Brief Genetics Report Variation in the Interleukin-6 Receptor Gene Associates With Type 2 Diabetes in Danish Whites Yasmin H. Hamid, 1 Søren A. Urhammer, 1 Dorit P. Jensen, 1 Charlotte Glu ¨ mer, 1,2 Knut Borch-Johnsen, 1,3 Torben Jørgensen, 2 Torben Hansen, 1 and Oluf Pedersen 1,3 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 het- erodimeric receptor complex consisting of a soluble IL-6 -subunit (IL-6 receptor [IL6R]) and a signal trans- ducing subunit (gp130). The IL6R gene maps to an important candidate locus for type 2 diabetes on chro- mosome 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 pre- diabetic 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 glu- cose-tolerant control subjects, we found a significant difference in genotype distribution (P  0.008) and in allele frequency (Ala-allele 38.3% [95% CI 36.5– 40.1] in diabetic subjects vs. 41.2% [40.2– 42.2] in control sub- jects; P  0.007). The odds ratio for the Asp/Asp carri- ers versus Ala/Ala carriers was 1.38 (1.09 –1.71). Among 4,251 middle-aged glucose-tolerant subjects, the Asp358Ala polymorphism was not associated with esti- mates of obesity, post– oral glucose tolerance test se- rum insulin release, or the homeostasis model assessment of insulin resistance index. In conclusion, the Asp358Ala polymorphism of the IL6R associates with type 2 diabetes in Danish whites. Diabetes 53: 3342–3345, 2004 I nterleukin-6 (IL-6) is a pleiotropic cytokine secreted by various cell types, including leukocytes and en- dothelial cells, muscle tissue, and adipocytes (1,2). IL-6 is a mediator of some of the inflammatory response involved in the pathophysiology of metabolic disorders such as type 2 diabetes and obesity (3,4). IL-6 exerts its signal transduction effect by binding to the IL-6 receptor (IL6R), and this complex subsequently binds to the gp130 subunit (also named IL6ST) (5,6). The gp130 plays an important role in stabilization of the ligand complex (7). The expression of IL6R is predominantly confined to hepatocytes and subpopulations of leukocytes (8). However, a biological active soluble form of the IL6R also exists (sIL6R). The IL6/sIL6R complex potentiates the effect of IL-6 and is capable of activating cells not express- ing membrane-bound IL6R (8). Interestingly, a signifi- cantly higher plasma level of IL-6 and IL6/sIL6R complex has been shown among type 2 diabetic patients (9); in addition, sIL6R correlates with BMI among end-stage renal disease patients (10). IL6-IL6R double-transgenic mice overexpressing IL-6 and sIL6R are not diabetic but remarkably smaller and have reduced body fat compared with single-transgenic or nontransgenic mice. IL-6 and IL6R single-transgenic mice do not differ from their wild-type littermates according to weight gain, food and water intake, or behavior (11). The IL6R gene is located on chromosome 1q21 (12) in a region where several family studies in different ethnic populations have reported linkage to type 2 diabetes. The IL6R is located within a 1–logarithm of odds interval of the linkage peak in at least four of these studies (13–17). Several single nucleotide polymorphisms (SNPs) of the IL6R have been identified among Pima Indian, Korean, African-American, and white subjects (18 –20). One of these SNPs, a nonsynonymous variant in exon 9, Asp358Ala, has in a preliminary communication (18) been reported to associate with type 2 diabetes in whites and with indexes of obesity but not with diabetes in Pima Indians (20). The objective of the present investigation was in a large-scale setting to replicate whether the IL6R Asp358Ala polymorphism, which is localized to a func- tional domain of the protein (21), associates with type 2 diabetes, obesity, or other quantitative traits of metabo- lism among Danish whites. From the 1 Steno Diabetes Center and Hagedorn Research Institute, Gentofte, Copenhagen, Denmark; the 2 Research Centre for Prevention and Health, Copenhagen County, Glostrup University Hospital, Glostrup, Denmark; and the 3 Faculty of Health Science, University of Aarhus, Aarhus, Denmark. Address correspondence and reprint requests to Yasmin Hassan Hamid, MD, Steno Diabetes Center, Niels Steensens Vej 2, DK-2820 Gentofte, Copen- hagen, Denmark. E-mail: yah@steno.dk. Received for publication 3 June 2004 and accepted in revised form 30 August 2004. Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org. IFG, impaired fasting glucose; IGT, impaired glucose tolerance; IL-6, interleukin-6; IL6R, IL-6 receptor; OGTT, oral glucose tolerance test; NGT, normal glucose tolerance; sIL6R, soluble IL6R; SNP, single nucleotide poly- morphism. © 2004 by the American Diabetes Association. 3342 DIABETES, VOL. 53, DECEMBER 2004 Downloaded from http://diabetesjournals.org/diabetes/article-pdf/53/12/3342/377606/zdb01204003342.pdf by guest on 21 February 2024