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OBJECTIVE--To examine the associations between common variations in the IL6R gene and circulating interleukin (IL)-6 levels and diabetes risk. RESEARCH DESIGN AND METHODS--We determined 10 linkage disequilibrium (LD)-tagging single nucleotide polymorphisms (SNPs) (SNP1 to SNP10) for the IL6R gene in a nested case-control study of 672 diabetic and 1,058 healthy European Caucasian women (IL-6 levels were measured in a subgroup of 1,348 women). RESULTS--In both control and diabetic patients, polymorphisms within an LD block spanning ∼42 kb were significantly associated with plasma IL-6 levels. A missense variant SNP7 in exon 9 (rs8192284, Asp358Ala) showed the strongest association (P = 0.0005 in control and P = 0.004 in case subjects). The corresponding false-discovery rates, which accounts for multiple testing, were 0.008 and 0.02, respectively. We inferred five common haplotypes to capture 94% allele variance of the LD block using SNP5, -7, -8, -9, and -10. Compared with the most common haplotype 12111 (one codes the common and two codes the minor alleles), haplotypes 11211 [difference in log(IL-6) = -0.11 (95% CI -0.23 to -0.01); P = 0.01] and 21122 (-0.15 [-0.27 to -0.03]; P = 0.01) were associated with significantly lower IL-6 levels (global test, P = 0.01). However, IL6R genotypes were not significantly associated with the risk of type 2 diabetes. CONCLUSIONS--IL6R genetic variations, especially SNP7 (rs8192284, Asp358Ala), were significantly associated with plasma IL-6 levels but not with diabetes risk in women. The strong associations between IL6R genetic variability and IL-6 concentrations deserve further investigation. Diabetes 56: 3075-3081, 2007 [ABSTRACT FROM AUTHOR]

Little is known about the genetic influence on BMI trajectory throughout adulthood. We created a genetic risk score (GRS) comprising 97 adult BMI-associated variants among 9,971 women and 6,405 men of European ancestry. Serial measures of BMI were assessed from 18 (women) or 21 (men) years to 85 years of age. We also examined BMI change in early (from 18 or 21 to 45 years of age), middle (from 45 to 65 years of age), and late adulthood (from 65 to 80 years of age). GRS was positively associated with BMI across all ages, with stronger associations in women than in men. The associations increased from early to middle adulthood, peaked at 45 years of age in men and at 60 years of age in women (0.91 and 1.35 kg/m2 per 10-allele increment, respectively) and subsequently declined in late adulthood. For women, each 10-allele increment in the GRS was associated with an average BMI gain of 0.54 kg/m2 in early adulthood, whereas no statistically significant association was found for BMI change in middle or late adulthood or for BMI change in any life period in men. Our findings indicate that genetic predisposition exerts a persistent effect on adiposity throughout adult life and increases early adulthood weight gain in women. [ABSTRACT FROM AUTHOR]

Recent evidence suggests that the fat mass and obesity-associated gene (FTO) genotype may interact with dietary intakes in relation to adiposity. We tested the effect of FTO variant on weight loss in response to 2-year diet interventions. FTO rs1558902 was genotyped in 742 obese adults who were randomly assigned to one of four diets differing in the proportions of fat, protein, and carbohydrate. Body composition and fat distribution were measured by dual-energy x-ray absorptiometry and computed tomography. We found significant modification effects for intervention varying in dietary protein on 2-year changes in fat-free mass, whole body total percentage of fat mass, total adipose tissue mass, visceral adipose tissue mass, and superficial adipose tissue mass (for all interactions, P < 0.05). Carriers of the risk allele had a greater reduction in weight, body composition, and fat distribution in response to a high-protein diet, whereas an opposite genetic effect was observed on changes in fat distribution in response to a low-protein diet. Likewise, significant interaction patterns also were observed at 6 months. Our data suggest that a high-protein diet may be beneficial for weight loss and improvement of body composition and fat distribution in individuals with the risk allele of the FTO variant rs1558902. [ABSTRACT FROM AUTHOR]