G protein β3 subunit gene variant, twenty-four-hour blood pressure, and hypertensive cerebrovascular disease in a Japanese population

Recently, a few papers on the relationship between the G protein β3 subunit gene variant, a C to T change at nucleotide 825 of exon 10 of the gene encoding the β3 subunit of heterotrimeric G proteins (GNB3 825T), and hypertension have been published.1,2,3 This gene variant was first reported by Siffert et al1 to be associated with enhanced intracellular signal transduction and hypertension in a German population. Hegele et al2 reported that this variant was associated with lower systolic blood pressure (BP) in a young, essentially normotensive study sample of aboriginal people (a Canadian Oji-Cree population). These two studies show quite different results both in the gene frequency of the 825T allele (0.50 in Canadian Oji-Cree population v 0.25 in a German population) and in the relationship with BP level. In addition to the establishment of hypertension, the increased intracellular transduction caused by this G protein variation may contribute to hypertensive target organ damage. There are marked racial differences in cardiovascular disease between whites and Japanese; Japanese show a much lower incidence of coronary artery disease, but a higher incidence of cerebrovascular disease, especially that associated with underlying hypertension. We investigated the association between GNB3 825T, hypertension, and ischemic stroke in the Japanese population. We studied 189 hypertensive patients with office systolic BP ≥140 mm Hg or office diastolic BP ≥90 mm Hg [120 asymptomatic patients and 69 patients with clinically overt cerebral infarction (cerebral infarction group)] and 106 normotensive healthy control subjects (normotensive group). For the assessment of silent hypertensive cerebrovascular disease, brain magnetic resonance imaging (MRI) was performed in all 120 asymptomatic hypertensive patients, and they were classified into a hypertensive noninfarction group without any lacunae (n = 81), or a hypertensive silent infarction group with one or more lacunae (n = 39), as described previously.4 The subjects all resided in the same district (Awaji-Hokudan), and did not include any first-degree relatives. The cerebral infarction was diagnosed when neurologic deficits were accompanied by corresponding abnormal findings depicted by brain computed tomography, MRI, or magnetic resonance angiography on the basis of the clinical categories delineated in the National Institute of Neurological Disorders and Stroke, as described previously.5 We also performed 24-h ambulatory BP monitoring in the 106 subjects who were normotensive and the 161 hypertensive subjects who were untreated or whose antihypertensive therapy could be stopped for at least 7 days before the study, as described previously.4 Genomic DNA was extracted from citrated whole blood using salt/chloroform by a modification of a previously described method,6 and GNB3 825T was identified by the method modified polymerase chain reaction method.1 The genotype distribution was in Hardy-Weinberg equilibrium and the calculated gene frequency of the GNB3 825T allele in the normotensive Japanese was 0.55. This value is very similar to that of the Canadian Oji-Cree population (0.50) and is much higher than that of the German population (0.25). Kato et al3 reported that this gene frequency is 0.50 in normotensives, 0.49 in hypertensives, and 0.49 in hypertensives with impaired glucose tolerance or diabetes in a Japanese population. Thus, the distribution of this allele shows marked racial differences, suggesting that the mutation coding the 825T allele spread as a founder effect. In the present study there were no significant differences in the gene frequency of the 825T allele among the normotensive group (0.55), the hypertensive noninfarction group (0.53), the hypertensive silent infarction group (0.49), or the cerebral infarction group (0.54). When we divided the total subjects studied into the CC group (homozygotes of normal G protein β3 subunit 825C allele, n = 51), the TC group (heterozygote with 825T variant, n = 144), and the TT group (homozygote with 825T variant, n = 72), there were no differences in age (mean ± SD; 70 ± 9.0, 69 ± 12, and 72 ± 11 years, respectively) and distribution of men (36%, 31%, and 34%, respectively) among each group (CC, TC, and TT, respectively). There were also no differences in 24-h ambulatory BP monitoring (mean ± SD) (office systolic BP, 145 ± 24, 151 ± 27, and 147 ± 27 mm Hg; office diastolic BP, 84 ± 17, 86 ± 15, and 85 ± 15 mm Hg), the average 24-h BPs (systolic BP, 134 ± 15, 135 ± 16, and 133 ± 16 mm Hg; diastolic BP, 76 ± 8.8, 77 ± 10, and 75 ± 9.1 mm Hg; CC, TC, and TT group, respectively). When the ambulatory BPs were divided into daytime and nighttime, there were still no differences among the three genotype groups (data not shown). There were also no differences in the prevalence of hypertension defined using office BP (57%, 65%, and 54%, respectively) and sustained hypertension defined as ≥135 mm Hg for 24-h systolic BP or ≥80 mm Hg for 24-h diastolic BP (43%, 46%, and 39%, respectively) among the three groups (CC, TC, and TT, respectively). There were no significant differences in body mass index (24.7 ± 4.2, 23.5 ± 3.4, 23.5 ± 3.3 kg/m2, respectively) or its relationships with office and 24-h BPs among three groups (CC, TC, and TT, respectively). In addition, there were also no significant differences in the distribution of left ventricular hypertrophy diagnosed by electrocardiogram (18%, 14%, and 15%, respectively), and levels of cardiovascular risk factors including total cholesterol, HDL-cholesterol, hematocrit, fibrinogen, and creatinine (data not shown). The limitations of this study are the relatively small number of subjects studied. However, in the analysis between the hypertensive group (n = 189) and the normotensive group (n = 106), for example, we had 94% power to detect a difference of 0.50 v 0.65 in allele frequencies, using an α = 0.05 two-tailed χ2 test. In conclusion, although we could not address the association between the 825T allele and the risk of coronary artery disease in Japan, given the absence of associations of this allele with hypertension and cerebrovascular disease in the 295 Japanese subjects studied, this allele seems to have a less important influence on hypertension and hypertensive target organ damage and cardiovascular events in Japan than has been reported in other societies.1,2 The consistency of the relationships of GNB3 825T allele, hypertension, and cardiovascular disease in different racial populations and the pathologic relevance still need to be assessed by larger prospective association studies or linkage-based family studies.