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A Combination of Human Leukocyte Antigen DQB1*02 and the Tumor Necrosis Factor Promoter G308A Polymorphism Predisposes to an Insulin-Deficient Phenotype in Patients with Type 2 Diabetes

Diabetes and Endocrine Research Laboratory (H.L., L.G., A.N., T.T.), Department of Endocrinology, Lund University, S-20502 Malmö, Sweden; Department of Endocrinology (J.W.), The First University Hospital, Sun Yat-Sen University, Guangzhou, China 510080; and Department of Internal Medicine (T.T.), Helsinki University Central Hospital, Helsinki FIN-00029, Finland

Address all correspondence and requests for reprints to: Haiyan Li, Ph.D., Wallenberg Laboratory, Department of Endocrinology, Lund University, S-20502 Malmö, Sweden. E-mail: haiyan.li{at}endo.mas.lu.se.

Our previous results have suggested that genes outside the human leukocyte antigen (HLA) class II locus may affect the phenotype of type 2 diabetic patients from families with both type 1 and type 2 diabetes (mixed type 1/2). To study whether the TNF gene could be such a modifying gene, we studied TNF promoter polymorphisms (GA substitution at positions -308 and -238) in relation to HLA-DQB1 genotypes in type 2 patients from mixed type 1/2 families or common type 2 diabetes families as well as in patients with adult-onset type 1 diabetes and control subjects. The TNF₃₀₈ AA/AG genotype frequency was increased in adult onset type 1 patients (55%, 69 of 126), but it was similar in type 2 patients from type 1/2 families (35%, 33/93) or common type 2 families (31%, 122 of 395), compared with controls (33%, 95/284; P < 0.0001 vs. type 1). The TNF₃₀₈ A and DQB1*02 alleles were in linkage disequilibrium in type 1 patients (Ds = 0.81; P < 0.001 vs. Ds = 0.25 in controls) and type 2 patients from type 1/2 families (Ds = 0.59, P < 0.05 vs. controls) but not in common type 2 patients (Ds = 0.39). The polymorphism was associated with an insulin-deficient phenotype in the type 2 patients from type 1/2 families only together with DQB*02, whereas the common type 2 patients with AA/AG had lower waist to hip ratio [0.92 (0.12) vs. 0.94 (0.11), P = 0.008] and lower fasting C-peptide concentration [0.48 (0.47) vs. 0.62 (0.46) nmol/liter, P = 0.020] than those with GG, independently of the presence of DQB1*02. In conclusion, TNF is unlikely to be the second gene in the HLA area responsible for our previous findings in type 1/2 patients. However, we could show an association between TNF₃₀₈ polymorphism and the phenotype of common type 2 diabetes.

This work was supported by the Sigrid Juselius Foundation, Påhlsson Foundation, Medical Faculty of the Lund University, Malmö University Hospital, Swedish National Board of Health and Welfare, Swedish Medical Doctors Association, Crafoord Foundation, and Novo Nordisk Foundation. The Botnia study is supported by the Sigrid Juselius Foundation, JDF Wallenberg, EC (BM4-CT95-0662), Swedish Medical Research Foundation, Academy of Finland, Finnish Diabetes Research Society, Swedish Diabetes Association, and Novo Nordisk Foundation.

Abbreviations: BMI, Body mass index; D, coefficient of disequilibrium; Ds, standardized value of D; HbA1C, hemoglobin A1C; HLA, human leukocyte antigen; HOMA, homeostasis model assessment for insulin resistance; OGTT, oral glucose tolerance test; GADab, glutamic acid decarboxylase antibody; WH, waist to hip ratio.

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