Variation in the Interleukin-6 Receptor Gene Associates With Type 2 Diabetes in Danish Whites

Abstract

Interleukin-6 (IL-6) is a pleiotropic cytokine involved in the pathophysiology of various human diseases such as type 2 diabetes and obesity. IL-6 signals via a heterodimeric receptor complex consisting of a soluble IL-6 ␣-subunit (IL-6 receptor [IL6R]) and a signal transducing subunit (gp130). The IL6R gene maps to an important candidate locus for type 2 diabetes on chromosome 1q21. An Asp358Ala polymorphism of the IL6R has been reported to associate with obesity in Pima Indians. We investigated the Asp358Ala polymorphism in relation to type 2 diabetes, obesity, and other prediabetic quantitative traits among Danish whites. By applying a recessive genetic model in a case-control study of 1,349 type 2 diabetic patients and 4,596 glucose-tolerant control subjects, we found a significant difference in genotype distribution (P ‫؍‬ 0.008) and in allele frequency (Ala-allele

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

“…It was reported that variant Asp358Ala (SNP7) was associated with BMI in Pima Indians (9). However, the relations between IL6R variations and adiposity were not found in some other studies (11,13).…”

“…We suspect that these metabolic and inflammation changes may affect the expression of IL-6 and thus dilute the genetic effects of IL6R variants. Hamid et al (13) reported that the amino acid change variant Asp358Ala (SNP7) was associated with risk of type 2 diabetes in Danish whites under a recessive inheritance model. However, IL6R variations were not associated with diabetes in Pima Indians and North European whites (9,11), as well as in our study sample of U.S. women.…”

“…Several studies (9,10) have documented that IL6R gene variants were associated with obesity, insulin sensitivity (11), metabolic syndrome (12), and diabetes risk (13). However, few studies have used genetic markers that represent the overall variability of the gene, and the results are not consistent across populations.…”

“…In this study, we selected linkage disequilibrium (LD)-tagging single nucleotide polymorphisms (SNPs) for the IL6R gene and also included a polymorphism (rs8192284) previously associated with functional changes of the IL6R gene and diabetes risk (13,14). We examined the associations between IL6R variations, plasma IL-6 levels, and diabetes risk in a nested case-control study of women from a prospective cohort, the Nurses' Health Study.…”

Combined effect of C-reactive protein gene SNP +2147 A/G and interleukin-6 receptor gene SNP rs2229238 C/T on anthropometric characteristics among school children in Taiwan

“…It may be that the elevated sIL-6R levels in Asp358 allele carriers cause an increase in the level of the IL-6/sIL-6R complex, which then results in greater IL-6 signal transduction and activation of Combined effect of CRP and IL-6R gene SNP F-H Lin et al cells that do not express IL-6R, resulting in obesity and metabolic diseases. However, Hamid et al 28 failed to detect an association between the IL-6R Asp358Ala polymorphism and BMI in 4251 middle-aged glucose-tolerant Danish Caucasians in the Inter99 cohort study. Differences in the frequencies of genotypes or alleles might generate discrepancies in the results of such studies, but differences in the mean BMI or obesity status of populations should also be considered.…”