J. Fletcher

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.

Trans-racial studies implicate HLA-DQ as a component of genetic susceptibility to type 1 (insulin-dependent) diabetes.

SummaryType 1 (insulin-dependent) diabetic patients and control subjects of Afro-Caribbean Negroid racial origin were investigated by serological HLA-DR-typing and restriction fragment length polymorphism analysis using DNA probes corresponding to the DQα, DQβ and DRβ chain genes. Combined analysis indicated that four DR antigens are positively associated with the condition in Negroid subjects — DR3, 4, 7 and w9. DR3 and 4 are also associated in Caucasians, but the relative risk for DR3 is lower in Negroid subjects. The DR7 association is specific for the Negroid race, and DRw9 is only weakly associated in Caucasoid subjects. Restriction fragment length polymorphism analysis demonstrated a DQβ restriction pattern in Negroid subjects which is absent from Caucasoid subjects. This pattern was associated with DRw9 and a subset of DR7, and was markedly increased in frequency in diabetic patients compared with control subjects (48.7% vs 10.4%, respectively; P<10−4). In the absence of this pattern, DR7 showed no positive association. DR3 in Negroid subjects was associated with two distinct DQα-DQβ patterns, only one of which was positively associated with diabetes. A DQβ pattern, in linkage disequilibrium with different DR antigens in different races, conferred a consistent protective effect against the development of Type 1 diabetes. Trans-racial genetic analysis thus supports a primary role for DQ in susceptibility to Type 1 diabetes.

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.

Class II HLA DNA polymorphisms in Type 1 (insulin-dependent) diabetic patients of North Indian origin

SummaryGenetic associations with Type 1 (insulin-dependent) diabetes may be primary or secondary to linkage disequilibrium. Studies of different racial groups should allow these to be distinguished. We have reported that Type 1 diabetes is associated with HLA-DR3 and -DR4 in subjects of North Indian (Punjab) origin and now present the results of a study of HLA class II DNA polymorphisms in this group and in white caucasoid subjects. DR4 in North Indian Type 1 diabetic patients was associated with DQβ and DXα DNA polymorphisms identical to those found in DR4-positive white caucasoid patients. This DQβ/DXα pattern was increased in frequency in North Indian diabetic patients vs control subjects (33.3% vs 8.5%,p<0.001, relative risk=5.12 (95% confidence limits: 1.96–13.4)). A DQβ polymorphism with very low relative risk for Type 1 diabetes in white caucasoid subjects was also markedly reduced in North Indian diabetic patients vs control subjects (2.3% vs 24.7%,p<0.02, relative risk = 0.10 (95% confidence limits: 0.02–0.46)). This pattern was associated with DR2 in white caucasoid subjects, but with DRw6 in North Indians. A DR3-associated DRβ polymorphism was markedly increased in North Indian diabetic patients vs control subjects (90.2% vs 40.7%,p<10−6, relative risk = 12.1 (95% confidence limits: 4.32–33.9)). The DQ subregion may be a primary site of genetic influence on susceptibility to Type 1 diabetes. Further studies in different racial groups will clarify the HLA associations of Type 1 diabetes.

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.

Diabetes in the UK West Indian Community: the Wolverhampton Survey

A survey was carried out to determine the prevalence of known diabetes amongst West Indians living in Wolverhampton. Two hundred and fifty‐one West Indians with diabetes were identified from a computerized register, which records all diabetic patients in the Wolverhampton area attending either the hospital diabetic clinic or general practitioner mini‐clinics, and from questionnaire data obtained through local general practitioners. An estimated 4.4% of the Wolverhampton population are of West Indian origin determined by the 1981 census, giving a prevalence of known diabetes of 2.2% compared with 1.2% in the indigenous UK white Caucasian population. Only 4% of these patients were truly insulin‐dependent but 38% were insulin‐treated, 43% were on oral hypoglycaemic agents and 19% on diet alone. Only 1.6% were diagnosed below the age of 20 years, with peak frequency of diabetes occurring in the age group 45–64 years. Thirty‐eight percent of all patients were obese, 40% were hypertensive, but only 4% had a history of angina or myocardial infarction. In UK West Indians non‐insulin‐dependent diabetes is common and is predominantly a disease of middle age, whereas insulin‐dependent diabetes is relatively uncommon.

The HLA-D associations of type 1 (insulin-dependent) diabetes in Punjabi Asians in the United Kingdom.

SummaryType 1 (insulin-dependent) diabetes is less common in Asian Indians than in white Caucasoids. Forty-five Punjabi Asians with Type 1 diabetes and 96 racially matched control subjects were HLA-DR typed. DR3 was increased in diabetic patients vs control subjects (82% vs 38%, p<10−5) with relative risk 7.7 and etiological fraction 0.72. DR4 was increased in diabetic patients vs control subjects (31% vs 7%, p<0.003) with relative risk 5.7 and etiological fraction 0.26. DR2 showed a negative association (relative risk 0.19, etiological fraction −0.28), as did DR7 (relative risk 0.21, etiological fraction −0.33). HLA-DQβ-chain gene probing using restriction enzyme BamHI in 43 diabetic patients and 90 control subjects showed that the DR1-associated 6.2 and 3.2kb fragments were less common in diabetic patients than in the control subjects (12% vs 36%, p<0.02). A 12kb fragment was associated with DR4 in both diabetic patients and control subjects. DR3 is the major susceptibility factor for Type 1 diabetes in Punjabi Asians and DR4 is a second marker. Gene probing indicates that the same DR4 subset is associated with the condition as in white Caucasoids. DR1 and its associated DQβ restriction fragments are reduced in Asian Type 1 diabetic patients making it unlikely that DR1 haplotypes carry a predisposing factor in this racial group. We conclude that the genetic component of Type 1 diabetes in Punjabis shows differences from that of the white Caucasoid population and that the lower frequency of DR4 in this population may contribute to the lower prevalence of Type 1 diabetes.