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Interleukin-6 Genetic Variability and Adiposity: Associations in Two Prospective Cohorts and Systematic Review in 26,944 Individuals

Departments of Nutrition and Epidemiology, Harvard School of Public Health, and Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Dr. Lu Qi, Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115. E-mail: nhlqi{at}channing.harvard.edu.

Context: IL-6 (IL6) is an immune-modulating cytokine associated with obesity in humans.

Objective: Our objective was to assess the associations between the genetic variability of IL6 gene and adiposity and long-term changes.

Design and Subjects: We determined the linkage disequilibrium-tagging single-nucleotide polymorphisms of IL6 gene in 2255 healthy women and 980 healthy men from two prospective cohorts. We also conducted a metaanalysis on the associations between polymorphism –174G>C (rs1800795) and adiposity.

Results: IL6 haplotype 222211 (possessing rs2069827, rs1800797, rs1800795, rs1554606, rs2069861, and rs1818879; 1 codes the common and 2 codes the minor alleles) was consistently and significantly associated with greater waist circumference (P = 0.009 in men; P = 0.0003 in women) and baseline body mass index (BMI) (P = 0.01 in men; P = 0.046 in women) compared with the most common haplotype 111112. Haplotype 222211 was also associated with significantly higher early-adulthood BMI in women (P = 0.007). The haplotype-associated difference in BMI persisted significantly during the follow-up. A 5' promoter polymorphism, rs2069827, was consistently associated with significantly higher early-adulthood BMI, baseline BMI, and waist circumference in men (carriers vs. noncarriers, P = 0.01, 0.007, and 0.008) and women (P = 0.01, 0.10, and 0.0016). The data from this study and a metaanalysis of 26,944 individuals did not support substantial relations between the best-studied polymorphism, –174G>C, and adiposity.

Conclusions: Our data from two independent cohorts indicate that the variability of the IL6 gene is significantly associated with adiposity. Such associations are less likely to be caused by polymorphism –174G>C.