Immunogenetics of Systemic Lupus Erythematosus in Spanish Patients: Differential HLA Markers

Gémez-Reino, Juan J.; Martı́nez-Laso, Jorge; Vicário, José L.; Paz‐Artal, Estela; Aragón, Angel; Martín-Villa, José Manuel; Juan, M D de; Pérez-Aciego, Paloma; Arnaiz‐Villena, Antonio

doi:10.1016/s0171-2985(11)80210-x

Cited by 20 publications

(1 citation statement)

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“…However, ~ values show that none of the DR alleles defined either by serology or RFLPs, show a stronger association with the disease than the o~-~DQ markers. Also, several results from studies in our and other populations suggest that regulatory non-coding DRB1 or DRB3 regions may have a role in Type 1 diabetes aetiopathogenesis: (1) A difference at the DRB1 gene non-coding region has been found between the B8-DR3(w17.1)-Dw24-DQw2 and the B18-DR3(wlT.2)-Dw25-DQw2 haplotypes [40], in addition to other RFLPs differences found at the DRB3 and DQA level [41], (2) Type 1 diabetes is predominantly associated with B8-DR3 (w17.1)-Dw24 in North European/American subjects and B18-DR3 (w17.2)-Dw25 in Mediterranean subjects [2, [36][37][38], (3) Systemic lupus erythematosus is similarly associated to B8-DR3 (w17.1)-Dw24 inNorth European/American subj ects and B 18-D R3 (wl 7.2) -Dw25 in Spanish subjects [42] and (4) Neonatal lupus is associated with B8-DR3 (w17.l)-Dw24 in both North European/American and Spanish subjects [43]. Taken together, these data support that Type 1 diabetes or adult systemic lupus develop in B8-DR3-Dw24 or B18-DR3-Dw25 bearing individuals depending on the geographical location in which they live and this preference may be based on both an HLA (based on differences at non-coding regions of DR or at other neighbouring genes) or non-HLA genetical background and also on specific environmental factors.…”

Section: Discussionmentioning

confidence: 99%

Comparison between HLA-DRB and DQ DNA sequences and classic serological markers as Type 11 (insulin-dependent)diabetes mellitus predictive risk markers in the Spanish population

et al. 1992

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The question of HLA susceptibility to Type 1 (insulin-dependent) diabetes mellitus remains unresolved. In the present study, 127 diabetic patients and 177 unrelated control subjects have been analysed for their class I and class II serological antigens, class II (DR, DQ) DNA restriction fragment length polymorphisms and DQA1 and B1 exon-2 nucleotide sequences and their corresponding amino acid residues. By using the aetiologic fraction (delta) as an almost absolute measure of the strongest linkage disequilibrium of an HLA marker to the putative Type 1 diabetes susceptibility locus, it has been found that the strength of association of the HLA markers may be quantified as follows: DR4 less than DR3 less than DR3 or DR4 less than non-Aspartate 57 beta DQ and Arginine 52 alpha DQ less than Arginine 52 alpha DQ. Thus, molecular HLA-DQ markers appear to be more accurate as susceptibility markers than the classic serologically defined ones (DR3 and DR4); however, any effect of DQ markers disappears when non-DR3/DR4 individuals are considered, suggesting that DR factors (or others in between DQ and DR) are also important. In addition, a dominant non-Aspartate 57 beta DQ susceptibility theory does not hold (but a recessive one does) in our diabetic population (probably due to the high frequency of the protective DR7-non-Aspartate 57 beta DQ haplotypes); Arginine 52 alpha DQ is the best single HLA marker found in our population, both as a recessive or as a dominant one. Also there are 13 patients in our sample who bear neither Arginine 52 alpha DQ nor non-Aspartate 57 beta DQ susceptibility factors.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionmentioning

confidence: 99%

Comparison between HLA-DRB and DQ DNA sequences and classic serological markers as Type 11 (insulin-dependent)diabetes mellitus predictive risk markers in the Spanish population

et al. 1992

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HLA-DR7 in Association with Chlorpromazine-induced Lupus Anticoagulant (LA)

Vargas‐Alarcón

Yamamoto-Furusho

Zúñiga

et al. 1997

Journal of Autoimmunity

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Polymorphism of the DQA1 promoter region (QAP) and DRB1, QAP, DQA1, DQB1 haplotypes in systemic lupus erythematosus

Yao

Kimura

Hartung³

et al. 1993

Immunogenetics

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We have investigated the DNA polymorphism for the DQA1 promoter region (QAP) and HLA-class II DRB1, DQA1, and DQB1 genes in 178 central European patients with Systemic lupus erythematosus (SLE) using polymerase chain reaction and Dig-ddUTP labeled oligonucleotides. Increased frequencies of DRB1*02 and *03 are confirmed by DNA typing. In addition, the frequencies of DQA1*0501, *0102 and DQB1*0201, *0602 alleles are increased in the patients as compared to controls. The strongest association to SLE is found with DRB1*03 and DOB1*0201 alleles (p < 10(-7), p corr. < 10(-5) and p < 10(-6), p corr. < 10(-4), respectively). By investigating the DQA1 promoter region in the SLE patients we have detected nine different QAP variants. Increased frequencies of QAP1.2 and QAP4.1 are observed in patients as compared to controls (p < 0.05, p corr. = n.s.). Analysis of linkage disequilibria demonstrates a very strong association between QAP variants and DQA1, DRB1 alleles. Certain QAP variants are completely associated with DQA1 and DRB1 alleles, whereas others can combine with different DQA1 and DRB1 alleles. All DRB1*02-positive patients and controls carry QAP1.2, and all DRB1*03-positive patients and controls carry QAP4.1. Conversely, the QAP1.2 variant appears only in DRB1*02 haplotypes, while the QAP4.1 variant can be observed in DRB1*03, *11, and *1303 haplotypes. Based on the strong linkage disequilibria between DRB1-DQA1-DQB1 genes and between DRB1-QAP-DQA1, we have deduced the four-point haplotypes for DRB1-QAP-DQA1-DQB1 in patients and controls. Two haplotypes DRB1*02-QAP1.2-DQA1*0102-DQB1*0602 and DRB1*03-QAP4.1-DQA1*0501-DQB1*0201 are significantly increased in patients as compared to controls (p < 0.01, p corr. = n.s., RR = 1.8 and p < 10(-7), p corr. < 10(-5), RR = 3.1, respectively). The analysis of relative risks attributed to the various alleles of QAP, DQA1, and DQB1 as well as the investigation of the deduced DRB1-QAP-DQA1-DQB1 haplotypes leads to the conclusion that QAP4.1 and DQA1*0501 on the DR3 haplotypes are probably not involved in SLE susceptibility.(ABSTRACT TRUNCATED AT 400 WORDS)

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Immunogenetics of Systemic Lupus Erythematosus in Spanish Patients: Differential HLA Markers

Cited by 20 publications

References 20 publications

Comparison between HLA-DRB and DQ DNA sequences and classic serological markers as Type 11 (insulin-dependent)diabetes mellitus predictive risk markers in the Spanish population

Comparison between HLA-DRB and DQ DNA sequences and classic serological markers as Type 11 (insulin-dependent)diabetes mellitus predictive risk markers in the Spanish population

HLA-DR7 in Association with Chlorpromazine-induced Lupus Anticoagulant (LA)

Polymorphism of the DQA1 promoter region (QAP) and DRB1, QAP, DQA1, DQB1 haplotypes in systemic lupus erythematosus

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