ADRB2 and LEPR gene polymorphisms: synergistic effects on the risk of obesity in Japanese.

The objective of the present study was to validate a recently reported synergistic effect between variants located in the leptin receptor (LEPR) gene and in the ß-2 adrenergic receptor (ADRB2) gene on the risk of overweight/obesity. We studied a middle-aged/elderly sample of 4,193 nondiabetic Japanese subjects stratified according gender (1,911 women and 2,282 men). The LEPR Gln223Arg (rs1137101) variant as well as both ADRB2 Arg16Gly (rs1042713) and Gln27Glu (rs1042714) polymorphisms were analyzed. The primary outcome was the risk of overweight/obesity defined as BMI ≥25 kg/m(2), whereas secondary outcomes included the risk of a BMI ≥27 kg/m(2) and BMI as a continuous variable. None of the studied polymorphisms showed statistically significant individual effects, regardless of the group or phenotype studied. Haplotype analysis also did not disclose any associations of ADRB2 polymorphisms with BMI. However, dimensionality reduction-based models confirmed significant interactions among the investigated variants for BMI as a continuous variable as well as for the risk of obesity defined as BMI ≥27 kg/m(2). All disclosed interactions were found in men only. Our results provide external validation for a male specific ADRB2-LEPR interaction effect on the risk of overweight/obesity, but indicate that effect sizes associated with these interactions may be smaller in the population studied.

Meta-analysis of the association of 4 angiotensinogen polymorphisms with essential hypertension: a role beyond M235T?

Angiotensinogen (AGT) gene polymorphisms have been linked to increased risk of hypertension, but the data remain controversial. In this study we review the most commonly investigated polymorphisms at the AGT locus (other than M235T) and provide summary estimates regarding their association with essential hypertension, while addressing heterogeneity, as well as publication biases. Data on 26 818 subjects from 46 studies for the 4 most-studied AGT variants (T174M in exon 2 and 3 promoter variants: A-6G, A-20C, and G-217A) were meta-analyzed. Statistically significant associations with hypertension were identified for the T174M (odds ratio [OR]: 1.19; 95% CI: 1.07 to 1.33; P=0.002) and G-217A (OR: 1.37; 95% CI: 1.17 to 1.59; P=0.00006) polymorphisms. A dual but consistent effect was observed for the -20C allele, which was associated with a decreased risk of hypertension in populations of mixed and European ancestries (OR: 0.64; 95% CI: 0.44 to 0.92; P=0.02 and OR: 0.77; 95% CI: 0.65 to 0.91; P=0.003, respectively), but with a 24% increase in the odds of hypertension in Asian subjects (OR: 1.24; 95% CI: 1.04 to 1.48; P=0.02). No association of the A-6G variant with hypertension was detected. Current studies support the notion that single variants at the AGT might modulate the risk of hypertension but indicate caution in interpreting these results because of the putative presence of publication bias and gene-environment interactions.

Three endothelial nitric oxide (NOS3) gene polymorphisms in hypertensive and normotensive individuals: meta-analysis of 53 studies reveals evidence of publication bias.

BACKGROUND: Studies on the relationship between endothelial nitric oxide (NOS3) gene variants and hypertension have been conflicting. To explore this hypothesis further, we performed a meta-analysis and re-evaluated the relationship between the three most widely studied NOS3 polymorphisms and hypertension status and blood pressure levels. METHODS: Data on 40,413 subjects from 53 studies were combined in five distinct meta-analyses, and heterogeneity and publication bias were explored. RESULTS: Heterogeneity was observed in all meta-analyses. By a random-effects model, carriers of the four 27-basepair repeat variable number of tandem repeats in intron 4 were associated with a 28% increase in the risk of hypertension compared with those homozygous for the 5 repeat: odds ratio (OR) 1.28, 95% confidence interval (CI) 1.11-1.47, P=0.001. In Asian individuals, Asp allele carriers displayed a similar association: OR 1.28, 95% CI 1.06-1.54, P=0.01, as well as a 2 mmHg increase in both systolic (P=0.04) and diastolic (P=0.009) blood pressure levels. Furthermore, meta-regression analysis indicated that the effect of the Glu298Asp genotype on the risk of hypertension might be dependent on total cholesterol status. No effect of the T-786C variant on hypertension was detected. There was evidence that such findings might be a result of selectively reporting/publishing positive reports. CONCLUSION: Our results suggest that current data on the relationship between NOS3 variants and hypertension are subject not only to important heterogeneity but also to publication bias. Future research should preferentially focus on gene-environment interactions as well as haplotype analyses.