ASSOCIATIONS BETWEEN ALLELES OF THE MAJOR HISTOCOMPATIBILITY COMPLEX-ENCODED ABC TRANSPORTER GENE TAP2, HLA CLASS-II ALLELES, AND CELIAC-DISEASE SUSCEPTIBILITY

作者：TIGHE MR; HALL MA; CARDI E; ASHKENAZI A; LANCHBURY JS; CICLITIRA PJ

来源：Human Immunology, 1994, 39(1): 9-16.

The study of celiac disease among Southern European populations has confirmed the hypothesis from Northern Europe that a close association exists between disease susceptibility and a combination of polymorphic alleles at th HLA-DQ loci (DQA1*0501-DQB1*0201) arranged either in a cis- or a trans-configuration. Attempts to identify additional genetic influences have been inconclusive, although many studies have raised possibilities of further major histocompatibility complex (MHC)-linked susceptibility genes. This study examines the disease associations of polymorphisms of a recently discovered gene located close to the DQ loci, TAP2, whose products are though to be involved in the transport of antigen peptides across the endoplasmic reticulum for binding to HLA class I molecules. Like the products of the DQ loci, the product of TAP2 forms part of a heterodimeric molecule with products of a second genetic locus, TAP1, which is located centromerically to TAP2. The populations studied were central Italians from Rome and Ashkenazi Jews from Rehovot, Israel. HLA studies demonstrate that the Roman celiac group has a high proportion of people with DR3-negative celiac disease in whom the combination DR5/7 is frequently found. In Israel, 20% of celiac patients lack the DQ susceptibility markers but are DR4 positive. The polymorphic substitutions of TAP2 studied encode amino acid changes in the trans-membrane region (position 379) and the ATP-binding cassette region (positions 565 and 665) of the protein. No TAP2-specific disease associations were found in any HLA subgroup. Associations were noted between HLA-DR subtypes and TAP2 polymorphisms, suggesting that linkage disequilibrium may exist between these loci, although the association was less significant compared with HLA-DR-DQ. This study suggests that the MHC-linked genetic influence toward celiac disease is located telomeric to TAP2 and continues to support a primary role for DQ alleles in the disease susceptibility.

• 出版日期1994-1