RESUMO
Rare genetic disorders (RGDs) often exhibit significant clinical variability among affected individuals, a disease characteristic termed variable expressivity. Recently, the aggregate effect of common variation, quantified as polygenic scores (PGSs), has emerged as an effective tool for predictions of disease risk and trait variation in the general population. Here, we measure the effect of PGSs on 11 RGDs including four sex-chromosome aneuploidies (47,XXX; 47,XXY; 47,XYY; 45,X) that affect height; two copy-number variant (CNV) disorders (16p11.2 deletions and duplications) and a Mendelian disease (melanocortin 4 receptor deficiency (MC4R)) that affect BMI; and two Mendelian diseases affecting cholesterol: familial hypercholesterolemia (FH; LDLR and APOB) and familial hypobetalipoproteinemia (FHBL; PCSK9 and APOB). Our results demonstrate that common, polygenic factors of relevant complex traits frequently contribute to variable expressivity of RGDs and that PGSs may be a useful metric for predicting clinical severity in affected individuals and for risk stratification.
Assuntos
Estatura/genética , Índice de Massa Corporal , LDL-Colesterol/sangue , Herança Multifatorial , Obesidade/genética , Doenças Raras/genética , Apolipoproteínas B/genética , Transtorno Autístico/genética , LDL-Colesterol/genética , Deleção Cromossômica , Transtornos Cromossômicos/genética , Duplicação Cromossômica/genética , Cromossomos Humanos Par 16/genética , Cromossomos Humanos X/genética , Feminino , Humanos , Hiperlipoproteinemia Tipo II/genética , Hipobetalipoproteinemias/genética , Deficiência Intelectual/genética , Síndrome de Klinefelter/genética , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9/genética , Receptor Tipo 4 de Melanocortina/deficiência , Receptor Tipo 4 de Melanocortina/genética , Receptores de LDL/genética , Aberrações dos Cromossomos Sexuais , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/genética , Trissomia/genética , Síndrome de Turner/genética , Cariótipo XYY/genéticaRESUMO
Variants in ABCB1 and CYP2C19 have been identified as predictors of cardiac events during clopidogrel therapy initiated after myocardial infarction (MI) or percutaneous coronary intervention (PCI). In addition, PON1 has recently been associated with stent thrombosis. The reported effects of these variants have not yet been replicated in a real-world setting. We used BioVU, the Vanderbilt DNA repository linked to de-identified electronic health records (EHRs), to find data on patients who were on clopidogrel treatment after an MI and/or a PCI; among these, we identified those who had experienced one or more recurrent cardiac events while on treatment (cases, n = 225) and those who had not experienced any cardiac event while on treatment (controls, n = 468). We found that CYP2C19*2 (hazard ratio (HR) 1.54, 95% confidence interval (CI) 1.16-2.06, P = 0.003) and ABCB1 (HR 1.28, 95% CI 1.04-1.57, P = 0.018), but not PON1 (HR 0.91, 95% CI 0.73-1.12, P = 0.370), were associated with recurrent events. In this population, genetic signals for clopidogrel resistance in ABCB1 and CYP2C19 were replicated, supporting the use of EHRs for pharmacogenomic studies. Our data do not show an association between PON1 and recurrent cardiovascular events.
