PROTECTION FROM INSULIN-DEPENDENT DIABETES-MELLITUS IS LINKED TO A PEPTIDE TRANSPORTER GENE

被引:82
作者
CAILLATZUCMAN, S
BERTIN, E
TIMSIT, J
BOITARD, C
ASSAN, R
BACH, JF
机构
[1] HOP BICHAT,SERV DIABET,F-75877 PARIS 18,FRANCE
[2] HOP NECKER ENFANTS MALAD,SERV IMMUNOL CLIN,F-75730 PARIS 15,FRANCE
关键词
ANTIGEN PRESENTATION; TAP PEPTIDE TRANSPORTER GENES; HLA CLASS-II GENES; INSULIN-DEPENDENT DIABETES-MELLITUS; SUSCEPTIBILITY GENES;
D O I
10.1002/eji.1830230808
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
HLA class II association with insulin-dependent diabetes mellitus (IDDM) is well established but is still difficult to map to a particular locus. Polymorphism of the genes coding for transporter associated with antigen processing (TAP1 and TAP2), and located in the HLA class II region, was studied in 167 IDDM patients (116 adult-onset and 51 childhood-onset patients) and 98 normal controls using oligotyping after genomic amplification. A dominant protective effect was observed for the TAP2*0201 allele [relative risk (RR) = 0.3, corrected probability (pc) < 0.001]. Conversely, susceptibility to IDDM was associated with apparent homozygosity for the TAP2*0101 allele (RR = 3.4, pc < 0.001). Protection was independent from but additive to the protection conferred by the DRB1*02 DQB1*0602 haplotype (RR = 0.06, pc < 0.05), and antagonistic to the DRB1*03 DQB1*0201 and DRB1*04 DQB1*0302 haplotypes predisposing effect (RR = 1.1, not significant), arguing in favor of an absence of linkage disequilibrium between TAP2 and HLA class II genes. This was assessed by chi2 analysis. TAP1 allelic distribution was not different among diabetics and controls. A significant association was observed between the presence of TAP2*0101 and that of islet cell antibodies (p < 0.05). These data suggest that the TAP2 gene, which encodes protein required for delivery of antigen peptides to class I molecules in the endoplasmic reticulum, could modulate the autoimmune response leading to beta cell destruction. From a practical point of view, they make the combined screening of HLA class II and TAP2 loci a highly valuable tool in IDDM prediction.
引用
收藏
页码:1784 / 1788
页数:5
相关论文
共 28 条
[1]   HAM-2 CORRECTS THE CLASS-I ANTIGEN-PROCESSING DEFECT IN RMA-S CELLS [J].
ATTAYA, M ;
JAMESON, S ;
MARTINEZ, CK ;
HERMEL, E ;
ALDRICH, C ;
FORMAN, J ;
LINDAHL, KF ;
BEVAN, MJ ;
MONACO, JJ .
NATURE, 1992, 355 (6361) :647-649
[2]   2 PUTATIVE SUBUNITS OF A PEPTIDE PUMP ENCODED IN THE HUMAN MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-II REGION [J].
BAHRAM, S ;
ARNOLD, D ;
BRESNAHAN, M ;
STROMINGER, JL ;
SPIES, T .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1991, 88 (22) :10094-10098
[3]   SYNGENEIC TRANSFER OF AUTOIMMUNE DIABETES FROM DIABETIC NOD MICE TO HEALTHY NEONATES - REQUIREMENT FOR BOTH L3T4+ AND LYT-2+ T-CELLS [J].
BENDELAC, A ;
CARNAUD, C ;
BOITARD, C ;
BACH, JF .
JOURNAL OF EXPERIMENTAL MEDICINE, 1987, 166 (04) :823-832
[4]   ISLET-CELL ANTIBODIES IN DIABETES-MELLITUS WITH AUTOIMMUNE POLY-ENDOCRINE DEFICIENCIES [J].
BOTTAZZO, GF ;
FLORINCH.A ;
DONIACH, D .
LANCET, 1974, 2 (7892) :1279-1283
[5]   AGE-DEPENDENT HLA GENETIC-HETEROGENEITY OF TYPE-1 INSULIN-DEPENDENT DIABETES-MELLITUS [J].
CAILLATZUCMAN, S ;
GARCHON, HJ ;
TIMSIT, J ;
ASSAN, R ;
BOITARD, C ;
DJILALISAIAH, I ;
BOUGNERES, P ;
BACH, JF .
JOURNAL OF CLINICAL INVESTIGATION, 1992, 90 (06) :2242-2250
[6]  
CARRINGTON M, 1993, IMMUNOGENETICS, V37, P266
[7]   ALLELIC VARIANTS OF THE HUMAN PUTATIVE PEPTIDE TRANSPORTER INVOLVED IN ANTIGEN PROCESSING [J].
COLONNA, M ;
BRESNAHAN, M ;
BAHRAM, S ;
STROMINGER, JL ;
SPIES, T .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1992, 89 (09) :3932-3936
[8]   MHC CLASS-II REGION ENCODING PROTEINS RELATED TO THE MULTIDRUG RESISTANCE FAMILY OF TRANSMEMBRANE TRANSPORTERS [J].
DEVERSON, EV ;
GOW, IR ;
COADWELL, WJ ;
MONACO, JJ ;
BUTCHER, GW ;
HOWARD, JC .
NATURE, 1990, 348 (6303) :738-741
[9]   LINKAGE OF FAULTY MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-I TO AUTOIMMUNE DIABETES [J].
FAUSTMAN, D ;
LI, XP ;
LIN, HY ;
FU, YE ;
EISENBARTH, G ;
AVRUCH, J ;
GUO, J .
SCIENCE, 1991, 254 (5039) :1756-1761
[10]  
GAKSINS H, 1992, SCIENCE, V256, P1826