Hypertension
studies confirm some of the loci reported from European ancestry populations. However, it is difficult to properly evaluate potential novel loci until more studies are done. Meta-analyses comparable to those done in European ancestry subjects can only be carried out when more African-American GWAS become available.
Admixture Mapping Studies for Hypertension and Blood Pressure in African Americans African Americans are an admixed population group; in other words, a group with ancestry from more than one parental population (in this case, African and European ancestry). As such, they provide an opportunity to map disease genes, especially diseases showing disparities across populations. HTN is such a disease and it is no surprise that attempts have been made to use admixture mapping to identify HTN genes in African Americans. Early admixture mapping studies used panels of genetic markers with large differences in frequency between the ancestral populations (‘ancestry informative markers’ or AIMs). Zhu et al.,25
using a panel of markers designed for linkage studies, reported 6q24 and 21q21 loci in the first admixture mapping study for HTN in African Americans. This was followed by two other studies,26,27 found weaker evidence for the 6q24 locus,26
one that and the other finding
evidence that VNN1 gene variants accounted for the 6q24 signal.27 Two recent developments have breathed new life into the use of admixture mapping. The first of these is the availability of economical high-throughput genotyping coupled with new statistical methods for inferring ancestry with such dense markers, with resulting better power and finer resolution.28,29
This means that admixture mapping can be done
with hundreds of thousands to millions of SNPs, rather than the usual few hundred to a couple of thousand AIMs. The second development is the potential to combine association and admixture in the same study or do a joint association-admixture/ancestry analysis,30
to attain greater
study power than using either approach alone. The latter approach has been applied to HTN and SBP within the CARe resource. Lettre et al.24 used joint association and admixture testing to identify a novel HTN locus (rs10218356); however, this finding needs to be confirmed. Zhu et al.31 performed admixture mapping analysis for SBP and DBP, followed by trait-marker association analysis, in 6,303 unrelated CARe participants. The study identified five genomic regions harboring genetic variants contributing to BP variation. Six independent SNPs were examined for replication in five large, independent studies (total replication sample size 11,882). The meta-analysis combining the discovery and replication samples identified a novel variant (rs7726475) between the SUB1 and NPR3 genes, showing significant association with SBP and DBP.31
1. Mensah GA, The global burden of hypertension: good news and bad news, Cardiol Clin, 2002;20:181–5.
2. Mein CA, Caulfield MJ, Dobson RJ, Munroe PB, Genetics of essential hypertension, Hum Mol Genet, 2004;13(Spec No. 1):R169–75.
3. Altshuler D, Daly MJ, Lander ES, Genetic mapping in human disease, Science, 2008;322: 881–8.
4. McCarthy MI, Abecasis GR, Cardon LR, et al., Genome-wide association studies for complex traits: consensus, uncertainty and challenges, Nat Rev Genet, 2008;9:356–69.
5. Rosenberg NA, Huang L, Jewett EM, et al., Genome-wide association studies in diverse populations, Nat Rev Genet, 2010;11:356–6.
6. Roger VL, Go AS, Lloyd-Jones DM, et al., Heart disease and stroke statistics—2011 update: a report from the American Heart Association, Circulation, 2011;123:e18–209.
7. Wu X, Kan D, Province M, et al., An updated meta-analysis of genome scans for hypertension and blood pressure in the
As methods improve, these approaches applied to admixed populations (e.g. African Americans and Hispanic Americans) have great potential to identify disease loci not easily identifiable by other means or that are population specific, as exemplified by the recent success in identifying MYH9-APOL1 as important in focal segmental glomerulosclerosis and end-stage renal disease.32,33,34
Concluding Thoughts
The genetic architecture of HTN is still being slowly elucidated. Multiple challenges remain, including choice and definition of phenotype, choice of types of genetic variants, effect of gene–gene and gene–environment interactions, as well as integration of high-throughput data from multiple sources. Despite these challenges, studies of the specific genetic variants underlying susceptibility to human HTN and BP are gradually starting to yield consistent results. At present, cross-population comparisons remain difficult because most studies include European ancestry populations, with far smaller numbers from other population groups. The common variants identified so far explain only a small fraction of the trait variance, implying that other types of variants (in particular, rare variants, structural variants, and epigenetic effects) need to be investigated. More studies of African Americans are needed so that sufficient numbers are attained for meta-analysis. Furthermore, better tools are needed. For example, the typical one million SNP GWAS array provides adequate coverage (approximately 93–96 %) of the European or Asian genome but only 67–70 % of the African genome. Therefore, SNP arrays designed to provide better coverage of the African genome are needed to ensure that common variants in these populations are better tagged and tested. Also, studies of rare variants in HTN and BP are needed in African Americans.
Studies on HTN and BP in African Americans remain valuable for several reasons. First, like other African ancestry populations, they are characterized by higher genetic diversity, lower linkage disequilibrium between markers, and smaller haplotypes. These features facilitate fine mapping of disease loci with the trade-off that discovery is more difficult. Second, as an admixed population, other approaches not feasible in most other populations (such as admixture mapping) can be used. Third, the findings of studies can be informative for both European and African ancestry groups. Finally, as a minority population showing significant health disparities, these studies can help us to understand and redress some of these health disparities. More studies of the genomics of HTN and BP in African Americans (and other minority groups) have the potential to enrich ongoing efforts to unravel the genetic architecture of essential HTN. n
NHLBI Family Blood Pressure Program (FBPP), Am J Hypertens, 2006;19:122–7.
8. Rice T, Cooper RS, Wu X, Bouchard C, et al., Meta-analysis of genome-wide scans for blood pressure in African American and Nigerian samples. The National Heart, Lung, and Blood Institute GeneLink Project, Am J Hypertens, 2006;19:270–4.
9. Need AC, Goldstein DB, Next generation disparities in human genomics: concerns and remedies, Trends Genet, 2009;25:489–94.
10. Cooper RS, Tayo B, Zhu X, Genome-wide association studies: implications for multiethnic samples, Hum Mol Genet, 2008;17:R151–5.
11. Wellcome Trust Case Control Consortium, Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls, Nature, 2007;447:661–78.
12. Doris PA, The genetics of blood pressure and hypertension: the role of rare variation, Cardiovasc Ther, 2011;29:37–45.
13. Wang Y, O’Connell JR, McArdle PF, et al., From the cover:
whole-genome association study identifies STK39 as a hypertension susceptibility gene, Proc Natl Acad Sci U S A, 2009;106:226–31.
14. Org E, Eyheramendy S, Juhanson P, et al., Genome-wide scan identifies CDH13 as a novel susceptibility locus contributing to blood pressure determination in two European populations, Hum Mol Genet, 2009;18:2288–296.
15. Cho YS, Go MJ, Kim YJ, et al., A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits, Nat Genet, 2009;41:527–34.
16. Levy D, Ehret GB, Rice K, et al., Genome-wide association study of blood pressure and hypertension, Nat Genet, 2009;41: 677–87.
17. Newton-Cheh C, Johnson T, Gateva V, et al., Genome-wide association study identifies eight loci associated with blood pressure, Nat Genet, 2009;41:666–76.
18. Franceschini N, Reiner AP, Heiss G, Recent findings in the
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