Identifying Genetic Susceptibility Loci for Hypertension in African Americans
multiethnic cohorts that included African Americans. While such studies were few, their findings have been combined in meta-analysis7,8
and will not
be discussed further in this article. In the current era of high-throughput genomics, the disparity in the number of studies conducted in various population groups has continued, leading to suggestions of how to remedy such next generation disparities in human genomics.9
Recent Advances in the Study of the Genomics of Hypertension
With regard to disease mapping, one of the most important recent advances is the widespread application of GWAS to identify common genetic variants that are associated with disease.3,4,5,10
The first GWAS for
HTN was conducted by the Wellcome Trust Case Control Consortium.11 Unlike the other six diseases in the study, no genetic variant was associated with HTN at a genome-wide significant level. While this study had an important design weakness in relation to HTN (controls were not screened for HTN and were rather young for HTN),12
several other
GWAS for HTN and/or BP followed, mostly in European and Asian ancestry populations. In general, each study found one or two loci with genome-wide significance, often after combination of the data with those from additional study cohorts. In this way, variants in STK39,13 CDH13,14
and ATP2B115 were shown to play important roles in HTN and/or
BP. With enough GWAS performed, it became possible to carry out combined studies using meta-analysis techniques. Meta-analysis GWAS have been the most successful approach so far for identifying HTN and BP loci.
The first two GWAS meta-analyses for BP16,17 were conducted in people
of European ancestry and revealed 13 novel loci, an unprecedented number of confirmed BP-related loci. Each study consortium was large, the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) consortium16
subjects and the Global BPgen consortium17
comprising six cohort studies with 29,136 having 13 population-based
Despite their success, it should be noted that the studies reported eight significant loci each, of which only three overlapped. Thus, the findings were not entirely consistent despite the large sample sizes and the common European ancestry of the subjects. More recently, a meta-analysis of eight studies of East Asians19
studies and 34,433 subjects. These studies have been reviewed in detail elsewhere.12,18
with 19,608 subjects
reported finding five novel loci for systolic BP (SBP) or diastolic BP (DBP), as well as replicating seven known loci reported from European ancestry subjects. Overall, GWAS have identified several common variants associated with BP. However, in common with other complex diseases such as type 2 diabetes, these variants explain only a small fraction of the heritability and the residual or ‘missing heritability’20
is
likely to be found in other types of genetic variants (e.g. rare variants and structural variants).
While common genetic variants contributing to disease can be identified through GWAS (and similar approaches), rare variants can only be identified through resequencing approaches. Convincing proof-of-concept evidence for the role of rare variants in HTN and BP has been produced by Lifton’s group in a study of SLC12A1, KCNJ1 and SLC12A3 in the Framingham Heart Study.21
However, it has been
difficult to scale up this approach until recently, with whole exome capture and whole genome sequencing becoming more affordable.
US NEPHROLOGY
The next few years should prove exciting as the findings of ongoing studies based on large-scale sequencing become available.
Genome-wide Association Studies for Hypertension and Blood Pressure in African Americans
in a study of 1,017 people from the Howard University Family Study. The study found genome-wide significant results only with SBP (not DBP or HTN) and these were with PMS1, SLC24A4, YWHAZ, IPO7, and CACANA1H. Two of these genes, SLC24A4 (a sodium/potassium/calcium exchanger), and CACNA1H (a voltage-dependent calcium channel), are potential candidate genes for BP regulation. Of note, CACNA1H is a T-type voltage-gated calcium channel protein and a known antihypertensive drug target for the following calcium channel blockers: mibefradil (Posicor®), efonidipine, benidipine, and manidipine. The most significant locus in the study, PMS1, encodes a DNA mismatch repair protein with known associations with hereditary non-polyposis colorectal cancer type 3 and Lynch syndrome, but not with HTN or BP. Interestingly, the CHARGE GWAS meta-analysis16
The first GWAS for HTN and SBP in African Americans was by Adeyemo et al.22
also found the PMS1 locus to
be significantly associated with HTN and SBP in Europeans. While the sample size for this study of African Americans was modest, the study found a few genome-wide association signals and confirmed a few loci reported from European ancestry subjects. The best association signals were found with SBP (a continuous measure that has more power than a binary variable such as HTN) and among normotensive subjects, i.e. without the confounding effect of antihypertensive treatment. These suggest that phenotype definition may influence the ability to find a significant signal. More importantly, the study provided data that can be used for replication of subsequent studies, and/or combined with other studies in meta-analyses.
A second GWAS for BP in African Americans was done by the National Heart, Lung, and Blood Institute Candidate Gene Association Resource (CARe) consortium.23
This GWAS included 8,591 African Americans
from five cohorts (ARIC, CARDIA, CFS, JHS, MESA) and investigated genome-wide association with SBP and DBP using the Affymetrix 6.0 GWAS array. The study also carried out candidate gene association using a 50K cardiovascular gene-centric SNP array (ITMAT-Broad-CARe [IBC] array). The strongest signal for DBP was in a SNP near GPR98 and ARRDC3 while that for SBP was in a SNP in C21orf91. However, the top IBC association for SBP was in a variant near SLC25A42 and that for DBP was in a SNP near HLA-B. Remarkably, none of the top variants were replicated in additional African-American (n=11,882) or European-American (n=69,899) cohorts. However, the study replicated three previously reported European-American blood pressure loci (SH2B3, TBX3-TBX5, and CSK-ULK3). The CARe GWAS for HTN was reported in a separate publication on coronary heart disease (CHD) and other CHD risk factors).24
That study
identified one novel HTN locus that reached genome-wide significance (SNP rs7801190 in SLC12A9). However, this was an imputed SNP and direct genotyping failed to confirm the association, meaning that it was most likely a false-positive finding. Of note, the study did not replicate any of the HTN SNPs from GWAS of European ancestry populations, including the large meta-analyses,16,17
African-American GWAS for HTN and BP.22
nor did it replicate the findings of the other In summary, there have been
few GWAS for HTN and BP in African Americans. The findings from the 107
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