K. H. Jacobs

HLA-DQA1 and -DQB1 Alleles Associated With Genetic Susceptibility to IDDM in a Black Population

Transracial analysis provides a method of distinguishing primary associations between insulin-dependent diabetes mellitus (IDDM) and HLA class II alleles from those secondary to linkage disequilibrium. Blacks show DR-DQ relationships that are different from other races and are a useful group in which to investigate HLA-D region associations with IDDM. In this study, the frequencies of HLA-DQA1 and -DQB1 alleles in Afro-Caribbean IDDM and control subjects were compared. Alleles were identified with sequence-specific oligonucleotide probing. The DQA1 allele A3 was positively associated with IDDM (relative risk [RR] = 25.3, corrected P [Pc] < 7.0 × 10−6. The DQB1 alleles DQw2 and DQw8 were also positively associated (RR = 4.7, Pc < 6.5 × 10−3 and RR = 12.3, Pc = 3.4 × 10−3, respectively). The A1.2 and DQw6 alleles were negatively associated (RR = 0.16, Pc < 3.5 × 10−3 and RR = 0.15, Pc = 2.4 × 10−2, respectively). These findings were compared to data from other races. The positive associations with A3 and DQw2 are consistent with all racial groups investigated. The negative association with DQw6 is present in all racial groups in which it is a common allele. These findings suggest that DQ alleles, and hence DQ molecules, may directly affect predisposition to IDDM.

Susceptibility to IDDM in a Chinese Population: Role of HLA Class II Alleles

MHC associations with IDDM in a Chinese population were studied to investigate genetic susceptibility to the disorder. The frequency of HLA-DR3 was significantly higher in the diabetic patients (19/49 [38.7%] vs. control subjects, 11/105 [10.5%], Pc < 1.3 × 10−3, RR = 5.3 [CI 2.3–12.1]), whereas DR4 was not (11/49 [22.4%] vs. 28/105 [26.7%], NS). The frequency of DR3/4 heterozygosity was higher in the diabetic patients (6/49 [12.2%] vs. control subjects, 0/105 [0%], P = 1.7 × 10−3, RR = 31.5 [CI 3.8–263.6]). The frequency of DR3/9 heterozygosity also was higher in the diabetic patients (6/49 [12.2%] vs. control subjects, 2/105 [1.9%], P = 0.03, RR = 6.2 [CI 3.0–12.7]). No significant associations were noted between DQB1 alleles and IDDM. Among DR4-positive subjects, the frequency of DQB1 allele DQB1*0302 was higher in the diabetic patients (10*11 [90.0%] vs. control subjects, 12/24 [50%], Pc < 0.05, RR = 7.0 [CI 1.3–38.0]), and the frequency of DQB1*0401 was significantly lower in the diabetic patients (2/11 [18.2%] vs. control subjects, 16/24 [66.7%], Pc = 0.04, RR = 0.1 [CI 0.02–0.46]). No DR4 subtype was associated significantly with IDDM. The frequency of DQA1*0501, a DQA1 allele, was higher in diabetic patients (22/41 [53.7%] vs. control subjects, 20/95 [21.1%], Pc < 3 × 10−3, RR = 4.3 [CI 2.0–9.3]). The frequency of DQA1*0301, which has been associated consistently with IDDM in other ethnic groups, was not significantly higher in the diabetic patients in this study (27/41 [65.9%] vs. control subjects, 53/95 [55.8%], NS). The frequency of the DR4 haplotype DRB1*0405-DQA1*0301-DQB1*0401 was lower among DR4- positive diabetic patients (2/10 [20%] vs. DR4-positive control subjects, 12/21 [57.1%], NS), in direct contrast with Japanese populations. These results suggest that if DQB1 and DQA1 alleles determine IDDM susceptibility, other MHC factors must modify their effect.

Identification of susceptibility loci for Type 1 (insulin-dependent) diabetes by trans-racial gene mapping

SummaryA major component of inherited susceptibility to Type 1 (insulin-dependent) diabetes mellitus has been mapped to the major histocompatibility complex. Certain gene alleles in this region determine susceptibility and resistance to the disease. Mapping of susceptibility is hindered by the limitations of conventional tissue typing techniques, and by strong linkage disequilibrium within this part of the genome. Recombinant DNA technology and trans-racial studies have been used to allow finer mapping of genetic predisposition to Type 1 diabetes. These techniques have localised alleles encoding susceptibility and resistance to the DQ region. Other alleles determining disease susceptibility remain poorly localised.

HLA class II gene polymorphism contributes little to Hashimoto's thyroiditis

Previous studies of HLA and Hashimotos thyroiditis have shown weak associations between the disease and various HLA‐DR antigens.

Both DQA1 and DQB1 genes are implicated in HLA-associated protection from Type 1 (insulin-dependent) diabetes mellitus in a British Caucasian population

SummaryInherited susceptibility to Type 1 (insulin-dependent) diabetes mellitus is partly determined by HLA genes. It has been suggested that protection from disease may be conferred by HLA-DQB1 genes which encode molecules with aspartate at position 57. We investigated the contributions of HLA-DRB1, DQA1 and DQB1 genes to protection from disease. Restriction fragment length polymorphism and sequence specific oligonucleotide analysis in 156 British Caucasian Type 1 diabetic and 116 control subjects showed protection from disease was associated with DR2, DRw6 and DR7 haplotypes. The most protective DQA1 allele was DQA1*0102 which occurred on both DR2 and DRw6 haplotypes. The DQB1 alleles DQB1*0303, DQB1*0602 and DQB1*0603 were associated with protection, as was DQB1*0604, which encodes an Asp-57 negative DQβmolecule. Heterozygosity for both protective and predisposing HLA markers was reduced in diabetic compared with control subjects. We conclude that both DQA1 and DQB1 genes are implicated in HLA-associated protection from Type 1 diabetes in this British Caucasian population. The overall structure of the DQ heterodimer is critical and DQβ-Asp 57 is of secondary importance in determining protection from disease. The effect of protective HLA types may predominate over that of predisposing markers.

Allele-specific gene probing supports the DQ molecule as a determinant of inherited susceptibility to Type 1 (insulin-dependent) diabetes mellitus

SummaryTrans-racial analysis of disease associations has improved mapping of MHC-linked susceptibility to Type 1 (insulin-dependent) diabetes mellitus. In this study the contributions of the MHC class II DQA1 and DQB1 genes were investigated. Sequence-specific oligonucleotide gene probing in Type 1 diabetic and control subjects of North Indian origin supported the DQw1.18 allele of the DQB1 gene as a determinant of inherited protection against Type 1 diabetes (RR=0.12, pc<0.05). The A3 allele of the DQA1 gene was positively associated with the disease, (RR=3.6, pc<0.05), as was the DQw2 allele of the DQB1 gene (RR=4.6, pc<0.01). Trans-racial comparison of these disease associations indicates that DQ alleles may directly determine an element of inherited susceptibility to Type 1 diabetes.

Genetic susceptibility to multiple sclerosis in a Shanghai Chinese population the role of the HLA Class II genes

The association of MS with the HLA class II loci DR and DQ was investigated in subjects of Shanghai Chinese and British Caucasian origin. Our aim was to determine whether common alleles predispose to the disease in both races. In the Caucasian population MS was significantly positively associated with the putative haplotype DRB1*1501, DQA1*0102, DQB1*0602. In contrast, HLA class II alleles were not found to predispose to the disease in the Shanghai Chinese, suggesting that this haplotype is unlikely to be a universal susceptibility determinant. The absence of a disease association with the HLA-DR and -DQ genes in the Chinese population has a number of possible explanations. Our study suggests that other genetic and/or environmental components may be more important in determining susceptibility to MS in this race.

An investigation of Japanese subjects maps susceptibility to type 1 (insulin-dependent) diabetes mellitus close to the DQA1 gene.

Insulin-dependent diabetic and control subjects of Japanese origin were HLA-DRB1, -DQB1, and -DQA1 typed using restriction fragment length polymorphism analysis and sequence-specific oligonucleotide gene probing. The DQA1 allele DQA1*0301 was positively associated with the disease [48/52 (92%) diabetic patients versus 44/64 (69%) control subjects, Pc less than 0.03, RR = 4.97]. Alleles of the DRB1 and DQB1 genes showed no significant association with the disease. The frequency of DQB1 genotypes encoding the amino acid aspartic acid at position 57 of the DQ beta chain did not differ significantly between subjects with insulin-dependent diabetes mellitus (IDDM) and controls. These findings suggest that a susceptibility allele for IDDM in the Japanese is more closely associated with the DQA1 gene than the DQB1 gene.

An investigation of the association between HLA-DQ heterodimers and type 1 (insulin-dependent) diabetes mellitus in five racial groups.

The association between HLA-DQ alpha Arg52-HLA-DQ beta non-Asp57 heterodimers and type 1 (insulin-dependent) diabetes was compared in Japanese, Chinese, Caucasian, North Indian Asian, and Afro-Caribbean patients to determine their importance in disease susceptibility. The potential to encode four Arg52-non-Asp57 DQ heterodimers, two in cis and two in trans, was significantly associated with increased risk of type 1 diabetes in all races except the Japanese. The possibility of encoding two Arg52-non-Asp57 heterodimers was also significantly associated with increased risk of the disease in all races except the Japanese. The possibility of encoding one heterodimer was not significantly associated with type 1 diabetes in any of the races studied. Heterogeneity testing revealed significant differences in RR values for four, two, and one heterodimers in all races except the Japanese and significant differences in RR for four and two heterodimers when compared across the races. This, together with the lack of an association between Arg52-non-Asp57 heterodimers and type 1 diabetes in the Japanese, suggests that, assuming the same genetic basis for disease in all races, the heterodimer is unlikely to be of primary importance in susceptibility to the disease.

Tumour necrosis factor-beta polymorphism is unlikely to determine susceptibility to Type 1 (insulin-dependent) diabetes mellitus

SummaryTumour necrosis factor gene polymorphism has been proposed as a determinant of Type 1 (insulin-dependent) diabetes mellitus. Tumour necrosis factor-beta gene polymorphisms were analysed in 40 North Indian Asian Type 1 diabetic patients and 63 control subjects. A 5.5 kilobase gene fragment was significantly increased among the patients (82.5% vs 52%, pc<0.01). A 10.5 kilobase fragment was significantly reduced among the patients (70% vs 90.5%, pc<0.02). The 5.5 kilobase fragment was associated with DR3, and was not significantly increased among DR3-positive patients compared with DR3-positive control subjects. The 5.5 kilobase/5.5 kilobase genotype was increased among the diabetic subjects (30% vs 9.5%, pc<0.03). The 10.5 kilobase/10.5 kilobase genotype was reduced among the diabetic subjects (17.5% vs 47.5%, pc<0.02). The 5.5 kilobase/10.5 kilobase genotype was not significantly associated with disease. These findings contrast with those in a white Caucasian population, suggesting that tumour necrosis factor-beta polymorphisms do not predispose to Type 1 diabetes directly, but are in linkage disequilibrium with disease susceptibility alleles at other MHC loci.