Genetics of the HLA Region in the Prediction of Type 1 Diabetes

Abstract

Type 1 diabetes (T1D) is one of the most widely studied complex genetic disorders, and the genes in HLA are reported to account for approximately 40% to 50% of the familial aggregation of T1D. The major genetic determinants of this disease are polymorphisms of class II HLA genes encoding DQ and DR. The DR-DQ haplotypes conferring the highest risk are DRB1*03:01-DQA1*05:01-DQB1*02:01 (abbreviated “DR3”) and DRB1*04:01/02/04/05/08-DQA1*03:01-DQB1*03:02/04 (or DQB1*02; abbreviated “DR4”). The risk is much higher for the heterozygote formed by these two haplotypes (OR = 16.59; 95% CI, 13.7–20.1) than for either of the homozygotes (DR3/DR3, OR = 6.32; 95% CI, 5.12–7.80; DR4/DR4, OR = 5.68; 95% CI, 3.91). In addition, some haplotypes confer strong protection from disease, such as DRB1*15:01-DQA1*01:02-DQB1*06:02 (abbreviated “DR2”; OR = 0.03; 95% CI, 0.01–0.07). After adjusting for the genetic correlation with DR and DQ, significant associations can be seen for HLA class II DPB1 alleles, in particular, DPB1*04:02, DPB1*03:01, and DPB1*02:02. Outside of the class II region, the strongest susceptibility is conferred by allele B*39:06 (OR =10.31; 95% CI, 4.21–25.1) and other HLA-B alleles. In addition, several loci in the class III region are reported to be associated with T1D, as are some loci telomeric to class I. Not surprisingly, current approaches for the prediction of T1D in screening studies take advantage of genotyping HLA-DR and HLA-DQ loci, which is then combined with family history and screening for autoantibodies directed against islet-cell antigens. Inclusion of additional moderate HLA risk haplotypes may help identify the majority of children with T1D before the onset of the disease.

Protective major histocompatibility complex allele prevents type 1 diabetes by shaping the intestinal microbiota early in ontogeny

“…Development of autoimmune diabetes is regulated by multiple genetic polymorphisms and largely unknown environmental factors. This and many other autoimmune diseases have their strongest genetic association with the HLA-D locus (1). Certain HLA-D haplotypes, such as DRB1*0401-DQB1*0302 and DRB1*0301-DQB1*0201, confer elevated risk for T1D; others, notably DRB1*1501-DQB1*0602, promote dominant protection (estimated to be as high as 97%) (2).…”

“…Similar to the disease in humans, diabetes in NOD mice is a T cell-dependent, polygenic disorder that is modified by environmental factors. Parallel to the situation in humans, the MHC locus is by far the dominant genetic determinant in mice (1). The NOD strain expresses an unusual MHC-II A complex, termed A g7 , and does not express an E complex due to deletion of the Eα promoter (3).…”

Concise review: Hematopoietic stem cell transplantation to treat insulin-dependent diabetes mellitus

“…Genetically, the MHC HLA region of chromosome 6p21 (also called the IDDM1 locus) is well-known for increasing susceptibility for T1D. It is associated with 40-50% of the familial aggregation of T1D (Noble and Valdes, 2011). The HLA haplotypes contain high risk haplotypes, moderate haplotypes, and protective haplotypes.…”

Maturity onset diabetes of the young: Diagnosis and treatment options

“…Thus antibodies are an effective tool in diagnosing MODY but rarely a combination of monogenic forms with T1DM may exist [30,31] Still the most exact diagnostic procedure that can be performed is genetic testing which is a gold standard when it comes to monogenic diseases [32]. Haplotypes may also have a significant impact when diagnosing MODY since T1DM usually is associated with specific human leukocyte antigens [33,34].…”