Gene panels to help identify subgroups at high and low risk of coronary heart disease among those randomized to antihypertensive treatment

Abstract

Objective To identify panels of genetic variants that predict treatment-related coronary heart disease (CHD) outcomes in hypertensive patients on one of four different classes of initial antihypertensive treatment. The goal was to identify subgroups of people based on their genetic profile who benefit most from a particular treatment. Methods Candidate genetic variants (n=78) were genotyped in 39,114 participants from GenHAT, ancillary to ALLHAT. ALLHAT randomized hypertensive participants (>=55 years) to one of four treatments (amlodipine, chlorthalidone, doxazosin, lisinopril). The primary outcome was fatal CHD or non-fatal MI (mean follow-up=4.9 years). A pharmacogenetic panel was derived within each of the four treatment groups. ROC curves estimated the discrimination rate between those with and without a CHD event, based on the addition of the genetic panel risk score. Results For each treatment group, we identified a panel of genetic variants that collectively improved prediction of CHD to a small but statistically significant extent. Chlorthalidone (A): NOS3, rs3918226; SELE, rs5361; ICAM1, rs1799969; AGT, rs5051; GNAS, rs7121; ROC comparison p=.004; Amlodipine (B): MMP1, rs1799750; F5, rs6025; NPPA, rs5065; PDE4D, rs6450512; MMP9, rs2274756; ROC comparison p=.006; Lisinopril (C): AGT, rs5051; PON1, rs705379; MMP12, rs652438; F12, rs1801020; GP1BA, rs6065; PDE4D, rs27653; ROC comparison p=.01; Doxazosin (D): F2, rs1799963; PAI1, rs1799768; MMP7, rs11568818; AGT, rs5051; ACE, rs4343; MMP2, rs243865; ROC comparison p=.007. Each panel was tested for a pharmacogenetic effect; panels A, B and D showed such evidence (p=.009, .006, and .001 respectively), panel C did not (p=.09). Conclusion Because each panel was associated with CHD in a specific treatment group but not the others, this research provides evidence that it may be possible to use gene panel scores as a tool to better assess antihypertensive treatment choices to reduce CHD risk in hypertensive individuals.

Pharmacogenomic Association of Nonsynonymous SNPs in SIGLEC12 , A1BG , and the Selectin Region and Cardiovascular Outcomes

“…22 Finally, variants in SELE have been associated with BP, 23 essential HTN, 24 CAD, 25 stroke, 26 and coronary heart disease in chlorthalidone (diuretic) treated patients from the GenHAT study. 27 …”

Exploring hypertension genome‐wide association studies findings and impact on pathophysiology, pathways, and pharmacogenetics

“…A similar risk score was analyzed for BP response to thiazide diuretics using the FGF5 , SH2B3 , and EBF1 genes ( P ‐value = 3 × 10 −4 ). Similarly, within a much larger sample of 39,114 hypertensive patients from the GenHAT study, panels of genes, including BP loci and other candidate genes, were found to be associated to coronary heart disease (CHD) only within specific antihypertensive treatment groups . This is the largest pharmacogentic study of antihypertensive treatments to date.…”

Study of the population frequencies of gene polymorphisms, associated with preeclampsia

“…The marker rs705379 (-108C > T) in the PON1 gene has been investigated earlier, mainly in relation to the effectiveness of certain medications in the treat ment of coronary heart disease (Lynch et al, 2012). It has been reported that this polymorphism can affect the expression of the PON1 gene (Brophy et al, 2001).…”