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Genetics & hypertension.

Hypertension is a complex disease involving interaction of many risk genes and environmental factors such as obesity, dietary salt intake, alcohol consumption, and stress. Approximately 20 to 60 per cent of the population variability in blood pressure is genetically determined (1). In the last decade, a large number of candidate genes have been tested for association with blood pressure and hypertension without convincing results.

Polymorphisms in genes of renin-angiotensin-aldosterone system (RAAS) comprising of angiotensinogen (AG7), angiotensin-converting enzyme (ACE), angiotensin II receptor type 1 (AT1R), and aldosterone synthase (CYP11B2) genes have been the most commonly studied for association with various aspects of hypertension. No single gene within the RAAS appears to predominate in the association studies and there appears to be an increasing complexity and sophistication in association studies involving RAAS. Haplotypes involving several polymorphisms in a single gene have been found to be better predictors than a single nucleotide polymorphism (SNP) (2). Further, adding to complexity are the observations that these genetic associations may vary according to hypertensive phenotypes (systolic, diastolic or pulse-components), with age and gender as confounding elements (3). For example, ACE gene polymorphism was specifically found to be associated with reduced diastolic blood pressure in men who were older than 50 years (4).

Amongst RAAS genes studied till date, CYP11B2 gene (CYP11B2) encoding aldosterone synthase has emerged as a strong candidate gene for hypertension. To date, three common genetic variants of the aldosterone synthase gene (CYP11B2) have been identified as possible determinants of high blood pressure in patients with essential hypertension (5,6). These are: (i) a single nucleotide polymorphism in the 5' promoter region at -344T/C; (ii) a polymorphism involving intron 2 of CYP11B2, which is partly replaced by the corresponding intron of CYP11B1 gene; and (iii) a point mutation K173R in exon 3. There are conflicting reports of association between -344T/C polymorphism and essential hypertension. A meta-analysis concluded that carriers of -344C CYP11B2 allele are at 17 per cent lower risk of hypertension with respect to homozygous TT subjects (7). However, Tang et al (8) suggested that the C allele may be associated with genetic predisposition to hypertension in Hani and Yi minorities in China. Several factors such as ethnicity, gender and age could be involved in the phenotypic expression of this polymorphism. The study by Rajan et al (9) in this issue shows significant association between CYP11B2 gene polymorphism and essential hypertension in male south Indian Tamil population. These results further support a potential role of -344T/C CYP11B2 gene polymorphism in hypertension. However, more large scale studies are needed in different populations to confirm these results. The exact mechanism, whereby the -344T/C polymorphism of CYP11B2 gene variant may lead to higher blood pressure remains unknown. It has been suggested that the -344T/C variant by itself does not directly influence promoter activity rather, binding of steroidogenic factor-1 (SF-1) to this site downregulates activity of CYP11B2 promoter by making SF-1 less available to functionally affect other CYP11B2 promoter sites, which could alter expression of the gene (10). Moreover, in vitro studies showed that C allele binds SF-1 four-fold more strongly than it does the T allele and this may allow a change in CYP11B2 promoter activity and expression (11).

Are polymorphisms of the RAAS genes equally associated with hypertension in all ethnic groups? This does not appear to be the case as is evident from lack of replication of association of risk variants in different ethnic populations.

Since hypertension has a complex pathophysiology involving multiple pathways that modulate blood pressure, it is being increasingly observed that genetics of hypertension is not based on single gene of major effect, rather epistatic interactions among multiple genes with mild to moderate effects may contribute to its pathophysiology.

Availability of fast and cost-effective genotyping technologies has resulted in examining hundreds of thousands single nucleotide polymorphisms across the whole genome in genome wide association studies (GWAS). To date, 12 GWAS on blood pressure and hypertension have been published, mostly on participants of European origin (12). Only two studies (CHARGE BP and Global BP Gen) have identified association of 14 independent loci for blood pressure traits that reached genome-wide significance, including replication in independent cohorts of European origin (13-15). The 14 loci are in or near genes encoding six enzymes (including three kinases and one cytochrome), two solute channels, two transcription factors, one growth factor, and one cell signaling protein, one structural protein, and one hypothetical gene. Out of these, only two, CYP17A1 (cytochrome P450, family 17, subfamily A) and MTHFR, are previously studied candidate genes, while others include previously largely unsuspected but plausible biologic candidates genes whose role in blood pressure regulation still needs to be confirmed.

Thus, it appears that there is no single significant hypertension gene; rather many genes act conjointly to confer a significant risk of high blood pressure. It is being proposed that a risk score comprising the most significantly associated variants for each blood pressure phenotype may be developed and evaluated for epistatic effect amounts to several millimeters mercury of blood pressure (13).

Inspite of availability of genomic tools that allow fast and reliable genotyping of hundreds of thousands of variants across the human genome, translation of the observed genetic information to be clinically relevant remains elusive. Several factors such as lack of quantification of gene-environment interactions; involvement of yet unknown biologic pathways, under powered studies and polygenic nature of blood pressure trait may be the limitations as seen in other complex diseases, however, these limitations may change in the future. Large scale genome wide association studies, replication studies in larger and different ethnic populations and formation of blood pressure consortiums will help in better understanding of the genetics of blood pressure and hypertension, with potential benefits for prediction, diagnosis, and treatment.

References

(1.) Ward R. Familial aggregation and genetic epidemiology of blood pressure. New York: Raven Press; 1995.

(2.) Bouzekri N, Zhu X, Jiang Y, McKenzie CA, Luke A, Forrester T, et al. Angiotensin I-converting enzyme polymorphisms, ACE level and blood pressure among Nigerians, Jamaicans and African-Americans. Eur J Hum Genet 2004; 12: 460-8.

(3.) Yagil Y, Yagil C. The search for the genetic basis of hypertension. Curr Opin NephrolHyperten 2005; 14: 141-7.

(4.) Rudnichi A, Safar ME, Lajemi M, Benetos A. Gene polymorphisms of the reninangiotensin system and age-related changes in systolic and diastolic blood pressure in subjects with hypertension. Am J Hypertens 2004; 17: 321-7.

(5.) White PC, Slutsker L. Haplotype analysis of CYP11B2. Endocr Res 1995; 21: 437-42.

(6.) Zhu H, Sagnella GA, Dong Y, Miller IMA, Onipinla A, Makandu ND, et al. Contrasting associations between aldosterone synthase gene polymorphisms and essential hypertension in blacks and in whites. J Hypertens 2003; 21: 87-95.

(7.) Sookoian S, Gianotti TF, Gonzalez CD, Pirola CJ. Association of the C-344T aldosterone synthese gene variant with essential hypertension: a meta-analysis. J Hypertens 2007; 25: 5-13.

(8.) Tang W, Wu H, Zhou X, Cheby B, Dong Y, He L, et al. Association of the C-344T polymorphism of CYP11B2 gene with essential hypertension in Hani and Yi minorities of China. Clin Chim Acta 2006; 364: 222-5.

(9.) Rajan S, Ramu P, Umamaheswaran G, Adithan C. Association of aldosterone synthese (CYP11B2 C-344T) gene polymorphism & susceptibility to essential hypertension in a south Indian Tamil population. Indian J Med Res 2010; 132: 379-85.

(10.) Clyne CD, Zhang Y, Slutsker L, Mathis JM, White PC, Rainey WE. Angiotensin II and potassium regulate human CYP11B2 transcription through common cis-elements. Mol Endocrinol 1997; 11: 638-49.

(11.) Matsubara M, Kikuya M, Ohkubo T, Metoki H, Omori F, Fujiwara T, et al. Aldosterone synthase gene (CYP11B2) C-344T polymorphism, ambulatory blood pressure and nocturnal decline in blood pressure in the general Japanese population: the Ohasama Study. J Hypertens 2001; 19: 217-984.

(12.) Ehret GB. Genome-Wide Association Studies: Contribution of genomics to understanding blood pressure and essential hypertension. Curr Hypertens Rep 2010; 12: 17-25.

(13.) Levy D, Ehret GB, Rice K, Verwoert GC, Launer LJ, Dehghan A, et al. Genome-wide association study of blood pressure and hypertension. Nat Genet 2009; 41: 677-87.

(14.) Newton-Cheh C, Johnson T, Gateva V, Tobin MD, Bochud M, Coin L, et al. Genome-wide association study identifies eight loci associated with blood pressure. Nat Genet 2009; 41: 666-76.

(15.) Wang Y, O'Connell JR, McArdle PF, Wade JB, Dorff SE, Shah SJ, et al. Whole-genome association study identifies STK39 as a hypertension susceptibility gene. Proc Natl Acad Sci USA 2009; 106: 226-31.

Madhu Khullar

Department of Experimental Medicine & Biotechnology

Postgraduate Institute of Medical Education & Research

Chandigarh 160 012, India

madhu.khullar@gmail.com
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Title Annotation:Commentary
Author:Khullar, Madhu
Publication:Indian Journal of Medical Research
Article Type:Report
Geographic Code:9INDI
Date:Oct 1, 2010
Words:1422
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