HLA-D region β-chain DNA endonuclease fragments differ between HLA-DR identical healthy and insulin-dependent diabetic individuals

Owerbach, David; Lernmark, Åke; Platz, P.; Ryder, Lars P.; Rask, Lars; Peterson, Per A.; Ludvigsson, Johnny

doi:10.1038/303815a0

Cited by 258 publications

(104 citation statements)

References 16 publications

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“…It has long been known that the first intervening sequence in DQB from diabetic patients is different from that of normal HLA-DR matched control subjects [3,4,51]. Also, a wealth of regulatory sequences has been uncovered in the DQB and DQA genes [52,53], with no inkling as to their possible significance in the pathogenesis of this disease.…”

Section: Discussionmentioning

confidence: 99%

“…In insulin-dependent diabetes mellitus (IDDM), genetic linkage in Caucasian populations has been shown for the serologically-defined antigens DR3 and DR4, while DR2 has been shown to confer protection from the disease [2]. Later studies revealed that this was due to linkage disequilibrium of these alleles to various DQ alleles [3,4]. Furthermore, genes telomeric and centromeric to HLA-DQ were shown to be less highly associated with the disease than DQ itself [5], Of even greater significance is the fact that susceptibility to diabetes can be conferred by DQ A and B genes in trans position giving credence to the hypothesis that DQ molecules are true susceptibility genes for IDDM [6].…”

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confidence: 99%

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Polymorphic structural features of modelled HLA-DQ molecules segregate according to susceptibility or resistance to IDDM

Routsias

Papadopoulos

1995

Diabetologia

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SummaryThe structural features of HLA-DQ alleles which are susceptible and resistant to insulin-dependent diabetes mellitus (IDDM) have been examined using a model of their three-dimensional structure obtained by energy minimisation, based on the published structure of HLA-DR1. The model shows DQ molecules to have an overall shape nearly identical to that of DR molecules, but with significant differences in the fine structure: 1) the antigen-binding groove of DQ molecules has a polymorphic first pocket; this pocket can be either amphiphilic or hydrophilic, 2) The [349-56 dimerisation domain of DQ is polymorphic: hydrophobic, or amphiphilic, or hydrophilic and positively charged, leading to spontaneous or T-cell receptor-induced homodimer formation, or difficulty of the formation of such dimers, respectively; 3) a prominent Arg-Gly-Asp loop is formed by some DQ alleles ([3167-169) and probably functions in cell adhesion. There are also small differences in the residues and sequences implicated in CD4 binding but the significance of these differences cannot be evaluated at present. All seven DQ alleles which confer susceptibility to IDDM posses a hydrophilic first pocket in the antigen-binding groove, a hydrophobic or amphiphilic [349-56 dimerisation patch that allows for spontaneous or T-cell receptor-induced dimerisation, and the Arg-Gly-Asp loop. By contrast, in the protective alleles at least one of these three features is absent. This segregation of phenotypes according to susceptibility or resistance can well explain the model of tighter autoantigen binding by the protective alleles compared to the susceptible alleles, previously proposed for the pathogenesis of IDDM. [Diabetologia (1995[Diabetologia ( ) 38: 1251[Diabetologia ( -1261

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Polymorphic structural features of modelled HLA-DQ molecules segregate according to susceptibility or resistance to IDDM

Routsias

Papadopoulos

1995

Diabetologia

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“…The DQw8 serological specificity, previously called DQw3.2, is associated with type I (insulin-dependent) diabetes, whereas the DQw7 specificity, previously called DQw3.1, is not associated with type I diabetes (3)(4)(5)(6)(7)(8)(9). Tait et al (10) recently reported that the DQw8 association exists only in type I diabetic individuals who type as HLA-DR4/3.…”

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Primary Association of HLA-DQw8 With Type I Diabetes in DR4 Patients

1989

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DNA from 164 Caucasian type I (insulin-dependent) diabetic patients and 200Caucasian nondiabetic control blood donors were analyzed by the polymerase chain reaction technique for HLA-DR4 and the associated Dw and DQB subtypes of DR4. The DQw8 subtype of HLA-DR4 was associated with type I diabetes in all DR4 subgroups (DR4/3 and DR4/non-3). Dw subtypes of DR4 other than Dw10 did not confer additional association with type I diabetes. Thus, the DQ region appears to provide the primary major histocompatibility association with type I diabetes in most DR4 patients. Diabetes 38: 1989 T he serological type HLA-DR4 is associated with five alleles of the DRB1 locus (Dw4, Dw10, Dw13, Dw14, and Dw15) and two alleles of the DQB1 locus (DQw7 and DQw8) (1,2). The DQw8 serological specificity, previously called DQw3.2, is associated with type I (insulin-dependent) diabetes, whereas the DQw7 specificity, previously called DQw3.1, is not associated with type I diabetes (3-9). Tait et al. (10) recently reported that the DQw8 association exists only in type I diabetic individuals who type as HLA-DR4/3. DR4 subtypes (Dw4 and Dw10) are also associated with type I diabetes (11-13); however, the role of other Dw specificities remains controversial (11)(12)(13)(14).To further clarify the specific major histocompatibility associations with type I diabetes, we typed 164 type I diabetic patients, of which 120 typed as HLA-DR4, and 200 blood donor controls, of which 55 typed as HLA-DR4, for DQB1 and DRB1 subtypes. The association of DQw8 and type I diabetes was seen in all DR4 subgroups analyzed (DR4/3 and DR4/non-3). The distribution of Dw subtypes, other than Dw10, was similar in our HLA-DR4 type I diabetic patients and nondiabetic control subjects. With these data, we calculated that the absolute risks for type I diabetes in unrelated individuals homozygous for DR4 (DQw8) or heterozygous for DR4 (DQw8) /DR3 (DQw2) are 6.7 and 8.5%, respectively, frequencies approaching those seen in family studies (14). Thus, the presence of DQw8 appears to be the primary association with type I diabetes in DR4 patients. RESEARCH DESIGN AND METHODS

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“…class II HLA-DQA1, -DQB1, and -DRB1 loci determine whether a haplotype is associated with susceptibility, or protection, to type 1 diabetes (Owerbach et al 1983 ;Svejgaard et al 1989 ;Todd et al 1989 ;Cucca & Todd, 1996 ;She, 1996). Direct sequence analysis has demonstrated that the effect of the different DQ molecules can, in part, be correlated with amino acid variation at residue 57 of the DQβ chain (Todd et al 1987).…”

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Conditional ETDT analysis of the Human Leukocyte Antigen region in type 1 diabetes

Koeleman

Herr

Zavattari³

et al. 2000

Annals of Human Genetics

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Several studies have indicated that additional genes in the major histocompatibility complex (MHC) region, other than the class II genes HLA-DQB1 and -DRB1 (the IDDM1 locus), may contribute to susceptibility and resistance to type 1 diabetes. The relative magnitude of these non-DR\DQ effects is uncertain and their map location is unknown owing to the extraordinary linkage disequilibrium that extends over the 3.5 Mb of the MHC. The homozygous parent test has been proposed as a method for detection of additional risk factors conditional on HLA-DQB1 and -DRB1. However, this method is inefficient since it uses only parents homozygous for the primary disease locus, the DQB1-DRB1 haplotype. To overcome this limitation, Conditional ETDT was used in the present report to test for association conditional on the DQB1-DRB1 haplotype, thereby allowing all parents to be included in the analysis. First, we confirm in UK and Sardinian type 1 diabetic families that allelic variation at HLA-DRB1 has a very significant effect on the association of DQB1 and vice versa. The Conditional ETDT was then applied to the HLA TNF (tumour necrosis factor) region and microsatellite marker D6S273 region, both of which have been reported to contribute to IDDM1 independent of the HLA-DQB1-DRB1 genes. We found no evidence for a major role for either of these two regions in IDDM1. Combined genetic and biological studies in the last two decades have shown that alleles of the Correspondence :

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HLA-D region β-chain DNA endonuclease fragments differ between HLA-DR identical healthy and insulin-dependent diabetic individuals

Cited by 258 publications

References 16 publications

Polymorphic structural features of modelled HLA-DQ molecules segregate according to susceptibility or resistance to IDDM

Polymorphic structural features of modelled HLA-DQ molecules segregate according to susceptibility or resistance to IDDM

Primary Association of HLA-DQw8 With Type I Diabetes in DR4 Patients

Conditional ETDT analysis of the Human Leukocyte Antigen region in type 1 diabetes

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