Genetic influence of the R/Q353 genotype on factor VII activity is overwhelmed by environmental factors in Chinese patients with Type II (non-insulin-dependent) diabetes mellitus

Abstract

Diabetes mellitus is associated with a two to threefold increase in cardiovascular mortality [1]. The mechanism whereby diabetes increases cardiovascular risk is probably multifactorial. Recent studies suggest that this may in part be attributed to an increase in thrombotic tendency [2] including an increase in circulating level of factor VII, a key enzyme in the initiation of coagulation. A positive correlation between increased factor VII activity and cardiovascular mortality has been shown in the Northwick Park Heart Study [3]. A similar trend Diabetologia (1998) In both diabetic and control subjects the allele frequencies of the R (M1) and Q (M2) alleles were 0.96 and 0.04; the corresponding reported frequencies in Caucasians being 0.90 and 0.10: VIIc were 21 % lower in Chinese control subjects and Type I diabetic patients with R/Q, compared with R/R subjects (p < 0.001 and p < 0.05). The corresponding difference was 4 % for Type II diabetc patients (p = NS). Type II diabetic patients had higher mean VIIc levels than control subjects and Type I diabetic patients (p < 0.01); they were also older, and had higher serum creatinine and triglyceride (all p < 0.01). They also had higher VIIc levels than an age-matched older control group (p < 0.01; n = 182) in whom the genotype effect was clearly seen. On stepwise linear regression analysis, the significant independent determinants of VIIc were serum triglyceride (contributing 20 % and 25 % to variance in control subjects and diabetic patients), the R/Q353 genotype (contributing to 12 % of the variance in control subjects but only 1 % in diabetic patients), age and total cholesterol in all subjects, and in the diabetic patients female sex, urinary albumin excretion rate and serum creatinine. VIIc was higher in diabetic patients with macroangiopathy and retinopathy (both p < 0.0001). We conclude that compared with Caucasians, the Q allele frequency is significantly lower in these Chinese subjects. Plasma VIIc is determined by both genetic and environmental influences such that in Chinese Type II diabetic patients, the effect of environmental factors predominates, almost negating the influence of the R/Q353 genotype. High VIIc may contribute to the increased cardiovascular risk in Type II diabetic patients. [Diabetologia (1998) 41: 760±766]

β-fibrinogen gene G/A-455 polymorphism in relation to fibrinogen concentrations and ischaemic heart disease in Chinese patients with Type II diabetes

“…The allele frequency of the less frequent A allele was 27 %, comparable with the frequencies of 21 % [3] and 27 % [5] reported for Europeans. It is well known that genetic and environmental factors interact in determining plasma concentrations of haemostatic factors [7,8]. In this study, the effect of the AA genotype was strongest among male control subjects, in keeping with a gender-genotype interaction [8].…”

“…It is well known that genetic and environmental factors interact in determining plasma concentrations of haemostatic factors [7,8]. In this study, the effect of the AA genotype was strongest among male control subjects, in keeping with a gender-genotype interaction [8]. The higher fibrinogen concentrations in women has been attributed to environmental influences such as the menopause or oral contraceptives [7].…”

“…All subjects were unrelated southern Chinese with Type II diabetes (n = 264; 130 men and 134 women, aged 52.4 ± 16.2 years, mean ± SD). To provide an age-matched control group, data from 182 non-diabetic subjects were retrieved from the database of the Hong Kong Cardiovascular Risk Factor Prevalence Study [8] for comparative analysis. Studies were conducted after informed consent had been obtained from the subjects.…”

“…DNA was extracted from leucocytes in 5±10 ml EDTA blood as reported [8]. A 1.3 kb portion of the b-fibrinogen gene, spanning from ±1178 bp from the start of transcription to + 122 bp, was amplified by polymerase chain reaction, digested with Hae III, and the resultant fragments analysed as described [4±7].…”

“…Fibrinogen was measured by the Clauss method [6] on the Cobas Fibro (Roche Diagnostics, Nutley, N. J., USA) using fresh trisodium citrated samples. Fasting blood samples for HbA 1 c , creatinine, lipids and apolipoproteins were measured using standard methods as described [8]. Mean albumin excretion rate (MAER), assayed nephelometrically, was estimated from two consecutive 12-h overnight urine collections.…”