A new HLA-DR2 extended haplotype is involved in insulin-dependent diabetes mellitus susceptibility (original) (raw)
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Tissue Antigens, 1992
In the Sardinian population a very high incidence of insulin-dependent diabetes mellitus (IDDM) and the lack of HLA-DR2 protective effect due to the high frequency of the A2, Cw7, B17, 3F31, DR2, DQw1 extended haplotype has been reported. This haplotype, carrying a Serine at position 57 of the DQB1*0502 allele, has been previously reported to be underrepresented in patients when compared to controls. In order to provide an explanation for this finding, we defined by RFLP analysis the HLA haplotype of 45 Sardinian IDDM patients and 49 controls. All DR-2DQw1 subjects were molecularly characterized at the HLA DQA and DQB loci. All DR2-positive patients and the vast majority of the DR2-positive controls had the DQB1*0502 allele at the DR2-linked DQB1 locus, with no statistically significant difference between the two groups. All DQA1 genes were the ones expected, with only two exceptions. Nine out of 10 of the DR2-positive patients were compound heterozygotes for DQB1*0201/DQB1*0502 alleles; only this allele combination was significantly increased (p less than 0.0003). Our data suggests that a) the DQB1*0502 allele is neutral for IDDM development and b) the susceptibility to IDDM in our DR2-positive patients is related to the compound heterozygous state between the neutral DQA1*0102/DQB1*0502 and the susceptibility DQA1*0501/DQB1*0201 alleles.
American Journal of Medical Genetics, 1998
Several publications have shown that certain alleles at the HLA-DRB1, -DQA1, and -DQB1 loci are associated with insulindependent diabetes mellitus (IDDM). Many of these studies have claimed that HLA-DQ␣1 Arg52 and DQ1 Asp57 showed the strongest association with IDDM, but these results could not be confirmed in different populations. We have recently found that DR1 Lys71+ provided major susceptibility to IDDM and that DQ1 Asp57− had an additive effect to DR1 Lys71+ [Zamani et al., 1994a: Eur J Hum Genet 2:177-184]. This was confirmed with haplotype analysis in multiplex IDDM families [Zamani et al., 1996a: J Med Genet 33:899-905]. Therefore, we have reanalyzed the data from the literature on the association of the human leucocyte antigen (HLA) DRB1, DQB1, and DQA1 with IDDM in different ethnic groups to determine whether different amino acids in the antigen binding cleft of HLA class II molecules play a preponderant role in the development of IDDM. The results showed that the DR1 Lys71+ allele provided the highest relative risk for IDDM in the Belgian, Danish, Greek Taiwanese, and Chinese population while this was not the case in Norwegians, Sardinians, and Algerians. Indeed, in the Sardinian and Algerian population the DRB1*0401 allele encoding Lys 71+ is very rare. Nevertheless, the few positive cases were always in the patient group. We also measured the clinical relevance of the testing for DR1 Lys71 , DQ1 Asp57 , and DQ␣1 Arg52 by calculating a prevalence-corrected positive predictive value (PcPPV), a prevalence corrected negative predictive value (Pc-NPV), the sensitivity and specificity of these tests. The results indicated that the sensitivity of the test for DR1 Lys71+ was lower than for DQ␣1 Arg52+ and DQ1 Asp57− , while testing for DR1 Lys71+ was more specific than testing for DQ1 Asp57− and DQ␣1 Arg52+ and that the DR1 Lys71+ allele had a higher PcPPV than DQ␣1 Arg52+ and DQ1 Asp57− in all studied populations. These results also showed that testing for DR1 Lys71+/+ can be useful in IDDM risk assessment particularly in populations with a high prevalence (P) of IDDM such as the Danish (P IDDM = 0.65%). PcPPV for DR1 Lys71+/+ was 0.2313 in the Danish, indicating a 23.13% risk for an individual who is homozygous for the genotype DR1 Lys71+/+ to develop IDDM. Some mechanisms which might explain the role of these HLA class II alleles in susceptibility to IDDM are discussed. Am.
Population genetic analyses of insulin dependent diabetes mellitus using HLA allele frequencies
Clinical Genetics, 2008
In order to try to detect heterogeneity within insulin dependent diabetes mellitus (IDDM) and to distinguish a mode of inheritance of IDDM, population genetic analyses were performed using HLA allele frequencies. HLA-A and-B typing performed on 231 IDDM individuals and 268 controls from the southeastern U.S. showed significant increases with IDDM in A2, B8, B15 and B18, and significant decreases in Aw23, B7, B14 and B17. The combination of HLA-B8/BI5 showed a greatly increased risk (RR=25.5). Between the 120 IDDM individuals and 123 controls HLA-DR typed, HLA-DR3 and-DR4 were significantly increased among the IDDM group and DR2 and DR7 were decreased. The risk for DR3/4 was 29.2. It appeared that the B15 association was secondary to the DR4, but the B8/DR3 association showed no difference. Using the method of Curie-Cohen, no significant increases in risk were found for the B8/Bl5 or DR3/DR4 heterozygotes when compared to the respective homozygotes. Using the method of Thomson and Bodmer, the dominant mode of inheritance was excluded for DR4 only. There was a significant increase in B15 and DR4 in those with onset before age 20. No significant differences were found among the DR phenotypes with respect to season.
HLA-D and -DR antigens in genetic analysis of insulin dependent diabetes mellitus
Diabetologia, 1981
Three groups of patients with insulindependent diabetes mellitus, ascertained by different procedures, were investigated for HLA-A, B, C and D antigens (n = 164), and a subset (n = 93) for HLA-DR. Both HLA-D/DR3 and D/DR4 were strongly positively associated and D/DR2 was negatively associated with insulin-dependent diabetes. HLA-DR4 was found to be a better marker for insulin-dependent diabetes than Dw4. The HLA-B associations (B8, B15 and B18) were clearly secondary to the increases of HLA-D/DR3 and D/DR 4. The HLA associations did not differ between familial and isolated cases indicating that these two groups may well have a common genetic background. Based on analysis of HLA-haplotype sharing in affected sibling pairs, a simple dominant model of inheritance could be ruled out, and a simple recessive model was found unlikely. The relative risks for the HLA-Dw3,4 and HLA-DR3,4 phenotype were 21.2 and 44.4 respectively and exceeded those of both the HLA-Dw3 and HLA-DR3 (5.6 and 4.3) as well as the HLA-Dw4 and DR4 (10.1 and 10.5) phenotypes. This argues against an intermediate genetic model but further studies are needed to clarify whether there is more than one susceptibility gene for insulin-dependent diabetes mellitus within the HLA-system.
ANALYSIS OF HLA HAPLOTYPES IN FAMILIES WITH TYPE 1 DIABETES MELLITUS IN LA R�UNION ISLAND
European Journal of Immunogenetics, 1996
To analyse HLA and insulin-dependent diabetes mellitus (IDDM) association in the ethnically mixed population of La RCunion island, we carried out a family study on 70 diabetic subjects. HLA-DQAI, -DQB 1 and -DRB 1 typing was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), completed by PCRsequence-specific oligonucleotide (SSO) and PCR-sequence-specific priming (SSP). Haplotype-relative risks (HRR) were determined with the non-transmitted parental haplotypes as controls, and relative risks (RR) were calculated with a classical case-control study. The most significant risks were found for the cis and trans combinations between DQA1*03 or *0501 (Arg52') and DQB1*02 or *0302 (Asp57-) alleles, suggesting a direct role for the HLA-DQ heterodimer in IDDM susceptibility. Interestingly, due to the mixed origin of the population, the trans-encoded DQ molecules in the (DR3)-DQAl*O50 I -DQB 1*02/(DR4)-DQA1*03-DQB 1 *0302 subjects were also found cisencoded in patients with the (DR7 or 9)-DQA1*03-DQB1*02 haplotype and in a patient with the rare (DRI I)-DQA1*0501-DQB 1 *0302 haplotype. A relative predispositional effect (RPE) analysis gave significant haplotype-IDDM+ associations in the following order: (DR3)-DQAl*O5Ol-DQBl*O2 >(DR4)-DQAl*03-DQB1*0302> (DR9)-DQA1*03-DQB*02>(DR7)-DQA1*03-DQB1*02~(DR2)-DQAl*O1-DQB1*0502. No protective effect remained significant once the susceptible haplotypes were removed. A stratification study showed a stronger influence of the DQ genes than DRBl alleles within the DR7 haplotypes. On the other hand, IDDM subjects with only one susceptible haplotype had inherited this haplotype more often from their father than from their mother. This paternal effect could be related to the greater risk of IDDM in offspring of diabetic fathers than the risk in offspring of diabetic mothers.
Human Immunology, 1991
A study of DR4 subtypes has been dooe io Spaoish unrelared cootrols and insulin-depen-den¡ diabe¡ics by usiog dot blot hybridizarioo wirh spe-ci6c DR4BI exon-2 oligonucleorides and automated dideoxy DNA seqr.rencing. Dwl5-DQr,8 is the pre-domio¿nt DR4 subcype preseot io our normal population ()7 Vo): this DR4 frequeocy cha¡acre¡istic singles out our populatioo from all orher Caucasoids resred so far and may also be a marker of the origioal lbedan paleo-North Afric¿n populario¡. Dwl t-DQv,¡8 is oot sig-oi6candy increased in our iosulio-dependen¡ diabetics ABBREVIATIONS 6 eriologic fractioo IDDM insulin-dependentdiabetes mellitus
Human Immunology, 2008
Patients with high-risk HLA-DR-DQ genotypes for type 1 diabetes (T1D) were compared to HLAmatched controls to evaluate T1D risk for other HLA loci, including HLA-A, -B, -Cw, and DPB1. Patients (n=133) with high-risk genotypes (DR3/DR3, DR3/DR4, DR4/DR4) were selected from the Lazio (Rome) region of Italy. Screening of more than 9000 subjects from the Lazio region and northern Italy yielded 162 controls with high-T1D-risk haplotypes. Although the overall distributions were not significantly different, allele frequency differences were discovered between the controls from Lazio and those from Northern Italy for some alleles previously shown to affect T1D risk, such as A*3002, DPB1*0301, and DPB1*0402. Therefore, Lazio patient data were compared both to the Lazio subset of controls (n=53) and to the entire group of controls for association analyses. Significant allele frequency differences between patients and DR-DQ-matched controls were found for specific alleles at all loci. Data for the DR3/DR3 subset of patients and controls showed an increase of Cw*0702 in patients. Reduced patient, compared to control, frequencies were seen for several alleles, including A*0101, B*0801, and Cw*0701, all found on the highly-conserved, extended DR3 haplotype known as 8.1 in DR3/DR3, but not DR3/DR4, subgroup. DPB1*0101, often found on 8.1 haplotypes, was also less frequent in DR3/DR3 patients than controls. Analysis of family-based data from the HBDI repository was consistent with the observed results from the Italian subjects, suggesting the presence of a T1D-protective locus at or near A*0101 and a second T1D-protective locus at or near DPB1*0101. These data suggest that T1D risk conferred by the 8.1 haplotype is genotype dependent.
Diabetologia, 1992
In Caucasians the predisposition to Type i (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[3 chain. In Finland the haplotypespecific absolute risk for developing Type i 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-DQc~ and DQI3 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 i 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,
Human Immunology, 1993
The Sardinian population has an extremely high incidence of IDDM (30.2 of 100.000 in the age group of 0-14 years). This study reports the molecular characterization of HLA class II genes in 120 IDDM sporadic patients and 89 healthy subjects of Sardinian origin. Compared with other Caucasians, both Sardinian patients and controls had an unusual distribution of haplotypes and genotypes. In particular, there was a high gene frequency of the DRBI*0301, DQAI*0501, DQBI*0201 susceptibility haplotype both in patients (0.58) and controls (0.23) while a reduction of the DRB1*1501, DQAl*0102, DQBl*0602 protective haplotype (0.03) was observed in the healthy population. This distribution may partially explain the high incidence of IDDM reported in Sardinia. The analysis of the DQf157 and DQa 52 residues showed that the absence of Asp 57 and the presence of Arg 52 were associated with IDDM in a dose-response manner. On the other hand, we found that (a) a very similar distribution of these residues was found when comparing Sardinians with another healthy Caucasian population from the same latitude but with a lower rate of IDDM incidence; (b) several genotypes encoding the identical DQa52/DQf157 phenotype carried very different relative risks; and (c) the DRBI*0403, DQAI*0301, DQB 1"0304 haplotype (DQf157 Asp-neg and DQa 52 Argpos) was found in 40% of the DR4-positive controls but not in patients (p-0.00034), while the DRBI*0405, DQAI*0301, and DQBI*0302 haplotype carrying the same residues at the same positions was found in 70% of the DR4-positive patients and in only one control (p = 0.00003). These findings suggest that IDDM susceptibility cannot be completely explained by the model in which only DQa 52 and DQf157 residues are taken into account. Human Immunology 37, 85-94 (1993) ABBREVIATIONS Arg arginine Asp aspartic acid IDDM insulin-dependent diabetes mellitus MHC major histocompatibility complex PCR RR SSO polymerase chain reaction relative risk sequence-specific oligonucleotide