Distribution of HERV-LTR elements in the 5′-flanking region of HLA-DQB1 and association with autoimmunity

被引:22
作者
Pascual, M
Martin, J
Nieto, A
Giphart, MJ
van der Slik, AR
de Vries, RRP
Zanelli, E
机构
[1] CSIC, Inst Parasitol & Biomed Lopez Neyra, Granada 18001, Spain
[2] Hosp Puerta del Mar, Serv Inmunol, Cadiz, Spain
[3] Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, NL-2300 RC Leiden, Netherlands
关键词
HERV-LTR; HLA-DQB1; autoimmunity; RA; IDDM;
D O I
10.1007/s002510100307
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
We established the detailed polymorphism of the 5'-flanking region and the first exon of the human leukocyte antigen (HLA)-DQB1 alleles. One hundred and forty-five Spanish rheumatoid arthritis (RA) patients and 200 healthy voluntary blood donors from southern Spain along with 42 B-cell lines were analyzed for the presence of the retrovirus-derived long terminal repeats (LTRs) LTR3, LTR5, and LTR13. LTR3 positivity was always associated with certain DQB1 alleles, i.e., *0302, *0402, *0601, *0202, and *0305. Sequencing analysis of the 5'-flanking region of DQB1*0301, *0303 and *0502 alleles in homozygous B-cell lines showed the absence of LTR3 and a massive deletion of 5635 base pairs. The undetected deletion in the flanking region of some DQB1 alleles and a lack of stratification for HLA typing explain previously reported associations of the LTR3 element with RA and type I diabetes (IDDM). LTRS showed identical distribution to LTRS, consistent with a previously suggested LTR3-LTR5 tandem arrangment. LTR13 positivity was associated with DQB1*0302, *0303, and *0402 alleles. Distributions of the LTR elements in all B-cell lines, RA patients, and controls could be explained entirely by linkage disequilibrium with DQB1 alleles, independently of the haplotypes carrying them. LTR elements are known to regulate gene expression. Therefore, a possible involvement of LTR13 in the association of DPB1*0302, *0303, and *0402 with IDDM requires further investigation. The sequencing results of the DQB1 first exon demonstrated that DPB1*0601 was generated by a recombination event between a DR53 and a non-DR53 haplotype. Our results shed new light on the phylogeny of the HLA region and the possible contribution of DQB1 to susceptibility to autoimmunity.
引用
收藏
页码:114 / 118
页数:5
相关论文
共 15 条
[1]   Complete sequence and gene map of a human major histocompatibility complex [J].
Beck, S ;
Geraghty, D ;
Inoko, H ;
Rowen, L ;
Aguado, B ;
Bahram, S ;
Campbell, RD ;
Forbes, SA ;
Guillaudeux, T ;
Hood, L ;
Horton, R ;
Janer, M ;
Jasoni, C ;
Madan, A ;
Milne, S ;
Neville, M ;
Oka, A ;
Qin, S ;
Ribas-Despuig, G ;
Rogers, J ;
Shiina, T ;
Spies, T ;
Tamiya, G ;
Tashiro, H ;
Trowsdale, J ;
Vu, Q ;
Williams, L ;
Yamazaki, M .
NATURE, 1999, 401 (6756) :921-923
[2]   Evolutionary dynamics of non-coding sequences within the class II region of the human MHC [J].
Beck, S ;
Abdulla, S ;
Alderton, RP ;
Glynne, RJ ;
Gut, IG ;
Hosking, LK ;
Jackson, A ;
Kelly, A ;
Newell, WR ;
Sanseau, P ;
Radley, E ;
Thorpe, KL ;
Trowsdale, J .
JOURNAL OF MOLECULAR BIOLOGY, 1996, 255 (01) :1-13
[3]   The presence or absence of a retroviral long terminal repeat influences the genetic risk for type I diabetes conferred by human leukocyte antigen DQ haplotypes [J].
Donner, H ;
Tönjes, RR ;
Van der Auwera, B ;
Siegmund, T ;
Braun, J ;
Weets, I ;
Herwig, J ;
Kurth, R ;
Usadel, KH ;
Badenhoop, K .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1999, 84 (04) :1404-1408
[4]   Intronic sequence motifs of HLA-DQB1 are shared between humans, apes and old world monkeys, but a retroviral LTR element (DQLTR3) is human specific [J].
Donner, H ;
Tönjes, RR ;
Bontrop, RE ;
Kurth, R ;
Usadel, KH ;
Badenhoop, K .
TISSUE ANTIGENS, 1999, 53 (06) :551-558
[5]   Insulin-dependent diabetes mellitus in non-DR3/non-DR4 subjects [J].
Dubois-Laforgue, D ;
Timsit, J ;
Djilali-Saiah, I ;
Boitard, C ;
Caillat-Zucman, S .
HUMAN IMMUNOLOGY, 1997, 57 (02) :104-109
[6]   Large-scale sequence comparisons reveal unusually high levels of variation in the HLA-DQB1 locus in the class II region of the human MHC [J].
Horton, R ;
Niblett, D ;
Milne, S ;
Palmer, S ;
Tubby, B ;
Trowsdale, J ;
Beck, S .
JOURNAL OF MOLECULAR BIOLOGY, 1998, 282 (01) :71-97
[7]   ENDOGENOUS RETROVIRAL LONG TERMINAL REPEATS WITHIN THE HLA-DQ LOCUS [J].
KAMBHU, S ;
FALLDORF, P ;
LEE, JS .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1990, 87 (13) :4927-4931
[8]   RESOLUTION OF THE HLA-DRB6 PUZZLE - A CASE OF GRAFTING A DE-NOVO-GENERATED EXON ON AN EXISTING GENE [J].
MAYER, WE ;
OHUIGIN, C ;
KLEIN, J .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (22) :10720-10724
[9]  
NEPOM GT, 1991, ANNU REV IMMUNOL, V9, P493
[10]  
Pascual M, 2001, ARTHRITIS RHEUM, V44, P307, DOI 10.1002/1529-0131(200102)44:2<307::AID-ANR47>3.3.CO