Distributions of HLA‐DRB1/DQB1 alleles and haplotypes in the North‐eastern Thai population: indicative of a distinct Thai population with Chinese admixtures in the Central Thais

Abstract

HLA-associated relative risks of type 1 (insulin-dependent) diabetes mellitus were analysed in population-based Swedish patients and controls aged 0-34 years. The age dependence of HLA-associated relative risks was assessed by likelihood ratio tests of regression parameters in separate logistic regression models for each HLA category. The analyses demonstrated an attenuation with increasing age at onset in the relative risk for the positively associated DQB1*0201-A1*0502/B1*0302-A1*0301 (DQ2/8) genotype (P = 0.02) and the negatively associated DQB1*0602-A1*0102 (DQ6.2) haplotype (P = 0.004). At birth, DQ6.2-positive individuals had an estimated relative risk of 0.03, but this increased to 1.1 at age 35 years. Relative risks for individuals with DQ genotype 8/8 or 8/X or DQ genotype 2/2 or 2/X, where X is any DQ haplotype other than 2, 8 or 6.2, were not significantly age-dependent. An exploratory analysis of DQ haplotypes other than 2, 8 and 6.2 suggested that the risk of type 1 diabetes increases with age for DQB1*0604-A1*0102 (DQ6.4) and that the peak risk for the negatively associated DQB1*0301-A1*0501 haplotype is at age 18 years. There was also weak evidence that the risk for DQB1*0303-A1*0301 (DQ9), which has a positive association in the Japanese population, may decrease with age. We speculate that HLA-DQ alleles have a significant effect on the rate of beta cell destruction, which is accelerated in DQ2/8-positive individuals and inhibited, but not completely blocked, in DQ6.2-positive individuals.

High frequency of abnormal glucose tolerance in DQA1*0102/DQB1*0602 relatives identified as part of the Diabetes Prevention Trial?Type 1 Diabetes

“…It is possible that many of the DQA1*0102/ DQB1*0602 subjects with abnormal glucose tolerance will either never manifest overt diabetes, or will develop diabetes only later in life. Such a scenario would be consistent with data indicating that the relative protection of DQA1*0102/DQB1*0602 against the development of type 1 diabetes wanes with increasing age of diagnosis [29,30]. Similarly, the frequency of high-risk alleles is decreased with increasing age at diagnosis [31,32].…”

Age-dependent variation of genotypes in MHC II transactivator gene (CIITA) in controls and association to type 1 diabetes

“…In the Caucasian population, there are two major susceptibility haplotypes for T1D, DRB1*03-DQA1*05:01-DQB1*02:01 and DRB1*04-DQA1*03:01-DQB1*03:02, and one protective haplotype, DRB1*15-DQA1*01:02-DQB1*06:02. 2,3 The regulation of the MHC II genes is mainly at the transcriptional level, and one of the crucial factors is the class II transactivator, encoded by the CIITA gene (16p13). The CIITA protein is a non-DNA-binding co-activator, which acts as a platform for the assembly of transcription factors that bind to MHC II promoters and control transcription.…”

“…9 The function of the PII promoter in humans has not yet been fully characterized. 8 Because CIITA has a unique role in the control of MHC II expression and the MHC II locus is the major genetic determinant 1 Neuroimmunology Unit, Department of Clinical Neuroscience, Centre for Molecular Medicine, L8:05, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; 2 Neurodegeneration and Inflammation Genetics Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden; 3 Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; 4 Molecular and Genetics Core, Diabetes Endocrinology Research Center, University of Washington, Seattle, WA, USA; 5 Salish Kootenai College, Pablo, MT, USA; 6 Department of Statistics and Actuarial Science, Simon Fraser University, Burnaby, British Columbia, Canada; 7 Diabetes and Cardiovascular Disease, Genetic Epidemiology, Department of Clinical Sciences, Skåne University Hospital, Lund, Sweden; 8 Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden; 9 Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden; 10 Department of Pediatrics, Ryhov County Hospital, Jö nkö ping, Sweden; 11 Department of Medicine, Skåne University Hospital, Lund, Sweden; 12 Department of Pediatrics, Skåne University Hospital, Lund, Sweden; for susceptibility to autoimmune diseases, CIITA is an interesting candidate gene in the study of autoimmune diseases like T1D. 10 Previously, we found genome-wide significant linkage on chromosome 16 in the region of CIITA to T1D (LOD ¼ 3.7), among T1D patients who also carry the DRB1*03 and DRB1*04 alleles.…”

“…11 The HLA association to T1D is also known to vary with age at onset, such that the association is stronger in younger patients compared with older patients. 3,12,13 Genome-wide significant association to celiac disease has recently been reported for markers in the CIITA gene. 14 In addition, increased susceptibility to myocardial infarction (MI), rheumatoid arthritis (RA) and multiple sclerosis (MS) has been demonstrated for a polymorphism (rs3087456) in the 5 0 region of type III CIITA.…”

D6S265*15 marks a DRB1*15, DQB1*0602 haplotype associated with attenuated protection from type 1 diabetes mellitus

“…Although diabetic patients carrying DRB1*15, DQB1*0602 are extremely rare, their existence indicates that the protective effect of this haplotype is not absolute. Sequence analysis of rare patients and autoantibody-positive first-degree relatives with DQB1*0602 have demonstrated that they carry normal alleles lacking any mutations that would affect the peptide binding site [2,3].…”