HLA-DQ rather than HLA-DR region might be involved in dominant nonsusceptibility to diabetes.

Sterkers, Ghislaine; Zeliszewski, Dominique; Chaussée, A M; Deschamps, I; Font, Marie-Pierre; Freidel, C; Hors, J; Bétuel, H; Dausset, J; Lévy, J. P.

doi:10.1073/pnas.85.17.6473

Cited by 45 publications

(25 citation statements)

References 24 publications

(37 reference statements)

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“…Extensive analysis at the DR locus has shown that the relative risk associated with these alleles is -4-6. When the analysis is performed at the DQ locus, two alleles seem associated with disease: DQw2 (DQBI*0201) and DQw8 (DQBI*0302) (22,26,44,45). In previous studies we demonstrated that approximately one-third of our patients with IDDM are positive only for DQBI *0201, approximately onethird are positive for DQBI *0302, and -25% are positive for both (23).…”

Section: Discussionmentioning

confidence: 99%

“…Several groups, including our own, have demonstrated an association of the DQBI*0302 allele with an increased risk for the development of IDDM, whereas other alleles (i.e., DQBI*0602) were associated with protection (21)(22)(23)(24)(25)(26). In subsequent studies it was determined that there was little association with known DP alleles and susceptibility to IDDM (25).…”

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confidence: 99%

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TAP1 alleles in insulin-dependent diabetes mellitus: a newly defined centromeric boundary of disease susceptibility.

Jackson

Capra

1993

Proc. Natl. Acad. Sci. U.S.A.

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It has been previously demonstrated that individuals with certain DR alleles have an increased relative risk of developing insulin-dependent diabetes mellitus (IDDM). The disease association is even stronger with certain DQ alleles but there is little association with DP providing a boundary of disease association to the 430 kb between DQ and DP. The recently described TAP (transporter associated with antigen processing) genes have been mapped approximately miiidway 6ietween DP and DQ. Therefore, it was of interest to determine if any TAP alleles were associated with IDDM. In addition to the alleles of TAP] that have been described, others were identified during this study. Diabetics and normal controls were screened for TAPI using single-stranded conformational polymorphism and relative risk was determined. In the same population group we have studied extensively in the past, we found a higher association of a TAPI allele with IDDM than with any single HLA-DP allele but the risk was lower than with HLA-DQBI*0302. These data provide new limits for IDDM susceptibility to the 190-kb interval between TAP) and HLA-DQBI.The recently identified TAP1 and TAP2 (transporter associated with antigen processing) proteins share homology with such proteins as MADR (multi-drug resistance) protein and CFTR (cystic fibrosis tra_nsmeTmbranie conductance regulator) profein ana other members of the ABC superfaimily of proteins, which transport materials across membranes (1-4). Although the actual function of the TAP genes is in question, indirect evidence has been presented to suggest that TAP proteins function as a heterodimer to transport peptides across the endoplasmic reticulum membrane, where the peptides associate with assembling class

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

TAP1 alleles in insulin-dependent diabetes mellitus: a newly defined centromeric boundary of disease susceptibility.

Jackson

Capra

1993

Proc. Natl. Acad. Sci. U.S.A.

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“…Among Caucasians, the disease is positively associated with DR3 and DR4 and negatively associated with DR2 (3)(4)(5). Recently, on the basis of restriction length fragment polymorphism (RFLP) and oligonucleotide typing, the notion has emerged that IDDM susceptibility or resistance is preferentially associated with a limited number of alleles of the HLA-DQB locus (6)(7)(8)(9)(10). Susceptibility has also been assigned to DQB1 alleles encoding amino acids other than aspartic acid (Asp) at position 57 of the DQI3 chain (11 -14).…”

Section: Introductionmentioning

confidence: 99%

Age-dependent HLA genetic heterogeneity of type 1 insulin-dependent diabetes mellitus.

Caillat‐Zucman¹,

Garchon²,

Timsit³

et al. 1992

J. Clin. Invest.

288

157

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The association of insulin-dependent diabetes mellitus (IDDM) with certain HLA alleles is well documented in pediatric patients. Whether a similar association is found in adult-onset IDDM is not clear, although the disease occurs after the age of 20 in 50% of cases. HLA class II DRB1, DQA1, and DQB1 alleles were studied in 402 type I diabetics and 405 healthy controls (all Caucasian) using oligonucleotide typing after gene amplification. Alleles DRB1 *03, DRB1 *04, DQB1 *0201, DQB1 *0302, DQA1 *0301, and DQA1 *0501 were indeed enriched in diabetics and the highest relative risk was observed in patients carrying both the DRB1 *03-DQB1 *0201 and the DRB1 *0402 or DRB1 *0405-DQB1 *0302 haplotypes. However none of these alleles, or specific residues, could alone account for the susceptibility to IDDM. Furthermore, there were major differences in HLA class II gene profiles according to the age of onset. Patients with onset after 15 yr (n = 290) showed a significantly higher percentage of non-DR3 /non-DR4 genotypes than those with childhood onset (n = 112) and a lower percentage ofDR3 /4 genotypes. These non-DR3 / non-DR4 patients, although presenting clinically as IDDM type 1 patients, showed a lower frequency of islet cell antibodies at diagnosis and a significantly milder initial insulin deficiency. These subjects probably represent a particular subset of IDDM patients in whom frequency increases with age. The data confirm the genetic heterogeneity of IDDM and call for caution in extrapolating to adult patients the genetic concepts derived from childhood IDDM. (J. Clin. Invest. 1992. 90:2242-2250

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“…14 The apparent decrease in transmission of the 87-bp allele could reflect one of two things. First, the allele might actually be protective, as has been suggested for HLA-DQ or HLA-DR in IDDM 15 and Apo E2 in Alzheimer's disease. 16,17 In both these examples, molecular models based on the changes in protein have been proposed to account for protective effects.…”

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confidence: 99%

Association between a GABRB3 polymorphism and autism

et al. 2002

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Autistic disorder (OMIM 209850) is a disease with a significant genetic component of a complex nature. 1 Cytogenetic abnormalities in the Prader-Willi/Angelman syndrome critical region (15q11-13) have been described in several individuals with autism. 1 For this reason, markers across this region have been screened for evidence of linkage and association, and a marker (155CA-2) in the ␥-aminobutyric acid type-A receptor ␤3 subunit gene (GABRB3) has been associated in one study 2 but not others. [3][4][5] We completed an association analysis with 155CA-2 using the transmission disequilibrium test (TDT) in a set of 80 autism families (59 multiplex and 21 trios). We also used four additional markers (69CA, 155CA-1, 85CA, and A55CA-1) localized within 150 kb of 155CA-2. The use of multi-allelic TDT (MTDT) (P < 0.002), as well as the TDT (P < 0.004), demonstrated an association between autistic disorder and 155CA-2 in these families. Meiotic segregation distortion could be excluded as a possible cause for these results since no disequilibrium was observed in unaffected siblings. These findings support a role for genetic variants within the GABA receptor gene complex in 15q11-13 in autistic disorder. Molecular Psychiatry ( Autism is a development disorder characterized by impairments in three domains: communication, reciprocal social interactions, and repetitive or stereotyped behaviors and interests (for review see TagerFlusberg et al 1 ). The concordance rate for monozygotic twins is much higher than that of dizygotic twins, which indicates that genetic factors play an important role in the etiology of autism. In addition, family studies indicate that the recurrence risk to siblings, estimated from multiple studies at 1-3%, is profoundly higher than the risk to the general population, which has been estimated at ෂ0.5-2 per 1000. The mode of inheritance of autism appears to be complex; latentclass analyses suggest that 3-10 genes may underlie the disorder, 6 although an interpretation of at least one genome-wide linkage analysis has argued for Ͼ10 genes underlying the disorder. 7 Cytogenetic studies have demonstrated that duplications within the 15q11-q13 region can be associated with autism (for review see Tager-Flusberg et al 1 ). Moreover, symptoms of autism can be associated with both Prader-Willi and Angelman syndromes, both of which involve alterations in the 15q11-q13 region. Because of this, the15q11-q13 region has been examined for genetic linkage to autism. A mapping of nine markers spanning a region of ෂ2 Mb within this region in 132 families demonstrated linkage disequilibrium at a marker within the GABRB3 gene, 155CA-2. 2 An additional locus within GABRB3 that is ෂ150 kb away from 155CA-2 (D15S97) did not demonstrate linkage disequilibrium.A genome-wide scan involving 51 autistic multiplex families demonstrated a broad peak with a LOD score of about 1 over the GABRB3 region. 8 Similarly, multipoint analyses over the region in 63 families demonstrated a peak Z-score of 1.78 in the region, near the marker ...

show abstract

HLA-DQ rather than HLA-DR region might be involved in dominant nonsusceptibility to diabetes.

Cited by 45 publications

References 24 publications

TAP1 alleles in insulin-dependent diabetes mellitus: a newly defined centromeric boundary of disease susceptibility.

TAP1 alleles in insulin-dependent diabetes mellitus: a newly defined centromeric boundary of disease susceptibility.

Age-dependent HLA genetic heterogeneity of type 1 insulin-dependent diabetes mellitus.

Association between a GABRB3 polymorphism and autism

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