Hypertension and genes: perspectives from this journal

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Hypertension is a complex multifactorial disorder with many genetic, environmental and demographic factors contributing to this disorder. As recently reviewed by Tanira and Balushi, the genetic element contribution to blood pressure variation ranges from 30 to 50%. There is therefore a viewpoint that identifying hypertension susceptibility genes would contribute to understanding the pathophysiology of the disorder, as well as targeted preventative strategies. The quest to find ‘a geney’(or genes) for hypertension has long been the Holy Grail, as reflected by the many publications in the Journal of Human Hypertension, on this topic (see Supplementary Table 1). Given that hypertension is a growing global healthcare issue many efforts have been directed towards understanding the aetiology and pathogenesis of this condition. Several research strategies have been explored to dissect the genetic determinants of hypertension and it is more likely that a number of genes rather than a single gene would account for the heritability of this genetically complex disease. One such research strategy is the ‘candidate gene’ approach and one of the most extensively studied pathways is the renin–angiotensin–aldosterone system (RAAS). Genes related to the RAAS pathway have been of considerable interest as candidate genes associated with essential hypertension, including the angiotensin 1-converting enzyme (ACE) and the angiotensinogen (AGT) gene. Recent studies conducted in relation to genetic susceptibility to hypertension suggest that the AGT gene has relatively more consistent positive associations. For example, Nakamura et al. reported that the M235T genetic variant of the AGT gene was associated with an increased risk of hypertension in Japanese population, but this association is not always observed in other ethnic populations, such as Australian Anglo-Celtic Caucasians or black AfroCaribbeans. Studies carried out on the ACE I/D polymorphisms are also conflicting—some show gender-specific associations, while others show that the D allele significantly increases the risk of hypertension in men of European and Japanese origin. One pathway that has been associated with hypertension is the G-protein/signal transduction pathway system. Until recently, the C825T polymorphism in the b3-subunit of G-protein gene (GNB3) has been significantly linked with essential hypertension in Africans and Caucasians. However, similar studies among Asians have presented conflicting results, perhaps due to the genetic and environmental heterogeneity among different ethnic backgrounds. Indeed, Bae et al. recently studied interactions between the GNB3 C825T and ACE I/D polymorphisms in essential hypertension in Koreans, and concluded that there was a significant interaction between the allelic variants GNB3 825T and ACE D, which may contribute to the genetic predisposition to essential hypertension in Koreans. There are also reported associations between molecular variants of AGT and serum levels of AGT and hypertension, but the results are similarly inconsistent, even between and within study populations. In one study, an association analysis using a selected set of single-nucleotide polymorphisms representing the overall haplotypes of AGT gene with AGT levels and hypertension did show that the two distantly related haplotypes 532T/235T and 6G/235M were associated with hypertension but had opposite effects on the serum AGT levels in the two studied populations of African origin which were genetically similar but environmentally diverse. An association between AGT haplotype containing 532T and hypertension was observed among African Americans, which was consistent with previous studies. Perhaps attention should be directed towards target organ damage consequent upon hypertension. A family-based study conducted in three populations (Polish, Russian and Italian) reported a positive association between left ventricular mass index (LVMI) and mean wall thickness with the AGT 532T allele in Slavic male offspring but not in Italians. This study is therefore more in agreement with the concept that phenotype–genotype Correspondence: Dr Jeetesh Patel, Sandwell Medical Research Unit, Sandwell Hospital, Lydon, West Bromwich, UK. E-mail: Jeetesh.Patel@swbh.nhs.uk Published online 9 August 2007 Journal of Human Hypertension (2007) 21, 851–853 & 2007 Nature Publishing Group All rights reserved 0950-9240/07 $30.00