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The β-adrenoceptor (β-AR)-stimulatory guanine nucleotide-binding (Gs) protein system has been shown to play important roles in the cardiovascular system. The gene encoding the α-subunit of Gs proteins (GNAS1) is a candidate genetic determinant for hypertension. Because alcohol consumption is known to affect blood pressure partly through the β-AR-Gs protein system, we examined the possible interaction between GNAS1 T393C polymorphism and drinking status in the association with hypertension in the present study. As a result, a non-significant but reasonable trend supporting the presence of an interaction was shown (p =0.076). In line with this trend, the T393C polymorphism significantly interacted with drinking status in the association with systolic blood pressure (p =0.028). Moreover, supporting the presence of an interaction, T allele carriers consistently had a higher probability of hypertension, higher systolic blood pressure, and higher diastolic blood pressure than CC homozygotes in non-drinkers and light drinkers. In contrast, CC homozygotes consistently had a higher probability of hypertension, higher systolic blood pressure, and higher diastolic blood pressure than T allele carriers in moderate to heavy drinkers. The present study also showed a significant interaction between the T393C polymorphism and drinking status in the association with pulse pressure (p =0.026), reflected by a significant association between the T393C polymorphism and pulse pressure in moderate to heavy drinkers (p =0.026). These findings may be helpful in conducting further molecular and biological studies on the relationship among the effects of alcohol, the β-AR-Gs protein system, and hypertension. (Hypertens Res 2003; 26: 439-444)

The renin-angiotensin system plays an important role in blood pressure regulation by influencing salt-water homeostasis and vascular tone. Angiotensin II, the major biologically active component of this system, exerts its effect via two pharmacologically distinct subtypes of angiotensin II receptors, the angiotensin II type 1 receptor (AT1-R) and the angiotensin II type 2 receptor (AT2-R). Thus, the AT2-R gene may be involved in hypertension. Accordingly, our objective was to examine whether polymorphisms of the AT2-R gene are involved in hypertension. The entire AT2-R gene including the promoter region was screened to find polymorphisms. As a result, two novel single nucleotide polymorphisms (SNPs), A1818T in intron 2 and G4303A in exon 3, as well as two known SNPs, A1675G in intron 1 and C4599A in exon 3, were identified. These four SNPs had similar allele frequencies, and the A1675G and C4599A polymorphisms were in almost complete linkage disequilibrium. Because the AT2-R gene is located on the X chromosome, we analyzed the possible association between the C4599A polymorphism and hypertension in men and in women separately in two large Japanese populations. This analysis showed that the C4599A polymorphism was associated with hypertension in women (p=0.0058), but not in men. Moreover, this female-specific association was pronounced in premenopausal women. The female-specific association may be helpful in conducting further molecular and biological studies on the relationship among sex, the renin-angiotensin system, and hypertension.

Hypertension is a common, complex phenotype resulting from the interaction between genetic and environmental factors. To select candidate regions potentially responsible for hypertension, we are conducting a genome-wide linkage disequilibrium (LD) mapping of hypertension using dinucleotide repeat markers in 146 hypertensive and 136 normotensive subjects. Although the LD mapping is still underway, 19 alleles of 15 markers have already shown a nominally significant association (p