Interleukin-6 receptor gene variations, plasma interleukin-6 levels, and type 2 diabetes in U.S. Women.
OBJECTIVE
To examine the associations between common variations in the IL6R gene and circulating interleukin (IL)-6 levels and diabetes risk.


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 approximately 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.
Qi
Lu
L
Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115, USA. nhlqi@channing.harvard.edu
Rifai
Nader
N
Hu
Frank B
FB
D000328:Adult; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000235:genetics*; D005091:Exons; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D006801:Humans; D015850:Interleukin-6 / Q000097:blood*; D015810:Linkage Disequilibrium; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D019947:Receptors, Interleukin-6 / Q000235:genetics*; D012016:Reference Values; D018570:Risk Assessment; D044465:White People / Q000235:genetics
D015850:Interleukin-6; D019947:Receptors, Interleukin-6