Tikhonoff, Valerie (2008) Blood pressure and metabolic phenotypes in relation to SAH gene variants and ADRB1 Arg389Gly and ADRAB2 I/D polymorphisms in white family-based population samples. [Ph.D. thesis]
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Objectives: Aim of the present doctoral dissertation is independent confirmation in family-based population samples, using strict appropriate statistical approach, of the associations, if any, between blood pressure (BP) and related metabolic phenotypes, analysed as continuous traits, and variations in candidate genes arising from experimental animal models [Spontaneously hypertensive rat-clone A-Hypertension-associated (SAH) gene], and from physiological cascades of the adrenergic system [alfa2B- (ADRAB2) and beta1- (ADRB1) adrenergic receptors].
Methods and Results: The SAH gene variants were evaluated in the frame of the European Project On Genes in Hypertension. In details, 2603 relatives from 560 families and 31 unrelated subjects (mean age 38.8?15.7 years; 52.1% women) were randomly recruited from six European populations. Systolic/diastolic BP, body mass index, triceps skinfold, waist-to-hip ratio, serum total and HDL cholesterol, serum triglycerides and blood glucose were measured. All subjects were genotyped for the G-1606A and -962 del/ins polymorphisms and the allele frequencies were 11.8% and 29.5% for -1606A and -962del, respectively. Lewontin’s D’ was 0.97 (p<0.0001). Haplotype frequencies were 58.8% for -1606G plus -962ins, 29.5% for -1606G plus -962del, and 11.7% for -1606A plus -962ins. Both before and after adjustment for covariates, none of the phenotype-genotype associations approached statistical significance. Family-based analyses did not reveal any population stratification (P?0.67) as a possible explanation of those negative results.
The association studies between ADRB1 Arg389Gly and ADRA2B I/D polymorphisms of the beta1- and alfa2B-adrenergic receptors with BP and metabolic phenotypes, were conducted in a subsample of the EPOGH cohort. 1802 relatives from 175 families and 79 unrelated subjects (mean age 45.5?15.7 years; 51.1% women) were randomly recruited from a Caucasian population living in Northern Belgium. Systolic/diastolic BP, body mass index, waist-to-hip ratio, serum total and HDL cholesterol were measured. All subjects were genotyped for the ADRA2B I/D and ADRB1 Arg389Gly polymorphisms. The ADRA2B genotypes (II 45.7%, ID 41.7%, and DD 12.5%; P=0.05) and the ADRB1 genotypes (ArgArg 56.2%, ArgGly 36.9%, and GlyGly 6.9%; P=0.66) did not deviate from Hardy–Weinberg proportions. ADRB1 ArgArg homozygotes, compared with Gly allele carriers, had higher diastolic BP (79.4 vs 78.4 mmHg; P=0.012), and higher serum HDL cholesterol (1.33 vs 1.29 mmol/l; P=0.020). None of the other cardiovascular or metabolic phenotypes in relation to the two polymorphisms reached significance. The family-based analyses did not reveal population stratification (P?0.23).
Conclusions: The present study gives evidence in favour of association of diastolic BP and HDL cholesterol with the ADRB1 Arg389Gly polymorphism in the absence of population stratification. However, the evidences supporting association of hypertension or hypertension-related phenotypes with the SAH gene remain equivocal in human studies.
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