Variant Discovery and Fine Mapping of Genetic Loci Associated with Blood Pressure Traits in Hispanics and African Americans

Abstract

Despite the substantial burden of hypertension in US minority populations, few genetic studies of blood pressure have been conducted in Hispanics and African Americans, and it is unclear whether many of the established loci identified in European-descent populations contribute to blood pressure variation in non-European descent populations. Using the Metabochip array, we sought to characterize the genetic architecture of previously identified blood pressure loci, and identify novel cardiometabolic variants related to systolic and diastolic blood pressure in a multi-ethnic US population including Hispanics (n = 19,706) and African Americans (n = 18,744). Several known blood pressure loci replicated in African Americans and Hispanics. Fourteen variants in three loci (KCNK3, FGF5, ATXN2-SH2B3) were significantly associated with blood pressure in Hispanics. The most significant diastolic blood pressure variant identified in our analysis, rs2586886/KCNK3 (P = 5.2 x 10−9), also replicated in independent Hispanic and European-descent samples. African American and trans-ethnic meta-analysis data identified novel variants in the FGF5, ULK4 and HOXA-EVX1 loci, which have not been previously associated with blood pressure traits. Our identification and independent replication of variants in KCNK3, a gene implicated in primary hyperaldosteronism, as well as a variant in HOTTIP (HOXA-EVX1) suggest that further work to clarify the roles of these genes may be warranted. Overall, our findings suggest that loci identified in European descent populations also contribute to blood pressure variation in diverse populations including Hispanics and African Americans—populations that are understudied for hypertension genetic risk factors.

Association of genetic variation with blood pressure traits among East Africans

“…In addition, rs11725861 and rs11953630 were significant for all the traits in the combined analysis. These SNPs have showed interethnic replication among diverse ethnicities . More importantly, the 3 variants have been associated with BP responsiveness to beta‐blocker and thiazide diuretic monotherapy with among Caucasians .…”

“…These SNPs have showed interethnic replication among diverse ethnicities. 32,47,48 More importantly, the 3 variants have been associated with BP responsiveness to beta-blocker and thiazide diuretic monotherapy with among Caucasians. 49 The SNP rs1458038 near FGF5, for example, was associated with significant BP responses to both atenolol and hydrochlorothiazide, albeit in opposite directions.…”

Genome-Wide Association Study of Blood Pressure Traits by Hispanic/Latino Background: the Hispanic Community Health Study/Study of Latinos

“…Hispanics/Latinos are the largest minority ethnic group in the US, yet the genetic determinants of hypertension in this population remain poorly examined. In particular, only four genome-wide scan of BP traits to date have included Hispanics/Latinos, and these studies interrogated a limited number of single nucleotide polymorphisms (SNPs) from the Metabochip array 18 , or had very small number of Hispanics/Latinos 15 – 17 .…”

Evaluating the promise of inclusion of African ancestry populations in genomics

“…42 The complexities of PRS in the context of ancestry and the potential to exacerbate health disparities has been addressed in-depth in recent articles. 40,42 Importantly, in addition to limitations in transferability conferred by ancestry-related genomic differences, there can be substantial variation in the performance of PRS for complex genetic Lipoprotein(a) 112 Chronic obstructive pulmonary disease 113 Rh antigens 114 Population Architecture using Genomics and Epidemiology II (PAGE II) study Adiposity traits [115][116][117] Serum lipids 118 Glycemic traits 119 QT interval 120 Age of reproductive events among women 121 C-reactive protein 122 Blood pressure 123 Complex traits 107 The Blood pressure 109,126,127 Serum lipids [128][129][130] The traits based on methodological decisions 40 and on environmental context. 44 If PRS do become useful clinically, the limitations of applying data from a subset of the global population to all global populations are clear.…”