HLA haplotypes in Type 1 (insulin-dependent) diabetes mellitus: molecular analysis of the HLA-DQ locus

Abstract

In Caucasians the predisposition to Type 1 (insulin-dependent) diabetes mellitus has been shown to associate with HLA-DR3,DQw2 and DR4,DQw8 and with the presence of amino acids other than aspartic acid at position 57 on the HLA-DQ beta chain. In Finland the haplotype-specific absolute risk for developing Type 1 diabetes differs between various DR3 and DR4 positive haplotypes. The aim of our present analysis was to find out whether this variation is attributable to polymorphism at the DQ locus. As part of a nationwide prospective study including 757 serologically HLA genotyped families, we determined HLA-DQ alpha and DQ beta restriction fragment polymorphisms in 17 selected families with important susceptibility haplotypes. Additionally, the DQA1 alleles were determined from 19 haplotypes using sequence-specific oligonucleotide probes, and the DQB1 second exon was sequenced from nine haplotypes. The DR3 as well as DR4 positive haplotypes frequently found in Type 1 diabetic patients showed no variation at the HLA-DQ locus, and they were DQw2 and DQw8, respectively. The absolute risk for Type 1 diabetes for DR4,DQw8 positive haplotypes A2,Cw4,Bw35,DR4 A3,Cw3,Bw62,DR4, A24,Cw7,Bw39,DR4, A2,Cw3,Bw62, DR4, and A2,Cw1,Bw56,DR4 was 35/100,000, 130/100,000, 166/100,000, 196/100,000, and 218/100,000, respectively. The absolute risks for DR3,DQw2 positive haplotypes A1, Cw7,B8,DR3 and A2,Cw7,B8,DR3 were 68/100,000 and 103/100,000, respectively. These results provide further evidence that not only the polymorphism at the DQ locus but also other genes of the haplotypes contribute to susceptibility to Type 1 diabetes.

A population-specific diabetogenic haplotype HLA-A2,Cw1,B56,DR4,DQ8 is associated with high birthweight in Finnish diabetic families

“…Alterations in fetal growth are known to associate with T1D in various ways. 9 Our finding is particularly interesting, since we show that the [B56,DR4] haplotype, which strongly increases the T1D risk in Finland, but has not been found in T1D patients outside this country, 5,6 is associated with high BW. At the present, we do not have data on BW in non-diabetic individuals without a family history of T1D who carry the [B56,DR4] haplotype.…”

“…The [A2,Cw1,B56,DR4,DQ8] haplotype is relatively rare in Finland, whereas the susceptibility haplotypes [B8,DR3], [B62,DR4] and [B39,DR4] are more common also in the general population. 5,6,45 Maternal age of 35 years or above is known to increase BW 32 as well as the risk of developing T1D in the offspring. 46 The proportion of parturients aged 35 years or above has increased over time and is now 19.0% in Finland.…”

“…4 In North Europe, HLA haplotypes [A1,Cw7,B8, DR3,DQ2], [A2,Cw3,B62,DR4,DQ8] and [A24,Cw7,B39, DR4,DQ8] predispose strongly to T1D, whereas haplotypes [A3,Cw4,B35,DR1] and [A3,Cw7,B7,DR2] are reduced in T1D patients and considered as 'protective'. 5,6 In Finland, a specific haplotype [A2,Cw1,B56,DR4,DQ8] that increases the risk of T1D only in the Finnish population has been identified. 5 It is the third most common susceptibility haplotype and the most common one transmitted from a diabetic parent to the T1D offspring.…”

“…5 It also carries the highest haplotype-specific risk for T1D. 6 The [Cw1,B56,DR4,DQ8] haplotype is conserved, associating only with HLA alleles A2, A1, A3 and A11; alleles other than A2 are, however, infrequently found in individuals with T1D. 7 It has been claimed that the proportion of Finnish T1D patients with a non-susceptibility HLA haplotype is presently higher than that in the 1960s, 8 suggesting a reduced genetic susceptibility in the disease pathogenesis.…”

A new marker in the HLA class I region is associated with the age at onset of IDDM

“…Recent serological and molecular typing of a large Finnish population suggests that the HLA-A alleles (MHC class I region) may be 'anchors' for disease-susceptibility haplotypes [8,9]. Finally, whilst previous studies have shown that the MHC class II association is dependent upon the age at onset of IDDM very little is known about the class I region [10][11][12][13].…”