Angiotensinogen Single Nucleotide Polymorphisms, Elevated Blood Pressure, and Risk of Cardiovascular Disease

Abstract

Abstract-In this study of 10 690 individuals, associations with elevated blood pressure, ischemic heart disease, and ischemic cerebrovascular disease were determined for two noncoding [A(Ϫ20)C, G(Ϫ6)A] and two coding (T174M, M235T) single nucleotide polymorphisms, analyzed alone and in combination (haplotypes). Participants from the general population with (nϭ4950) and without (nϭ4234) elevated blood pressure were compared (study 1), as were participants from the general population without ischemic heart disease and ischemic cerebrovascular disease (nϭ7965) and cases with either ischemic heart disease (nϭ1850, study 2) or ischemic cerebrovascular disease (nϭ848, study 3). Finally, 22-year follow-up of 9184 individuals from the general population examined risk of ischemic heart disease (study 4) and ischemic cerebrovascular disease (study 5). Individuals with Ϫ6AA, 174TT, or 235TT had plasma angiotensinogen levels increased by 80 ng/mL (Pϭ0.01 and 0.05 for women and men) compared with individuals with Ϫ6GG, 174TT, or 235 MM. In women, this difference was associated with an odds ratio of elevated blood pressure of 1.25 (1.03 to 1.51), which increased to 1.63 (1.05 to 2.51) in postmenopausal women receiving hormone replacement therapy. The promoter single nucleotide polymorphisms alone or as haplotypes did not predict the continuous variables of systolic, diastolic, or pulse pressure in cross section or the risk of ischemic heart disease or ischemic cerebrovascular disease in either gender in case-control or prospective studies. Individuals with Ϫ6AA, 174TT, or 235TT in the angiotensinogen gene have increased plasma angiotensinogen levels and moderately increased risk of elevated blood pressure (women only) but unaltered blood pressure examined as a continuous variable and unaltered risk of ischemic heart disease and ischemic cerebrovascular disease. Key Words: blood pressure Ⅲ hypertension, genetic Ⅲ cardiovascular diseases Ⅲ cerebrovascular disorders S ingle nucleotide polymorphisms (SNPs) in the angiotensinogen gene have been associated with elevated angiotensinogen levels, 1 elevated blood pressure, 1 ischemic heart disease (IHD), 2 and ischemic cerebrovascular disease (ICVD). 3 In the Copenhagen City Heart Study, 4 we have previously shown that the M235T SNP (T-allele) was associated with elevated plasma angiotensinogen levels in both genders and a 30% increased risk of elevated blood pressure in women homozygous for 235T. However, the risk of IHD and ICVD was not associated with variation in genotype. 5 SNPs in the transcription factor binding region (Ϫ25 to Ϫ1) of the angiotensinogen gene promoter have been reported to affect gene expression. 6 -8 The Ϫ6A SNP has been associated with increased gene transcription, 8,9 elevated blood pressure, and increased risk of IHD in some 10 -12 but not in all studies, [13][14][15] whereas the Ϫ20C SNP has been associated with increased gene transcription, elevated angiotensinogen levels, and elevated blood pressure in one 7 but not in other studies. 1,10,15 These ...

Both angiotensinogen M235T and α-adducin G460W polymorphisms are associated with hypertension in the Japanese population

“…The reason we found a distinct association between the angiotensinogen polymorphism and hypertension, with fewer subjects compared with those of Sethi et al 8 may be related to the fact that the salt intake in the Japanese population is much higher than that in the Western population, and the T allele frequency is also higher in the Japanese than that in the Western population. A report from the INTERMAP Study showed that the 24 h urinary sodium excretion was 211757 mmol/day for Japanese men, 186753 mmol/day for Japanese women, 183762 mmol/day for men in the US and 142748 mmol/day for women in the US.…”

“…1,2 Despite the several earlier reports, later studies on the association between these polymorphisms and hypertension reported conflicting results. [3][4][5][6][7][8] Studies in the Japanese population on the association between these salt-sensitivity related gene polymorphisms and hypertension may warrant special attention. Salt consumption by the Japanese is relatively high compared to other populations 9 and also they have a higher 235T allele frequency than M of the angiotensinogen M235T polymorphism, the former has been related to hypertension.…”

“…What is known about this topic K Both the angiotensinogen M235T and the a-adducin G460W polymorphisms have been reported to be linked to sodium retention (1-2) K Despite the earlier pioneers' works, later studies, including those in the Japanese population whose salt consumption has been relatively high, regarding the association between these polymorphisms and hypertension, have reported conflicting results (3)(4)(5)(6)(7)(8) What this study adds K Both the angiotensinogen M235T and the a-adducin G460W polymorphisms were associated with hypertension; independent of the classical hypertension risk factors in the Japanese…”

The effect of genetic variation in angiotensinogen on serum levels and blood pressure: a comparison of Nigerians and US blacks

“…Although significant associations between the 235T/À6A variants and HT have been reported in European and Asian populations, 28 it was not until recently that an association between a particular AGT haplotype and HT was observed in African Americans. 13,[29][30][31] Two recent studies involving African-American samples reported associations between the H1 haplotype (the variants that defined the associated haplotype in both studies are the ones that define our H1) and HT.…”

Association between the p22phox −930A/G polymorphism and blood pressure in normotensive subjects

“…Metaanalyses failed to show consistent findings regarding the association between polymorphisms in the RAAS genes and hypertension or elevation in blood pressure. [6][7][8][9] Oxidative stress is a status of excessive production of reactive oxygen species overwhelming antioxidant defense mechanisms. A number of studies have suggested that oxidative stress is deeply involved in the pathogenesis of hypertension.…”