Genetic and diabetic auto-antibody markers in Saudi children with type 1 diabetes

Manan, Hakbany; Angham, Al Mutair; Awadalla, Sitelbanat

doi:10.1016/j.humimm.2010.09.008

Cited by 28 publications

(33 citation statements)

References 37 publications

(33 reference statements)

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“…We previously demonstrated that the contribution of HLA haplotypes to T1DM genetic susceptibility among Tunisians depends on specific HLA class II haplotypes (29). The results showed that anti-GAD antibody levels were higher in DRB1*030101 allele carriers, in agreement with recent findings in the Saudi population (14) but in partial agreement with an earlier study on Taiwanese subjects, in which anti-GAD positivity was associated with DR3 and DR4 (4). These differences are likely attributable to racial differences in the contribution of HLA class II alleles and haplotypes to T1D pathogenesis (2,8,11).…”

Section: Discussionsupporting

confidence: 90%

Glutamic Acid Decarboxylase 65 and Islet Cell Antigen 512/IA-2 Autoantibodies in Relation to Human Leukocyte Antigen Class II DR and DQ Alleles and Haplotypes in Type 1 Diabetes Mellitus

Stayoussef¹,

Benmansour²,

Al-Jenaidi³

et al. 2011

Clin. Vaccine Immunol.

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The frequencies of autoantibodies against glutamic acid decarboxylase 65 (GAD65) and islet cell antigen (ICA) 512/IA-2 (512/IA-2) are functions of the specific human leukocyte antigen (HLA) in type 1 diabetes mellitus (T1D). We investigated the association of HLA class II (DR and DQ) alleles and haplotypes with the presence of GAD and IA-2 autoantibodies in T1D. Autoantibodies were tested in 88 Tunisian T1D patients and 112 age-and gender-matched normoglycemic control subjects by enzyme immunoassay. Among T1D patients, mean anti-GAD antibody titers were higher in the DRB1*030101 allele (P < 0.001), together with the DRB1*030101/DQB1*0201 (P < 0.001) and DRB1*040101/DQB1*0302 (P ‫؍‬ 0.002) haplotypes, while lower anti-GAD titers were associated with the DRB1*070101 (P ‫؍‬ 0.001) and DRB1*110101 (P < 0.001) alleles and DRB1*070101/DQB1*0201 (P ‫؍‬ 0.001) and DRB1*110101/DQB1*030101 (P ‫؍‬ 0.001) haplotypes. Mean anti-IA-2 antibody titers were higher in the DRB1*040101 allele (P ‫؍‬ 0.007) and DRB1*040101/DQB1*0302 (P ‫؍‬ 0.001) haplotypes but were lower in the DRB1*110101 allele (P ‫؍‬ 0.010) and the DRB1*110101 (P < 0.001) and DRB1*110101/DQB1*030101 (P ‫؍‬ 0.025) haplotypes. Multinomial regression analysis confirmed the positive association of DRB1*030101 and the negative association of DRB1*110101 and DQB1*030101, along with the DRB1*070101/DQB1*0201 and DRB1*110101/DQB1*030101 haplotypes, with anti-GAD levels. In contrast, only the DRB1*040101/DQB1*0302 haplotype was positively associated with altered anti-IA-2 titers. Increased GAD65 and IA-2 antibody positivity is differentially associated with select HLA class II alleles and haplotypes, confirming the heterogeneous nature of T1D.Type 1 diabetes mellitus (T1D) is an endocrine disease characterized by autoimmune destruction of pancreatic ␤ islet cells (2, 27). Several autoantigens have been implicated in triggering this process, including insulin; the 65-kDa isoform of glutamic acid decarboxylase (GAD) (2,19,26), an enzyme involved in the synthesis of the inhibitory neurotransmitter ␥-aminobutyric acid in pancreatic ␤ islet cells; and islet cell antigen 2 (IA-2), a tyrosine phosphatase expressed in ␤ islet cells (12). Up to 90% of newly diagnosed T1D cases are positive for anti-IA-2 and/or anti-GAD antibodies, compared to the very low prevalence of these autoantibodies in nondiabetic control populations (ϳ1%) (27, 28). Most peptides derived from GAD and IA-2 autoantigens can bind to T1D-predisposing and -protective HLA molecules, although some exceptions were observed (8). Functionally, T cell-proliferative responses from T1D patients identified GAD65 as a likely candidate in the development of anti-␤ islet cell immunity (16).We and others have confirmed the association of select HLA class II alleles and haplotypes with increased risk of T1D (1, 21, 29) and have identified both susceptible (DRB1*030101, DRB1*030101-DQB1*0201, and DRB1*040101-DQB1*0302) and protective (DRB1*070101, DRB1*110101, DRB1*070101-DQB1*0201, and DRB1*110101-DQB1*030101) alleles and ha...

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Section: Discussionsupporting

confidence: 90%

Glutamic Acid Decarboxylase 65 and Islet Cell Antigen 512/IA-2 Autoantibodies in Relation to Human Leukocyte Antigen Class II DR and DQ Alleles and Haplotypes in Type 1 Diabetes Mellitus

Stayoussef¹,

Benmansour²,

Al-Jenaidi³

et al. 2011

Clin. Vaccine Immunol.

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“…DQB1*0201 and DQB1*0302 were positively associated with T1D in various ethnic populations including Asians [34,35] , European [36][37][38][39][40][41][42][43] , and Americans [44][45][46] . Similar results were reported for Arab patients from Saudi Arabia [47,48] , Kuwait [49] , Tunisia [50] , Lebanon [51] , and Israeli [52] . On the other hand, DQB1*0301 and DQB1*0601 were negatively associated with T1D in Korean [34] , Latin American [46] , Lebanese [51] , Tunisian [50] , Saudi children [47,48] , Turkey [43] , and Romanian [37] populations.…”

Section: Discussionsupporting

confidence: 86%

“…Similar results were reported for Arab patients from Saudi Arabia [47,48] , Kuwait [49] , Tunisia [50] , Lebanon [51] , and Israeli [52] . On the other hand, DQB1*0301 and DQB1*0601 were negatively associated with T1D in Korean [34] , Latin American [46] , Lebanese [51] , Tunisian [50] , Saudi children [47,48] , Turkey [43] , and Romanian [37] populations. In the literature, there is only one previous study investigating the association of HLA-DQB1 alleles with T1D in Egyptians.…”

Section: Discussionsupporting

confidence: 86%

HLA-DQB1* alleles and genetic susceptibility to type 1 diabetes mellitus

Mosaad¹

2012

WJD

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AIM:To determine human leukocyte antigen (HLA)-DQB1 allele association with susceptibility to type 1 diabetes (T1D) and to clinical and laboratory findings. METHODS:This study was conducted on 85 unrelated Egyptian children with T1D recruited consecutively from the Pediatric Diabetes Endocrinology outpatients Clinic; Mansoura University Children's Hospital, Egypt. Patient mean follow up period was 2.5 years. Patients were subdivided according to level of HbA1c (optimal/suboptimal control < 8.5% and poor control ≥ 8.5%). The control group consisted of 113 unrelated age-and sexmatched healthy subjects without T1D or other autoimmune diseases. Genomic DNA extraction was done for all subjects using a DNA isolation kit. HLA-Class Ⅱ-DQB1 allele typing was carried out with a polymerase chain reaction-sequence-specific oligonucleotide probe using a INNO-LiPA HLA-DQB1 update kit.RESULTS: Significant differences were detected between Egyptian patients with T1D and control groups in the frequencies of DQB1*02 [44.4% vs 18.6%, corrected P value (Pc ) < 0.001] and DQB1*03 (41.2% vs 24.4%, Pc < 0.001). Significant differences were also observed between control groups and T1D patients in the frequencies of DQB1*05 (14.6% vs 7.2%, P = 0.029) and DQB1*06 (34.1% vs 7.2%, P < 0.001).However, after correction for multiple comparisons, the significance was retained for HLA-DQB1*06 (Pc < 0.001) but lost for HLA-DQB1*05. HLA-DQB1*0201, *0202, *030201 were positively associated with T1D (Pc = 0.014, Pc < 0.001, and Pc < 0.001 respectively), while HLA-DQB1*060101 was negatively associated (Pc < 0.001) with the condition. Although the HLA-DQB1 alleles 030101 and 050101 were significantly higher in controls (P = 0.016, P = 0.025 respectively), both of them lost statistical significance after correction of P value. The frequency of the HLA-DQB1 genotypes 02/02, 02/03, and 03/03 was higher in T1D patients, and the frequency of the genotypes 03/06, 05/06, and 06/06 was higher in controls, these differences being statistically significant before correction. After correction, the genotypes 02/02, 02/03 in T1D, and the genotypes 03/06, 06/06 in controls were still significant (Pc = 0.01, Pc < 0.001, Pc < 0.001, and Pc = 0.04, respectively). Non-significant associations were found between the frequency HLA-DQB1 alleles and genotypes in T1D in relation to the grade of diabetic control, Microalbuminuria, age, gender, age of presentation, weight, height, frequency of diabetic ketoacidosis (P = ORIGINAL ARTICLE 149August 15, 2012|Volume 3|Issue 8|

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…This concept stems from results obtained in T1DM (22,23) and was recently reinforced by the description of a possible protective role of HLA DRB1*02 in T2DM, probably by enhancement of self-tolerance, thereby protecting against the autoimmune-mediated reduction of insulin secretion (24).…”

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confidence: 93%

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

Al-Daghri

Al‐Attas

Alokail

et al. 2012

The Journal of Immunology

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The vitamin D receptor (VDR) gene has been involved in the modulation of susceptibility to inflammatory and autoimmune conditions, and could play a role in the pathogenesis of type 2 diabetes mellitus (T2DM). Susceptibility to T2DM was recently also suggested to associate with HLA alleles. We evaluated possible correlations between VDR polymorphisms, HLA alleles, and risk for development of T2DM by analyzing 627 individuals (368 T2DM patients and 259 healthy control subjects) part of a well-characterized cohort followed in Riyadh, Kingdom of Saudi Arabia. Genomic DNA was genotyped for the VDR gene single nucleotide polymorphisms of Fok-1, Taq-1, ApaI, and Bsm-I. Analyses were run by allelic discrimination real-time PCR. HLA genotyping was performed as well by PCR using sequence-specific primers, whereas cytokine production was evaluated by FACS. Results showed T2DM to be significantly associated with the VDR Taq1 (rs731236-AG) and Bsm-I (rs1544410-CT) genotypes, and the VDR rs1544410-T allele. Cosegregations resulting in significant increases of T2DM odds ratio were detected between Taq1 and Bsm-I VDR polymorphisms and HLA DRB1*04. Notably, the VDR polymorphisms observed to be more frequent in T2DM patients correlated with increased VDR expression and IL-12 production, as well as with metabolic parameters of susceptibility to T2DM, including serum cholesterol and high-density lipoprotein levels. VDR polymorphisms are present in T2DM, and correlate with HLA DRB1*04 and with immunologic and metabolic parameters; results from this study add T2DM to the list of diseases that are likely modulated by an HLA/VDR interaction.

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Genetic and diabetic auto-antibody markers in Saudi children with type 1 diabetes

Cited by 28 publications

References 37 publications

Glutamic Acid Decarboxylase 65 and Islet Cell Antigen 512/IA-2 Autoantibodies in Relation to Human Leukocyte Antigen Class II DR and DQ Alleles and Haplotypes in Type 1 Diabetes Mellitus

Glutamic Acid Decarboxylase 65 and Islet Cell Antigen 512/IA-2 Autoantibodies in Relation to Human Leukocyte Antigen Class II DR and DQ Alleles and Haplotypes in Type 1 Diabetes Mellitus

HLA-DQB1* alleles and genetic susceptibility to type 1 diabetes mellitus

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

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