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Circulating levels of the cytokine interleukin 6 (IL-6) are elevated in obesity, correlate with body mass index (BMI), and predict the development of type 2 diabetes mellitus (T2DM). A promoter polymorphism in the IL6 gene is associated with obesity, altered levels of insulin sensitivity, and T2DM. IL-6 exerts its effects by binding to the IL-6 receptor (IL-6R) and levels of IL-6R have been correlated with BMI. It is possible that IL6R variants may also be related to obesity, but to our knowledge, no study has yet examined this relationship. The objective of this study was to examine the relationship between genetic variants in the IL6R gene and obesity in Pima Indians, a population prone to excess adiposity. We sequenced 6 kb of the IL6R gene, corresponding to all exons, exon–intron boundaries, and 2 kb of promoter in 30 Pima Indians. We identified six single nucleotide polymorphisms (SNPs) in the IL6R gene: a predicted Asp → Ala substitution at position 358, a variant in the 3′-untranslated region, and 4 intronic SNPs. All SNPs were in strong linkage disequilibrium (D′⩾0.90) and varied in minor allele frequency from 0.33 to 0.48. Association between IL6R genotype and BMI (kg/m2) was assessed in approximately 700 nondiabetic, full-heritage Pima Indians. For each SNP, individuals carrying the variant allele had a higher mean BMI compared to those with the wild-type allele (range: [37.3 ± 7.2–38.2 ± 7.0] vs. [35.5 ± 7.3–36.0 ± 7.5]; P=0.02–0.004). Our findings suggest that genetic variants in the IL6R gene may play a role in susceptibility to obesity. Assessment of these SNPs in other populations will be useful to determine the magnitude of obesity risk. [Copyright &y& Elsevier]

Phospholipase A2, Group IVA (PLA2G4A) belongs to the class of cytosolic calcium-dependent phospholipases (cPLA2s) that preferentially cleave arachidonic acid (AA) from membrane glycerophospholipids. AA and AA metabolites play key roles in glucose disposal and insulin secretion. PLA2G4A is located on Chromosome 1q, where a number of groups have reported linkage to type 2 diabetes mellitus. We have screened the PLA2G4A gene and identified a C→G variant, which predicts a phenylalanine to leucine substitution. In logistic regression analyses adjusted for age, sex, ethnicity, and birth year, we found a trend toward association between this SNP and diabetes [OR=1.53 (0.97–2.40); p=0.06]. Individuals with the variant genotype had lower mean basal endogenous glucose output (1.8±0.03 vs. 1.9±0.01 mg/kg EMBS/min; p=0.04) and lower mean basal glucose oxidation (1.2±0.11 vs. 1.4±0.03 mg/kg EMBS/min; p=0.005) compared to individuals with the wild-type genotype. During a low dose insulin infusion, non-diabetic individuals with the variant genotype had a lower mean glucose oxidation (1.9±0.11 vs. 2.0±0.03 mg/kg EMBS/min; p=0.04) and total glucose turnover rate (2.5±0.22 vs. 2.6±0.06 mg/kg EMBS/min; p=0.01) compared to subjects with the wild-type genotype. In addition, under basal conditions, individuals with the variant genotype had a higher mean lipid oxidation rate compared to individuals with the wild-type genotype (0.77±0.25 vs. 0.67±0.23 mg/kg EMBS/min; p=0.02). These results provide evidence supporting a role for the eicosanoid biosynthesis pathway in type 2 diabetes mellitus pathophysiology. [Copyright &y& Elsevier]