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1 National Taiwan University College of Medicine, Graduate Institute of Physiology, Taipei, Taiwan
2 National Taiwan University Hospital and National Taiwan University College of Medicine, Department of Internal Medicine, Taipei, Taiwan
3 National Taiwan University College of Public Health, Institute of Epidemiology, Taipei, Taiwan
4 National Taiwan University College of Medicine, Graduate Institute of Physiology, Taipei, Taiwan; National Taiwan University Hospital and National Taiwan University College of Medicine, Department of Internal Medicine, Taipei, Taiwan
* To whom correspondence should be addressed. E-mail: yztseng{at}ha.mc.ntu.edu.tw.
Although some single polymorphism analyses of the angiotensinogen (AGT) gene have been found to be associated with hypertension, the results are still inconsistent. The objectives of this study are to evaluate the association of the genotype and haplotype distributions of three single-nucleotide polymorphisms (SNPs) (G-217A, A-6G, and M235T) in the AGT gene with hypertension. In a sample of 461 hypertensive patients and 327 normotensive subjects in Taiwan, we found that -217AA and -6GG homozygotes conferred independently an increased risk to hypertension (P = 0.008 and P = 0.037, respectively) as illustrated by their significant associations with hypertension in both single SNP and pair-wise SNPs analyses. Meanwhile, a very weak linkage disequilibrium was found between the G-217A and the A-6G polymorphisms in terms of r2
(< 0.05). On the basis of likelihood ratio test, only the set of haplotypes constituted of the A-6G and the M235T polymorphisms was associated with hypertension (
2 = 20.91, P = 0.0008), which was mainly due to the increased frequency of the recombinant haplotypes (-6A=235M and -6G=235T) and a pathophysiological role in the predisposition to hypertension was hence indicated. In functional assays, the promoter activities of the haplotypes -217A=-6A and -217G=-6G were significantly higher than the most common haplotype -217G=-6A. These results highlight the necessity of a thorough analysis of all reported variants of a candidate gene in the elucidation of genetic susceptibility to a complex disease like hypertension, even when the variants are in the same haplotype block.
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