Classical HLA-DRB1 and DPB1 alleles account for HLA associations with primary biliary cirrhosis

被引：56

作者：

Invernizzi, P. ^{[2
,3
]}

Ransom, M. ^{[1
]}

Raychaudhuri, S. ^{[4
,5
,6
,7
]}

Kosoy, R. ^{[1
]}

Lleo, A. ^{[3
]}

Shigeta, R. ^{[1
]}

Franke, A. ^{[8
]}

Bossa, F. ^{[9
]}

Amos, C. I. ^{[10
]}

Gregersen, P. K. ^{[11
]}

Siminovitch, K. A. ^{[12
,13
,14
,15
]}

Cusi, D. ^{[16
,17
]}

de Bakker, P. I. W. ^{[4
,5
,7
,18
]}

Podda, M. ^{[3
]}

Gershwin, M. E. ^{[2
]}

Seldin, M. F. ^{[1
,2
]}

机构：

[1] Univ Calif Davis, Dept Biochem & Mol Med, Davis, CA 95616 USA

[2] Univ Calif Davis, Div Rheumatol Allergy & Clin Immunol, Dept Med, Davis, CA 95616 USA

[3] IRCCS Ist Clin Hurnanitas, Ctr Autoimmune Liver Dis, Dept Med, Milan, Italy

[4] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA

[5] Brigham & Womens Hosp, Dept Med, Div Rheumatol, Boston, MA 02115 USA

[6] Partners HealthCare Ctr Personalized Genet Med, Boston, MA USA

[7] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA

[8] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany

[9] IRCCS CSS Hosp, Div Gastroenterol, San Giovanni Rotondo, Italy

[10] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA

[11] N Shore LIJ Hlth Syst, Feinstein Inst Med Res, Robert S Boas Ctr Genom & Human Genet, Manhasset, NY USA

[12] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada

[13] Mt Sinai Hosp, Toronto Gen Res Inst, Toronto, ON M5G 1X5, Canada

[14] Univ Toronto, Dept Immunol, Toronto, ON, Canada

[15] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada

[16] Univ Milan, Dept Med, Milan, Italy

[17] Fdn Filarete, Genom & Bioinformat Unit, Milan, Italy

[18] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Dept Med Genet, Utrecht, Netherlands

来源：

GENES AND IMMUNITY | 2012年 / 13卷 / 06期

关键词：

genetic risk; risk allele; imputation; antigen-binding pocket; autoimmune disease; GENOME-WIDE ASSOCIATION; HUMAN-LEUKOCYTE ANTIGEN; DIABETES GENETICS CONSORTIUM; CLASS-II MOLECULES; GENOTYPE IMPUTATION; MULTIPLE-SCLEROSIS; SUSCEPTIBILITY; POPULATION; HAPLOTYPES; LOCI;

D O I：

10.1038/gene.2012.17

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Susceptibility to primary biliary cirrhosis (PBC) is strongly associated with human leukocyte antigen (HLA)-region polymorphisms. To determine if associations can be explained by classical HLA determinants, we studied Italian, 676 cases and 1440 controls, genotyped with dense single-nucleotide polymorphisms (SNPs) for which classical HLA alleles and amino acids were imputed. Although previous genome-wide association studies and our results show stronger SNP associations near DQB1, we demonstrate that the HLA signals can be attributed to classical DRB1 and DPB1 genes. Strong support for the predominant role of ORB? is provided by our conditional analyses. We also demonstrate an independent association of DPB1. Specific HLA-DRB1 genes (*08, *11 and *74) account for most of the DRB1 association signal. Consistent with previous studies, DRB1*08 (P = 1.59 x 10(-11)) was the strongest predisposing allele, whereas DRB1*11 (P = 1.42 x 10(-10)) was protective. Additionally, DRB1*14 and the DPB1 association (DPB1*03:01; P = 9.18 x 10(-7)) were predisposing risk alleles. No signal was observed in the HLA class 1 or class 3 regions. These findings better define the association of PBC with HLA and specifically support the role of classical HLA-DRB1 and DPB1 genes and alleles in susceptibility to PBC.

引用

页码：461 / 468

页数：8

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