Genome-wide association study identifies a susceptibility locus for biliary atresia on 10q24.2.
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.
Garcia-Barceló
Maria-Mercè
MM
Department of Surgery, The University of Hong Kong, Hong Kong, China.
Yeung
Ming-Yiu
MY
Miao
Xiao-Ping
XP
Tang
Clara Sze-Man
CS
Cheng
Guo
G
Chen
Guo
G
So
Man-Ting
MT
Ngan
Elly Sau-Wai
ES
Lui
Vincent Chi-Hang
VC
Chen
Yan
Y
Liu
Xue-Lai
XL
Hui
Kenneth-Jeremy W S
KJ
Li
Long
L
Guo
Wei-Hong
WH
Sun
Xiao-Bin
XB
Tou
Jin-Fa
JF
Chan
Kin-Wai
KW
Wu
Xuan-Zhao
XZ
Song
You-Qiang
YQ
Chan
Danny
D
Cheung
Kenneth
K
Chung
Patrick Ho-Yu
PH
Wong
Kenneth Kak-Yuen
KK
Sham
Pak-Chung
PC
Cherny
Stacey S
SS
Tam
Paul Kwong-Hang
PK
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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