors also estimated that 398 potential adverse events could have been prevented with an effective preemptive genotyping. The study on genotype data of 44,000 participants of the Estonian Biobank showed that 99.8% of these individuals had a genotype associated with increased risks to at least one medication.48 Concordant results were reported in the RIGHT (Right Drug, Right Dose, Right Time Using Genomic Data to Individualize Treatment) protocol, created by the Mayo clinic/eMERGE initiative, which performed sequencing of a panel that included solute carrier organic anion transporter family member 1B1 (SLCO1B1), CYP2C19, CYP2C9, VKORC1 and CYP2D6. The study demonstrated that 99% of 1,013 individuals had at least one variant associated with increased risks to a medication.49

In the United States, medications with recommendations related to PGx constitute 18% of all prescriptions50 and 30% of the most prescribed medications that have a high PGx risk represent 738 million prescriptions a year.51 These data corroborate the idea of a positive impact of the preemptive PGx test, not only for the increase in therapeutic efficacy and cost-benefit, but also for the potential in preventing ADEs. In addition, a Dutch study showed a beneficial effect by reducing the risk of fluoropyrimidine-induced toxicity from 73% to 28% by genotype-guided dosing and reduction of drug-induced death from 10% to 0%.52

 Importance of Pharmacogenomics

Over the last years, PGx has emerged as an area of increasing interest and enthusiasm, as it essentially leads with the so-called “personalized medicine”, considering the influence of patients’ genomic variation on drug responses.53

Many benefits can be achieved with deployment of PGx:

To increase therapeutic power and reduce likelihood of intoxication;

To initiate a therapy in more appropriate time.

In addition, PGx may contribute to the reduction of costs in healthcare, as presented in Figure 1. It is important to mention that a large amount of deaths per year are related to ADEs, with a cost of approximately €80 billion.54

Advantages of pharmacogenomics and potential health cost reduction. *Due to possible earlier detection.

It is estimated that a considerable proportion of patients do not show a satisfactory response to drug treatment.55,56 In this regard, the FDA recommends, for example, that PGx tests be carried out before chemotherapy with mercaptopurine (a drug commonly used in the treatment of patients with acute leukemia) is initiated.57 This recommendation is based on the fact that, since the drug may cause severe side effects and increase the risk of infection, depending on individual’s genetic variant, the therapy may not achieve intended results.

The Genomics and Targeted Therapy Group, an arm of the FDA’s Office of Clinical Pharmacology, works to ensure that PGx strategies are applied appropriately by means of its functions of regulatory review, research, policy development, and professional education. Part of this work included the construction of a table describing pharmacological instructions of 161 drugs that display PGx information on the label. The last update provides a remarkable number of biomarkers associated to drugs used in several areas of medicine, many of them widely used in clinical practice58 (Table 1).

Number of pharmacogenomic biomarkers in drug labeling by medical field, based on the US Food and Drug Administration table
Area Biomarkers
Oncology 167
Infectious disease 35
Psychiatry 34
Neurology 29
Hematology 25
Anesthesiology 23
Cardiology 22
Gastroenterology 17
Rheumatology 11
Pneumology 10
Endocrinology 7
Inborn errors of metabolism 7
Urology 5
Dermatology 4
Toxicology 2
Transplant 1

Finally, it is expected that PGx soon become more accessible and that its responsible use contribute to more accurate drug prescription, with a higher likelihood of therapeutic success and a lower risk of ADEs.

 Association Between Genetic Variants and Drug Responses in Cardiovascular Diseases

It is widely known that factors like age, comorbidities, weight, and demographic aspects can contribute to significant differences in the response to a certain medication, as well as to the development of ADE.59,60 In this context, genetic variation may represent a cornerstone in this outcome. It is believed that many deaths could be prevented if physicians were aware of PGx profile of patients and prescribe them medications at correct doses.61 Patients diagnosed with the same disease are treated following the same therapeutic protocol although their responses to drug treatment may vary significantly. A tailored therapy can reduce ADEs and increase efficacy rates, as described in Figure 2. For example, there is a huge variation (up to 20 times) in the daily dose of one of the most used anticoagulants in clinical practice, warfarin, among patients.62 The dose of propranolol, a medication of the beta blocker class, may vary up to 40 times among users.60 Some medications widely used in cardiology, that may have important genetic associations, are listed in Table 2.

Potential clinical applications of Pharmacogenomics; Adapted from Johnson, 2003.<xref ref-type="bibr" rid="B99"><sup>99</sup></xref> Association between genes and medications
Genes Medications Class Genetic variant Allele effect
CYP2C9, VKORC1 Warfarin Vitamin K antagonist CYP2C9*2 (p.Arg144Cys; rs1799853) Reduced drug clearance; reduced dose required
CYP2C9*3 (p.Ile359Leu; rs1057910) Reduced drug clearance; reduced dose required
VKORC1 (-1639G>A; rs9923231) ↑ Sensitivity to medication; Reduced dose required
CYP2C19 Clopidogrel Receptor P2Y12 inhibitor CYP2C19*2 (c.681G>A; rs4244285) ↑ Risk of cardiovascular events; loss of function; lower antiplatelet effect.
CYP2C19*17 (c.-806C>T; rs12248560) ↑ Sensitivity to medication; loss of function; ↑ risk of bleeding
SLCO1B1 Simvastatin HMG-CoA reductase inhibitor SLCO1B1*5 (p.Val174Ala; rs4149056) ↑ Risk of myopathy or rhabdomyolysis
ADRB1 Atenolol, metoprolol Beta blocker ADRB1 (p.Ser49Gly; rs1801252) Better blood pressure control; ↑ LVEF
ADRB1 (p.Arg389Gly; rs1801253)
CES1 Dabigatran Direct oral anticoagulant CES1 (G143E, rs71647871) ↑ Metabolism of medication and its metabolites
ITGB3 Aspirin Antiplatelet agent ITGB3 (PlA1/A2 [T1565→C], rs5918) ↓ Antiplatelet effect

LVEF: left ventricular ejection fraction; CYP2C9: Cytochrome P450 2C9; VKORC1: vitamin K epoxide reductase C1; CYP2C19: P450 2C19; SLCO1B1: Solute carrier organic anion transporter family member 1B1; CYP4F2: cytochrome P450 family 4 subfamily F member 2; ADRB1: beta-1 adrenergic receptor; CYP11B2: Cytochrome P450 family 11 subfamily B member 2; FUT4: Fucosyltransferase 4; CES1: carboxylesterase 1; ITGB3: Integrin beta-3.

 Warfarin

Warfarin is a vitamin K antagonist that has been largely used for the prevention of thrombotic events.63 Evidence has suggested that the individual response to warfarin and to other vitamin K antagonists, may be influenced by genetic variations in cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase C1 (VKORC1), target of these drugs,64,65 and polymorphisms of cytochrome P450 family 4 subfamily F member 2 (CYP4F2).66 Variations in the CYP2C9*2 and CYP2C9*3 have been shown to reduce enzymatic activity of CYP2C9 and inhibit the anticoagulant metabolism,67 whereas the polymorphism of VKORC1- 1639G>A seems to influence the pharmacodynamic response to vitamin K antagonists.68 For these issues, the FDA indicated the need for displaying PGx information in the package insert of warfarin.

In practice, heterozygous carriers for CYP2C9*2 or CYP2C9*3 may require a reduced warfarin dose, by approximately 30% and 47%, respectively, and homozygous carriers for CYP2C9*3 may require greater reductions (~80%).69-71 The -1639 G>A variant of the VKORC1 gene seems to reduce the expression of proteins, which in theory represents the requirement of a lower maintenance dose of warfarin compared with non-carriers of the variant.72 Also, combinations of some variants associated with ultrarapid metabolism limit the systematic definition of a therapeutic INR of these patients.73 In this scenario, the CPIC guidelines recommend considering a direct oral anticoagulant (e.g. edoxaban).74

 Clopidogrel

In the United States, it is estimated that more than three million individuals are prescribed clopidogrel after stent implantation.75 Clopidogrel belongs to the class of thienopyridines and exerts antiplatelet effect.76 The individual response to clopidogrel may be altered by the polymorphism of CYP2C19.77

The CYP2C19*2 loss-of-function variant allele was associated with an increased risk of adverse cardiovascular events, including stent thrombosis during clopidogrel therapy.78 More specifically, the CYP2C19*2 (rs4244285) allele causes loss of function and was associated with reduced antiplatelet effect of the drug.79 Also, carriers of the CYP2C19 *3 (rs4986893) allele show poor response to clopidogrel and higher rates of recurrent adverse cardiovascular events as compared with non-carriers.80,81 It is important to mention that the frequencies of CYP2C19 *2 and CYP2C19 *3 are higher in Asian populations, suggesting that these individuals are more likely to be resistant to this medication.82 In contrast, the CYP2C19*17 (rs3758581) allele promotes gain of function and has been associated with increased enzymatic activity and improved platelet inhibition. Carriers of the CYP2C19*17 variant have been called ultrarapid metabolizers.83

In addition, race seems to play an important role in this scenario. Cresci et al.84 compared the effect of polymorphism of CYP2C19 on cardiovascular adverse events between patients with acute myocardial infarction in Caucasians and African Americans treated with clopidogrel. The authors found a significant association of the CYP2C19*2 allele with increased one-year mortality and an increasing trend in the incidence of recurrent myocardial infarction in Caucasians. The CYP2C19*17 was associated with higher one-year mortality and higher risk of bleeding in African Americans. Also, it is of note that CYP2C19*2 carriers that undergo percutaneous coronary intervention may have higher risk of stent thrombosis. In a RCT in which nearly 2,500 patients that were pre-treated with 600mg clopidogrel, there was a significanly higher stent thrombosis rate amongst CYP2C19*2 allele carriers, in 30 days, when compared with wild-type CYP2C19 allele carriers.85 In this same line, the meta-analysis conducted by Mega et al.,86 including studies on more severely ill patients receiving more aggressive treatment, found an increased risk of stent thrombosis when the allele *2 was identified by PGx.

Despite these evidences, a systematic review and meta-analysis including 15 studies did not corroborate these findings and did not show a clear influence of polymorphisms of the CYP2C19 gene on the clinical efficacy of clopidogrel,87 suggesting that the use of individualized antiplatelet regimens guided by CYP2C19 genotype is not justified.

Today, the American College of Cardiology, in conjunction with the American Heart Association, does not recommend PGx tests for CYP2C19 as a routine approach.88 However, a more recent meta-analysis demonstrated that patients who may benefit from the PGx study are those with coronary artery disease, undergoing percutaneous myocardial revascularization.89 In this context, the CPIC officially recommends that patients with acute coronary syndrome and even those undergoing percutaneous coronary intervention undergo PGx testing. The CPIC emphasizes that those patients with one or two copies of loss-of-function variants should receive alternative antiplatelet agents (prasugrel or ticagrelor), to reduce the risk of adverse cardiovascular events.90 On the other hand, PGx testing is not indicated for other patient populations (e.g. atrial fibrillation patients), in which the use of clopidogrel is debatable.

Claassens et al.91 conducted a recent RCT to evaluate the results of a genotype-guided antiplatelet therapy in patients with acute myocardial infarction with ST segment elevation. Patients were assigned to receive either clopidogrel, based on early CYP2C19 genetic testing (non-carriers of loss-of-function alleles received clopidogrel) or standard treatment with either ticagrelor or prasugrel. No difference was found between the groups in the incidence of thrombotic events and therefore, the genotype-guided strategy was noninferior to standard treatment with ticagrelor or prasugrel, which is more expensive and associated with higher incidence of bleeding.91

Results of the TAILOR PCI clinical trial were recently published. The authors assessed a genotype-guided strategy (n=2,652) versus standard therapy (n=2,650) in patients with stable or unstable coronary artery disease, aiming to determine whether genetic testing could identify the best anti-platelet therapy in these individuals. In the genotype-guided group, CYP2C19 *2 or *3 carriers received ticagrelor 90 mg twice a day or non-carriers received clopidogrel 75 mg daily. In the standard therapy group, patients received clopidogrel 75 mg daily and underwent genotyping test at 12 months. The primary outcome was cardiovascular death, myocardial infarction, stroke, stent thrombosis or recurrent ischemia in 12 months. The primary outcome and the incidence of bleeding were not different between the treatment groups. However, it is worth mentioning the 34% reduction in these events at one year and a 40% reduction in the number of events per patient in the genotype-guided group. Finally, a post-hoc analysis revealed a reduction of approximately 80% in the adverse event rate in the first three months of treatment in the group of patients randomized to the genotype-guided therapy arm.92,93

 Beta Blockers

This class of medications has been extensively used in the treatment of cardiac arrhythmias, chest pain, myocardial infarction, and hypertension.94 The genes associated with individual response to beta blockers include the CYP2D6, the beta-1 adrenergic receptor (ADRB1), the beta-2 adrenergic receptor (ADRB2) and G protein-coupled receptor kinase 5 (GRK5).95 For example, some beta-blockers, including propranolol and metoprolol, are metabolized by the CYP2D6, which very frequently presents with a ‘loss of funtion’ variant.34 Evidence has suggested that hypertensive patients, homozygous for the wild-type allelic variant Arg389, showed a 3-fold greater reduction in diurnal diastolic pressure with metoprolol compared with carriers of the allelic variant Gly389.96 Other findings,97 despite not so consistent, indicated that patients homozygous for the ADBR1 Arg389 haplotype seem to present a more satisfactory response to the family of beta-blockers, with a better left ventricular ejection fraction as compared with carriers of the Gly389 allele.97

Regarding the skin color, the higher frequency of the Gly389 allele in African Americans compared with white skin may be a plausible explanation for the reduced response to beta blockers. Although ethnicity and polymorphisms of ADRB1 have been reported as independent predictors of responses to beta blockers,98 further prospective studies to elucidate the role of these genetic variants in ethnicity-specific responses are needed.

Therefore, there are no recommendations for the use of PGx in guiding the use of beta blockers in heart failure treatment.

 Statins

Statins represent a class of medications that target the HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase) inhibition, and are used to reduce cholesterol levels, especially LDL cholesterol.99 Combined with changes in lifestyle, these drugs are considered first-line therapy for primary and especially secondary prevention of CVDs. However, large interindividual variability has been observed in the extension of LDL reduction, explained, in part, by environmental and genomic factors.100 Thus, a dose tailoring may be needed for each patient, to obtain a more effective response.

More recently, Licito et al.101 evaluated association of the PGx profile and neuromuscular pain in 76 type 2 diabetes mellitus patients and previous CVD using anti-diabetic and anti-cholesterolemic agents, such as statin. Different variants were studied, including the SLCO1B1, ABCB1, ABCC8, and drug biotransformers of cytochrome P450 Family (CYP) including CYP2C9*2 CYP2C9*3 CYP2C8*3, and CYP3A4*22. Approximately 17% of 35 patients treated with statin had neuromuscular pain. The PGx analysis showed a lack of any correlation between candidate gene polymorphisms and toxicity, except for the SLCO1B1 T521C allele. Thus, when available, analysis of the SLCO1B1 T521C variant is suggested, to enable clinicians to optimize the therapy prescribed, aiming at minimizing neuromuscular pain and maximizing the benefits from statins.

Also, the most strongly associated variant (with SLCO1B1), c.521T>C, reduces SLCO1B1 transport function, which can affect statin clearance, resulting in increased risk for toxicity in skeletal muscle. A meta-analysis of nine case-control studies, involving 4,500 patients, showed that individuals with the variant allele C were likely to experience statin-related myopathy (CT + CC versus TT: odds ratio = 2.09; 95%CI = 1.27-3.43).102

 Possible Barriers to the Implementation of Pharmacogenomics

Due to the advances in technology and sequencing techniques, the costs of PGx analysis have drastically reduced in the last years (Moore’s law), facilitating its use in clinical practice. However, the relatively high cost of PGx tests represents a barrier to its wider implementation. Also, there is a lack of familiarity by healthcare providers, a lack of a platform standardizing investigation and academic thinking and an insufficient volume of studies demonstrating the benefits of PGx. Those are factors that contribute to a low acceptance.

Nevertheless, there is currently a global effort to overcome these obstacles, including the development of large studies,103 like the UK’s 100.000 Genomes Project,104 the PREemptive PGx testing for prevention of Adverse drug REactions (PREPARE), with participation of seven European countries.105 On the other side of the North Atlantic, in the United States, the Electronic Medical Records and Genomics (eMERGE),106 the Network and the Implementation of Genomics in Practice (IGNITE),107 and the Clinical Sequencing Evidence Generating Research Consortium,108 are part of a series of projects funded by the National Human Genome Research Institute, with an estimated investment of at least U$ 775 million in genetic research from 2007 to 2022. In Asia, the South East Asian PGxs Research Network (SEAPharm) is a collaborative effort of five Asian countries to develop studies in PGx.109 In general, these studies are aimed to define, provide and analyze evidence of the clinical usefulness of genomic sequencing to guide treatment, cost-efficacy and the costs of its broad implementation in clinical practice. Of the available results, a review including 44 cost-benefit analyzes showed that 30% of them showed cost-effectiveness and 27% even showed a cost reduction.110 This may lead to an optimistic perspective of the future of PGx.

Among global initiatives’ many contributions for the expansion of PGx in clinical practice, some of the crucial aspects worth to highlight are: education and training of healthcare providers, investment in technology, in research and in healthcare centers’ structure. Projects involving PGx not only contribute to knowledge in the area, but also promote training of healthcare professionals to an adequate practice of genomic medicine, which requires the adoption of basic routines that may be less relevant to other medical specialties. For example, the involvement of family members in counseling and treatment planning, and confidentiality that ensures that genetic information is being used exclusively for the purpose of assistance (thereby avoiding the inappropriate use of PGx in relation to legislation, insurance, marketing or employment relationship). Education and training play a central role for the acceptance of genomic medicine in clinical practice, and acceptance, in turn, is the key to. The effort for data generation is of significant help, but commitment and involvement of healthcare providers that seek excellence are essential. The scale and the progress of efforts and investments in the world make clear the importance and potential attributed to genomic medicine, as it may be considered a component of high-quality medicine and one of the cornerstones of precision medicine.

 Final Considerations

Area of consensus: PGx tests may be helpful in the optimization of drug treatments, allowing greater pharmacological safety;

Area of controversy: whether PGx tests may be extensively applied, including for the prescription of medications whose benefits are not so clear;

Area of expansion: individual genotype data have become more and more available to consumers. This will probably increase the demand for a personalized prescription, indicating that prescribers should consider PGx data. For example, we can site the 100,000 Genomes Project. This amazing project will provide complete genome sequences that may someday be included in patients’ medical records. This seems to be a valuable information in personalized prescription.

Promising research areas: development of novel drugs targeting specific genetic risk factors of diseases. These medications could be prescribed for individuals with a high-risk genotype. It is likely that PGx information become routinely available in the future, mainly in technologically advanced environments. This could influence the prescription of several drugs other than those requiring PGx tests prior to prescription.

Sources of Funding

There were no external funding sources for this study.

Study Association

This article is part of the thesis of Doctoral submitted by Filipe Ferrari and Thaís Beuren, from Universidade Federal do Rio Grande do Sul.