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

Abstract

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

Three hundred twenty-six genetic variations in genes encoding nine members of ATP-binding cassette, subfamily B (ABCB/MDR/TAP), in the Japanese population

“…However, the nonsynonymous (Ala893Ser/Thr) polymorphism we detected was located in the region encoding the second transmembrane domain and may have phenotypic consequences. Many SNPs have been reported previously in the TAP1 and TAP2 genes, because of the high degree of polymorphism that pertains among MHC genes (Colonna et al 1992;Powis et al 1992;Jackson and Capra 1993;Jeffreys et al 2000). However, 5 of the 14 SNPs we detected in the TAP1 gene and 6 of the 37 genetic variations in TAP2 were novel.…”

“…Chen et al (1996) have described a case of human lung tumor with impaired TAP function due to a mutation in the Walker B region of TAP1, and a number of investigators have examined potential associations of TAP1 and TAP2 genotypes with altered susceptibilities to MHC-associated diseases. Results from these investigations suggest that mutations in the TAP1 and TAP2 genes may be associated with ankylosing spondylitis (Colonna et al 1992), insulindependent diabetes mellitus (Colonna et al 1992;Jackson and Capra 1993), and celiac disease (Colonna et al 1992). …”

Tap-1 and Tap-2 Gene Therapy Selectively Restores Conformationally Dependent HLA Class I Expression in Type I Diabetic Cells

“…This work was extensively expanded in French DNA by Bach and colleagues who confttmed the Spies stody and additionally suggested that susceptibility to type I diabetes was associated with apparent homozygosity of a given Tap-2 allele (p < 0.001) (Caillat-Zucman et al, 1993). Capra and colleagues looking for the centtomeric boundary of type I diabetic susceptibility reported that a given Tap-1 allele confirmed higher risk than any HLA-DP allele, but the risk was lower than HLA-DQ suggesting the most important diabetic susceptibility allele was between Tap-1 and HLA-DQ, a 190-kb interval containing Tap-2 (Jackson et al, 1993). Using Norwegian DNA, Thorsby and colleagues did not see a Tap-2 association higher than the DQ association but did observe Unkage disequiUbrium in this region (Ronningen et al, 1993).…”

Superantigens in insulin-dependent diabetes mellitus

“…Allelic polymorphism has been observed for the LMP [59] and TAP genes [30] and their possible involvement in IDDM susceptibility has been postulated. However, it has not been clear, until now, whether the suggested association is attributable to the strong phenomenon of linkage disequilibrium present in the HLA region or if LMP and TAP loci contribute to IDDM susceptibility independently [40,75,181]. Recently, it has been reported that genes outside the MHC complex may also influence disease susceptibility.…”