title: Genome-wide association study identifies a susceptibility locus for biliary atresia on 10q24.2.
abstract: Biliary atresia (BA) is characterized by the progressive fibrosclerosing obliteration of the extrahepatic biliary system during the first few weeks of life. Despite early diagnosis and prompt surgical intervention, the disease progresses to cirrhosis in many patients. The current theory for the pathogenesis of BA proposes that during the perinatal period, a still unknown exogenous factor meets the innate immune system of a genetically predisposed individual and induces an uncontrollable and potentially self-limiting immune response, which becomes manifest in liver fibrosis and atresia of the extrahepatic bile ducts. Genetic factors that could account for the disease, let alone for its high incidence in Chinese, are to be investigated. To identify BA susceptibility loci, we carried out a genome-wide association study (GWAS) using the Affymetrix 5.0 and 500 K marker sets. We genotyped nearly 500 000 single-nucleotide polymorphisms (SNPs) in 200 Chinese BA patients and 481 ethnically matched control subjects. The 10 most BA-associated SNPs from the GWAS were genotyped in an independent set of 124 BA and 90 control subjects. The strongest overall association was found for rs17095355 on 10q24, downstream XPNPEP1, a gene involved in the metabolism of inflammatory mediators. Allelic chi-square test P-value for the meta-analysis of the GWAS and replication results was 6.94 x 10(-9). The identification of putative BA susceptibility loci not only opens new fields of investigation into the mechanisms underlying BA but may also provide new clues for the development of preventive and curative strategies.
authors.affiliation: Department of Surgery, The University of Hong Kong, Hong Kong, China.
authors.forename: Maria-Mercè
authors.initials: MM
authors.lastname: Garcia-Barceló
authors.forename: Ming-Yiu
authors.initials: MY
authors.lastname: Yeung
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Miao
authors.forename: Clara Sze-Man
authors.initials: CS
authors.lastname: Tang
authors.forename: Guo
authors.initials: G
authors.lastname: Cheng
authors.forename: Guo
authors.initials: G
authors.lastname: Chen
authors.forename: Man-Ting
authors.initials: MT
authors.lastname: So
authors.forename: Elly Sau-Wai
authors.initials: ES
authors.lastname: Ngan
authors.forename: Vincent Chi-Hang
authors.initials: VC
authors.lastname: Lui
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Xue-Lai
authors.initials: XL
authors.lastname: Liu
authors.forename: Kenneth-Jeremy W S
authors.initials: KJ
authors.lastname: Hui
authors.forename: Long
authors.initials: L
authors.lastname: Li
authors.forename: Wei-Hong
authors.initials: WH
authors.lastname: Guo
authors.forename: Xiao-Bin
authors.initials: XB
authors.lastname: Sun
authors.forename: Jin-Fa
authors.initials: JF
authors.lastname: Tou
authors.forename: Kin-Wai
authors.initials: KW
authors.lastname: Chan
authors.forename: Xuan-Zhao
authors.initials: XZ
authors.lastname: Wu
authors.forename: You-Qiang
authors.initials: YQ
authors.lastname: Song
authors.forename: Danny
authors.initials: D
authors.lastname: Chan
authors.forename: Kenneth
authors.initials: K
authors.lastname: Cheung
authors.forename: Patrick Ho-Yu
authors.initials: PH
authors.lastname: Chung
authors.forename: Kenneth Kak-Yuen
authors.initials: KK
authors.lastname: Wong
authors.forename: Pak-Chung
authors.initials: PC
authors.lastname: Sham
authors.forename: Stacey S
authors.initials: SS
authors.lastname: Cherny
authors.forename: Paul Kwong-Hang
authors.initials: PK
authors.lastname: Tam
mesh_terms: D044466:Asian People / Q000235:genetics; D001656:Biliary Atresia / Q000235:genetics*; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide
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