A variant near the interleukin-6 gene is associated with fat mass in Caucasian men

Context: Regulation of fat mass appears to be associated with immune functions. Studies of knockout mice show that endogenous interleukin (IL)-6 can suppress mature-onset obesity. Objective: To systematically investigate associations of single nucleotide polymorphisms (SNPs) near the IL-6 (IL6) and IL-6 receptor (IL6R) genes with body fat mass, in support for our hypothesis that variants of these genes can be associated with obesity. Design and Study Subjects: The Gothenburg Osteoporosis and Obesity Determinants (GOOD) study is a population-based cross-sectional study of 18- to 20-year-old men (n=1049), from the Gothenburg area (Sweden). Major findings were confirmed in two additional cohorts consisting of elderly men from the Osteoporotic Fractures in Men (MrOS) Sweden (n=2851) and MrOS US (n=5611) multicenter population-based studies. Main Outcome: The genotype distributions and their association with fat mass in different compartments, measured with dual-energy X-ray absorptiometry. Results: Out of 18 evaluated tag SNPs near the IL6 and IL6R genes, a recently identified SNP rs10242595 G/A (minor allele frequency=29%) 3′ of the IL6 gene was negatively associated with the primary outcome total body fat mass (effect size −0.11 standard deviation (s.d.) units per A allele, P=0.02). This negative association with fat mass was also confirmed in the combined MrOS Sweden and MrOS US cohorts (effect size −0.05 s.d. units per A allele, P=0.002). When all three cohorts were combined (n=8927, Caucasian subjects), rs10242595*A showed a negative association with total body fat mass (effect size −0.05 s.d. units per A allele, P<0.0002). Furthermore, the rs10242595*A was associated with low body mass index (effect size −0.03, P<0.001) and smaller regional fat masses. None of the other SNPs investigated in the GOOD study were reproducibly associated with body fat. Conclusions: The IL6 gene polymorphism rs10242595*A is associated with decreased fat mass in three combined cohorts of 8927 Caucasian men.