T594M and G442V polymorphisms of the sodium channel beta subunit and hypertension in a black population.

Polymorphisms of the epithelial sodium channel may raise blood pressure by increasing renal sodium reabsorption. This study examines frequency distributions and associations with hypertension of the T594M and of the G442V polymorphisms of the beta subunit of the epithelial sodium channel in a population-based sample. We studied a stratified random sample of 459 subjects (279 women), aged 40-59 years, of black African origin from general practices' lists within a defined area of South London. All were first generation immigrants. The polymorphic variants were detected using single strand conformational polymorphism technique (SSCP). The prevalence of hypertension (BP > or =160 and/or 95 mm Hg or on drug therapy) was 43%; of these, 76% were on drug therapy. The main analysis was carried out by three ordered blood pressure categories (I to III) according to increasing blood pressure and presence or absence of drug therapy. The frequency of the 594M variant (heterozygotes and homozygotes) was 4.6%; the frequency of the 442V variant was higher (27.0%). The frequency of the 594M variant increased with increasing blood pressure category (P = 0.05) and was more common in hypertensives than normotensives. By contrast the frequency of the 442V variant did not vary across increasing blood pressure categories (P = 0.62). No gender difference was observed. Adjustment for age, sex and body mass index did not alter these findings. These results suggest that the 594M variant may contribute to high blood pressure in black people of African origin whereas the G442V polymorphism is unlikely to influence blood pressure in this population.

Ethnic differences in fibrinogen levels: the role of environmental factors and the beta-fibrinogen gene.

Fibrinogen is a cardiovascular risk factor, but little is known about levels in ethnic groups that differ in their cardiovascular risk. Fibrinogen was measured in 479 Black individuals, 459 South Asian Indians, and 453 Whites aged 40-59 years living in south London, England, from March 1994 to July 1996. Genotype was determined at two sites in the promoter of the beta-fibrinogen gene (G-455-->A and C-148-->T). Plasma fibrinogen levels were lower in Blacks than in Whites by 0.22 g/liter (95% confidence interval (CI): 0.08, 0.36) in men and 0.11 g/liter (95% CI: -0.01, 0.23) in women. These differences were not explained by measured environmental variables, including smoking, or by genotypes. The fibrinogen levels of South Asians were not consistently different from those of WHITES: The A-455 and T-148 alleles were less common in Blacks than in either Whites or South ASIANS: In Whites and South Asians, but not in Blacks, there was complete allelic association between the two variants. In Blacks, the T allele rather than the A allele was associated with higher fibrinogen levels. The average fibrinogen-raising effect of the T-148 allele across all ethnic groups was 0.14 g/liter (95% CI: 0.02, 0.26 g/liter) in women and 0.15 g/liter (95% CI: 0.03, 0.27 g/liter) in men. Low fibrinogen levels in Blacks may partly explain their lower risk of ischemic heart disease in the United KINGDOM:

Variable effects of the APOC3-482C > T variant on insulin, glucose and triglyceride concentrations in different ethnic groups.

AIMS/HYPOTHESIS: The apolipoprotein C3-482C> T variant modulates insulin and glucose concentrations after an oral glucose tolerance test (OGTT) in young healthy white men. We evaluated the effect of this variant in different ethnic groups with different rates of Type II (non-insulin-dependent) diabetes mellitus and coronary heart disease. METHODS: We investigated the -482C > T in a population-based cross-sectional study of white subjects (n = 462), South Asians (n = 442) and subjects of West African and Afro-Caribbean origin (n = 462), whose OGTT and fasting plasma triglyceride concentrations had been measured. RESULTS: The -482T allele frequency differed between the three groups: 0.25 (95 % CI 0.22-0.28) in white subjects, 0.44 (0.41-0.47) in South Asians and 0.71 (0.68-0.74) in black subjects (p < 0.0001). A positive association was found between body mass index and genotype in black women (p = 0.009) and in black men (p = 0.056) but not in white subjects or South Asians. Associations between -482C > T and fasting insulin were found in white subjects, where -482T allele carriers had higher concentrations (adjusted for age and sex, p = 0.007, also including smoking and body mass index, p = 0.038). Higher triglyceride concentrations (p = 0.004 and p = 0.007 in the two models) but not glucose concentrations were also associated with -482C > T. In black subjects, decreased fasting insulin (p = 0.04) and fasting glucose (p = 0.004) were associated with -482C > T. No relation was observed between genotype and any post-load measured. CONCLUSIONS/INTERPRETATION. Allele frequencies of the -482C > T and associations with insulin, glucose and triglyceride concentrations vary considerably among ethnic groups. Although the results are consistent among white subjects across different studies, the associations among black subjects and South Asians differ.

Frequency and allelic association of common variants in the lipoprotein lipase gene in different ethnic groups: the Wandsworth Heart and Stroke Study.

The lower serum triglyceride (Tg), higher high density cholesterol (HDL-C) levels and low coronary heart disease (CHD) mortality in black populations, contrast with that in whites. By comparison, South Asian populations display a higher mortality from CHD associated with increased Tg and low HDL-C levels. Lipoprotein lipase (LPL) plays a major role in Tg metabolism. To determine if variation in the LPL gene contributes to the differences in lipid levels, we studied the frequencies and allelic associations of five common variants in the lipoprotein lipase (LPL) gene (-93T/G, D9N, N291S, S447X, and the HinddIII RFLP in intron 8) with serum Tg and HDL-cholesterol concentrations in population samples of middle-aged men and women of whites, South Asians, and blacks of African origin co-resident in South London. Significantly higher frequencies of the H(-) (P < 0.00001), N9 (P < 0.001), and -93G (P < 10(-10)) alleles were seen in blacks compared to the other two groups. Allelic association between -93G and N9, and H(+) and X447 was strong in all three groups. However, no association was observed between serum Tg and HDL-cholesterol concentrations and these variants in the three ethnic groups. A single common polymorphism in the LPL gene is unlikely to account for the differences in fasting serum Tg in populations of different ethnic background. The importance of the differences in frequencies and the mechanism(s) whereby these may contribute towards a beneficial LPL genotype in black populations remain to be determined.

Impact of the new American Diabetes Association and World Health Organisation diagnostic criteria for diabetes on subjects from three ethnic groups living in the UK.

BACKGROUND AND AIM: The American Diabetes Association (ADA) recommends basing diabetes diagnosis on a fasting plasma glucose (FPG) of > or = 7.0 mmol/L and impaired fasting glucose (IFG) on 6.1 < or = FPG < 7.0 mmol/L. The new World Health Organisation (WHO) recommendations also adopt this FPG cut-off, but retain the oral glucose tolerance test (OGTT) where possible and the intermediate group of impaired glucose tolerance (IGT) in addition to IFG. We compare the effect of the new ADA and WHO diagnostic criteria in three ethnic groups. METHODS AND RESULTS: Three hundred and eighty whites, 340 South Asians and 347 subjects of African descent, aged 40-59 years and not known to have diabetes, were identified through South London general practices. Inevitably, the prevalence of new diabetes was lower under ADA than under WHO criteria (including post-load levels) for all three groups, falling from 5.7% overall to 3.3% (fall 2.4% 95% CI 1.6% to 3.6%). The largest fall was for South Asians from 9.1% to 5.0% (fall 4.1% 95% CI 2.2% to 6.8%). The prevalence of impaired glucose homeostasis under ADA criteria (IFG) was substantially less than under WHO criteria (IFG + IGT). Under WHO criteria, including a glucose tolerance test, there was marked variation by ethnic group in diabetes prevalence (p < 0.001) and IGT (p < 0.0001), both were most prevalent amongst South Asians. Under ADA criteria, (or new WHO criteria without OGTT) diabetes prevalence still differed significantly between groups (p < 0.01), but there was no difference in IFG prevalence (p = 0.43). CONCLUSIONS: Subjects with IGT but normal FPG are at greater risk of coronary heart disease. The new ADA definition fails to identify substantial numbers of such subjects, particularly among South Asians. Our study supports the retention of the OGTT in the new WHO criteria, particularly for South Asians.

A population study of ethnic variations in the angiotensin-converting enzyme I/D polymorphism: relationships with gender, hypertension and impaired glucose metabolism.

BACKGROUND: The presence of the deletion allele of the angiotensin-converting enzyme (ACE) I/D polymorphism is associated with an excess risk of vascular disease and diabetic nephropathy. OBJECTIVE: To examine the importance of this polymorphism as a determinant of hypertension and impaired glucose metabolism in a population-based study of three ethnic groups and assess the potential modifying effect of gender. DESIGN: Population-based cross-sectional study in South London. The population-based sample of 1577 men and women, age 40-59 years, was obtained from stratified random sampling of general practice lists where 25% of the residents were born outside the UK. The ACE I/D polymorphism was determined for 1366 individuals (86.6%): 462 whites, 462 of African descent and 442 of South Asian origin. RESULTS: The genotype frequency within each ethnic group was in Hardy-Weinberg equilibrium. The frequencies were similar in whites and those of African descent (II, ID, DD: 18.4%, 49.6%, 32.0% for whites and 18.4%, 50.5%, 30.9% for those of African descent), but there was a much higher frequency of the II genotype in those of South Asian origin (39.8%, 41.8%, 18.3%; chi2 = 77.6; P < 0.0001). There was no association between the I/D polymorphism and impaired glucose metabolism in any ethnic group. There were also no significant associations between the I/D polymorphism and hypertension in whites and in those of South Asian origin. This contrasts with a highly significant association between the D allele and hypertension in women of African descent (OR = 2.54; 95% CI 1.38-4.65; P = 0.003) but not in men of African descent (0.79; 0.36-1.72) (test for differences between sexes P = 0.023). CONCLUSIONS: These observations provide estimates of the frequency distribution of the ACE I/D polymorphism in whites, in people of African descent and in people of South Asian origin. Moreover, these results highlight the potential importance of gender-dependent interactions between genetic background and expression of hypertensive phenotype.

Arylethanolamines derived from salicylamide with alpha- and beta-adrenoceptor blocking activities. Preparation of labetalol, its enantiomers, and related salicylamides.

A series of phenethanolamines (3) based on salicylamide has been prepared and shown to possess beta-adrenergic blocking properties. When the basic nitrogen atom was substituted by some aralkyl groups, the compounds also blocked alpha-adrenoceptors. The 1-methyl-3-phenylpropyl derivative labetalol (34) is antihypertensive in animals and man, and syntheses of its four stereoisomers are described. The enantiomer 90 with the R configuration at both asymmetric centers possessed most of the beta-blocking activity but little alpha-blocking activity. That with the S configuration at the alcoholic carbon and the R configuration on the amino substituent, 89, is predominantly an alpha-adrenoceptor blocking agent.