Association of Selective HLA Class II Susceptibility-Conferring and Protective Haplotypes with Type 2 Diabetes in Patients from Bahrain and Lebanon

Abstract

The association of HLA class II with type 2 diabetes (T2DM) was investigated in Bahraini and Lebanese subjects. DRB1*070101 (Lebanese and Bahraini) and DQB1*0201 (Lebanese) were susceptibility-conferring alleles, and unique susceptibility-conferring/protective haplotypes were found in both patient groups. Regression analysis confirmed that DRB1*070101-DQB1*0201 (Bahraini) and DRB1*110101-DQB1*0201 (Lebanese) were susceptibility-conferring haplotypes.Type 2 (non-insulin-dependent) diabetes mellitus (T2DM) is the most common diabetes form (19), and susceptibility to it is determined by environmental and genetic factors (9, 19), the latter being complex and poorly defined (5,19). While the association of HLA class II genes in type 1 diabetes pathogenesis was reported for several ethnicities (1,14), studies on HLA class II association with T2DM provided inconsistent results, since an association (16), no association (7), or a weak link between HLA class II and T2DM has been reported. A number of studies focused on the association of HLA with T2DM morbidity and mortality (17), highlighted by increased frequency of HLA-DR3 and -DR4 in islet cell autoantibody (ICA)-positive patients refractory to oral anti-diabetic drugs as reported by some (11) but not others (20), and association of HLA-DRB1*1502 with T2DM in anti-glutamic acid decarboxylase (GAD)-positive patients (10).We previously reported on the distribution of HLA class II alleles and haplotypes among T2DM patients in the Bahraini population (16), an Arab Peninsula population with a high prevalence (24% of the adult population) of T2DM (2). In view of the heterogeneity of Arabs with distinct ethnic backgrounds and racial origins (3), this study addresses the association of HLA-DRB1 and HLA-DQB1 haplotypes with T2DM in Bahraini and Lebanese Arabs.T2DM patients comprised 115 Lebanese (59 males and 56 females; mean age, 55.2 Ϯ 13.5 years) and 110 Bahraini (59 males and 51 females; mean age, 52.3 Ϯ 9.6 years) unrelated patients. Exclusion criteria included other types of diabetes, autoimmune diseases, and positive anti-GAD, anti-protein tyrosine phosphatase-related protein (IA-2), or ICA autoantibody responses. Family history of diabetes (80/110 Bahraini patients and 77/115 Lebanese patients) or body mass index did not influence selection of subjects. The control group included 121 Lebanese (57 males and 64 females; mean age, 54.5 Ϯ 13.8 years) and 154 Bahraini (79 males and 75 females; mean age, 52.9 Ϯ 9.0 years) subjects with normal fasting/random glucose levels and no known personal or family history of diabetes. Demographic details, which included duration, first-degree family history, complications, and treatment for diabetes, were recorded. The Arabian Gulf University Ethics Committee approved the study (which was done according to Helsinki guidelines), and informed consent was obtained from all participants.Total genomic DNA was extracted from EDTA-anticoagulated venous blood by the phenol-chloroform method. HLA-DRB1 and HLA-DQB1 gene alleles were analyzed us...

Vitamin D Receptor Gene Polymorphisms and HLA DRB1*04 Cosegregation in Saudi Type 2 Diabetes Patients

“…T1DM has been long known to be associated with HLA (22,23); correlations between T2DM and HLA alleles have only been shown recently (24,29,30). Thus, data obtained in the seminal Pima Indian cohort study have indicated that the presence of HLA-DRB1*02 confers a lower risk for development of T2DM, possibly as a secondary effect on self-tolerance.…”

“…Several genes involved in the metabolic pathway of T2DM have been regarded as candidates for the onset of the disease (27), and among these, the VDR gene is considered as a particularly good candidate for disease susceptibility (28). Notably, as is the case with a number of inflammatory and autoimmune diseases, recent data have indicated a role for certain HLA alleles as well in the pathogenesis of T2DM (24,29,30).…”

Vitamin D receptor (FokI, BsmI and TaqI) gene polymorphisms and type 2 diabetes mellitus : A North Indian study

“…[1][2][3][4][5][6][7][8][9] An association study of candidate genes, viz., fatty acid binding protein 2 (FABP2), uncoupling protein type 1 gene (UCP1), protein phosphatase type 1 (PP1G), β3 adrenergic receptor (β3AR), VDR, was carried out on T2DM patients in a migrant Indian population as well by Boullus-Sanchis et al [10] Genome-wide association studies have led to the identiÞ cation of several single nucleotide polymorphisms in genes such as CDKAL1, CDKN2B, HHEX/IDE, IGF2BP2, KCNJ11, SLC30A8, TCF2, TCF7L2 and WFS1. [11] Several genes were studied but only a handful showed conÞ rmed association, such as resistin, alpha-endosulfine, calpain10, peroxisome proliferators-activated receptor-gamma 2 (PPARγ-2), abundant transcript 1 gene (apM1), TCF7L2, insulin-like growth factor-binding protein 5 (IGFBP5), to name a few.…”

Genotyping of HLA ClassI and II Molecules in Type 2 Diabetic Iraqi Patients

“…Mix study for type 2 diabetes patients from Bahrain and Lebanon done by Almawi et al,(2006) ,using PCR-SSP technique revealed that the allele which showed significant positively associated with diabetes was DRB1*0701 (Lebanese and Bahraini) while, DRB1*1101; DQB1*0201(Lebanese).…”