Adrenergic Alpha-1 Pathway is Associated with Hypertension Among Nigerians in a Pathway-focused Analysis

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2012 May 23

PMID 22615923

Citations 14

Authors

Nicholas P Reder

Bamidele O Tayo

Babatunde Salako

Adesola Ogunniyi

Adebowale Adeyemo

Charles Rotimi

Richard S Cooper

Affiliations

Soon will be listed here.

Abstract

Background: The pathway-focused association approach offers a hypothesis driven alternative to the agnostic genome-wide association study. Here we apply the pathway-focused approach to an association study of hypertension, systolic blood pressure (SBP), and diastolic blood pressure (DBP) in 1614 Nigerians with genome-wide data.

Methods And Results: Testing of 28 pathways with biological relevance to hypertension, selected a priori, containing a total of 101 unique genes and 4,349 unique single-nucleotide polymorphisms (SNPs) showed an association for the adrenergic alpha 1 (ADRA1) receptor pathway with hypertension (p<0.0009) and diastolic blood pressure (p<0.0007). Within the ADRA1 pathway, the genes PNMT (hypertension P(gene)<0.004, DBP P(gene)<0.004, and SBP P(gene)<0.009, and ADRA1B (hypertension P(gene)<0.005, DBP P(gene)<0.02, and SBP P(gene)<0.02) displayed the strongest associations. Neither ADRA1B nor PNMT could be the sole mediator of the observed pathway association as the ADRA1 pathway remained significant after removing ADRA1B, and other pathways involving PNMT did not reach pathway significance.

Conclusions: We conclude that multiple variants in several genes in the ADRA1 pathway led to associations with hypertension and DBP. SNPs in ADRA1B and PNMT have not previously been linked to hypertension in a genome-wide association study, but both genes have shown associations with hypertension through linkage or model organism studies. The identification of moderately significant (10(-2)>p>10(-5)) SNPs offers a novel method for detecting the "missing heritability" of hypertension. These findings warrant further studies in similar and other populations to assess the generalizability of our results, and illustrate the potential of the pathway-focused approach to investigate genetic variation in hypertension.

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References

Rotimi C, Dunston G, Berg K, Akinsete O, Amoah A, Owusu S . In search of susceptibility genes for type 2 diabetes in West Africa: the design and results of the first phase of the AADM study. Ann Epidemiol. 2001; 11(1):51-8. DOI: 10.1016/s1047-2797(00)00180-0. View

Ritchie M . Using biological knowledge to uncover the mystery in the search for epistasis in genome-wide association studies. Ann Hum Genet. 2010; 75(1):172-82. PMC: 3092784. DOI: 10.1111/j.1469-1809.2010.00630.x. View

Rotimi C, Morrison L, Cooper R, Oyejide C, Effiong E, Ladipo M . Angiotensinogen gene in human hypertension. Lack of an association of the 235T allele among African Americans. Hypertension. 1994; 24(5):591-4. DOI: 10.1161/01.hyp.24.5.591. View

Jacob H, Lindpaintner K, Lincoln S, Kusumi K, Bunker R, Mao Y . Genetic mapping of a gene causing hypertension in the stroke-prone spontaneously hypertensive rat. Cell. 1991; 67(1):213-24. DOI: 10.1016/0092-8674(91)90584-l. View

Levy D, Ehret G, Rice K, Verwoert G, Launer L, Dehghan A . Genome-wide association study of blood pressure and hypertension. Nat Genet. 2009; 41(6):677-87. PMC: 2998712. DOI: 10.1038/ng.384. View

Sober S, Org E, Kepp K, Juhanson P, Eyheramendy S, Gieger C . Targeting 160 candidate genes for blood pressure regulation with a genome-wide genotyping array. PLoS One. 2009; 4(6):e6034. PMC: 2699027. DOI: 10.1371/journal.pone.0006034. View

Liu J, McRae A, Nyholt D, Medland S, Wray N, Brown K . A versatile gene-based test for genome-wide association studies. Am J Hum Genet. 2010; 87(1):139-45. PMC: 2896770. DOI: 10.1016/j.ajhg.2010.06.009. View

Cooper , Puras , TRACY , KAUFMAN , Asuzu , Ordunez . Evaluation of an electronic blood pressure device for epidemiological studies. Blood Press Monit. 1999; 2(1):35-40. View

Harrap S . Hypertension: genes versus environment. Lancet. 1994; 344(8916):169-71. DOI: 10.1016/s0140-6736(94)92762-6. View

10.

Exner D, Dries D, Domanski M, Cohn J . Lesser response to angiotensin-converting-enzyme inhibitor therapy in black as compared with white patients with left ventricular dysfunction. N Engl J Med. 2001; 344(18):1351-7. DOI: 10.1056/NEJM200105033441802. View

11.

Rafiq S, Anand S, Roberts R . Genome-wide association studies of hypertension: have they been fruitful?. J Cardiovasc Transl Res. 2010; 3(3):189-96. DOI: 10.1007/s12265-010-9183-9. View

12.

Ehret G, Munroe P, Rice K, Bochud M, Johnson A, Chasman D . Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature. 2011; 478(7367):103-9. PMC: 3340926. DOI: 10.1038/nature10405. View

13.

Hilbert P, Lindpaintner K, Beckmann J, Serikawa T, Soubrier F, Dubay C . Chromosomal mapping of two genetic loci associated with blood-pressure regulation in hereditary hypertensive rats. Nature. 1991; 353(6344):521-9. DOI: 10.1038/353521a0. View

14.

Kunz R, Kreutz R, Beige J, Distler A, Sharma A . Association between the angiotensinogen 235T-variant and essential hypertension in whites: a systematic review and methodological appraisal. Hypertension. 1997; 30(6):1331-7. DOI: 10.1161/01.hyp.30.6.1331. View

15.

Kearney P, Whelton M, Reynolds K, Muntner P, Whelton P, He J . Global burden of hypertension: analysis of worldwide data. Lancet. 2005; 365(9455):217-23. DOI: 10.1016/S0140-6736(05)17741-1. View

16.

Papademetriou V, Kaoutzanis C, Dumas M, Pittaras A, Faselis C, Kokkinos P . Protective effects of angiotensin-converting enzyme inhibitors in high-risk African American men with coronary heart disease. J Clin Hypertens (Greenwich). 2009; 11(11):621-6. PMC: 8673026. DOI: 10.1111/j.1751-7176.2009.00174.x. View

17.

Clayton D . Testing for association on the X chromosome. Biostatistics. 2008; 9(4):593-600. PMC: 2536723. DOI: 10.1093/biostatistics/kxn007. View

18.

Cooper R, Kaufman J, Ward R . Race and genomics. N Engl J Med. 2003; 348(12):1166-70. DOI: 10.1056/NEJMsb022863. View

19.

Torkamani A, Topol E, Schork N . Pathway analysis of seven common diseases assessed by genome-wide association. Genomics. 2008; 92(5):265-72. PMC: 2602835. DOI: 10.1016/j.ygeno.2008.07.011. View

20.

Kang S, Chiang C, Palmer C, Tayo B, Lettre G, Butler J . Genome-wide association of anthropometric traits in African- and African-derived populations. Hum Mol Genet. 2010; 19(13):2725-38. PMC: 2883343. DOI: 10.1093/hmg/ddq154. View