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Interleukin-6 Receptor Gene Variations, Plasma Interleukin-6 Levels, and Type 2 Diabetes in U.S. Women

¹ Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts
² Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
³ Department of Laboratory Medicine, Children's Hospital and Harvard Medical School, Boston, Massachusetts
⁴ Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts

Address correspondence and reprint requests to Dr. Lu Qi, Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115. E-mail: nhlqi{at}channing.harvard.edu; or Dr. Frank Hu, frank.hu{at}channing.harvard.edu

Abbreviations: FDR, false-discovery rate; IL, interleukin; LD, linkage disequilibrium; SNP, single nucleotide polymorphism

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.

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