title: Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants.
abstract: To further characterize the genetic basis of primary biliary cirrhosis (PBC), we genotyped 2426 PBC patients and 5731 unaffected controls from three independent cohorts using a single nucleotide polymorphism (SNP) array (Immunochip) enriched for autoimmune disease risk loci. Meta-analysis of the genotype data sets identified a novel disease-associated locus near the TNFSF11 gene at 13q14, provided evidence for association at six additional immune-related loci not previously implicated in PBC and confirmed associations at 19 of 22 established risk loci. Results of conditional analyses also provided evidence for multiple independent association signals at four risk loci, with haplotype analyses suggesting independent SNP effects at the 2q32 and 16p13 loci, but complex haplotype driven effects at the 3q25 and 6p21 loci. By imputing classical HLA alleles from this data set, four class II alleles independently contributing to the association signal from this region were identified. Imputation of genotypes at the non-HLA loci also provided additional associations, but none with stronger effects than the genotyped variants. An epistatic interaction between the IL12RB2 risk locus at 1p31and the IRF5 risk locus at 7q32 was also identified and suggests a complementary effect of these loci in predisposing to disease. These data expand the repertoire of genes with potential roles in PBC pathogenesis that need to be explored by follow-up biological studies.
authors.affiliation: Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, MN, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Juran
authors.forename: Gideon M
authors.initials: GM
authors.lastname: Hirschfield
authors.forename: Pietro
authors.initials: P
authors.lastname: Invernizzi
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Atkinson
authors.forename: Yafang
authors.initials: Y
authors.lastname: Li
authors.forename: Gang
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authors.lastname: Xie
authors.forename: Roman
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authors.lastname: Kosoy
authors.forename: Michael
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authors.lastname: Ransom
authors.forename: Ye
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authors.lastname: Sun
authors.forename: Ilaria
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authors.lastname: Bianchi
authors.forename: Erik M
authors.initials: EM
authors.lastname: Schlicht
authors.forename: Ana
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authors.lastname: Lleo
authors.forename: Catalina
authors.initials: C
authors.lastname: Coltescu
authors.forename: Francesca
authors.initials: F
authors.lastname: Bernuzzi
authors.forename: Mauro
authors.initials: M
authors.lastname: Podda
authors.forename: Craig
authors.initials: C
authors.lastname: Lammert
authors.forename: Russell
authors.initials: R
authors.lastname: Shigeta
authors.forename: Landon L
authors.initials: LL
authors.lastname: Chan
authors.forename: Tobias
authors.initials: T
authors.lastname: Balschun
authors.forename: Maurizio
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authors.lastname: Marconi
authors.forename: Daniele
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authors.lastname: Cusi
authors.forename: E Jenny
authors.initials: EJ
authors.lastname: Heathcote
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Mason
authors.forename: Robert P
authors.initials: RP
authors.lastname: Myers
authors.forename: Piotr
authors.initials: P
authors.lastname: Milkiewicz
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Odin
authors.forename: Velimir A
authors.initials: VA
authors.lastname: Luketic
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Bacon
authors.forename: Henry C
authors.initials: HC
authors.lastname: Bodenheimer
authors.forename: Valentina
authors.initials: V
authors.lastname: Liakina
authors.forename: Catherine
authors.initials: C
authors.lastname: Vincent
authors.forename: Cynthia
authors.initials: C
authors.lastname: Levy
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Bossa
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
authors.forename: Mariza
authors.initials: M
authors.lastname: deAndrade
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.forename: Konstantinos N
authors.initials: KN
authors.lastname: Lazaridis
authors.forename: Michael F
authors.initials: MF
authors.lastname: Seldin
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Siminovitch
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D002878:Chromosomes, Human, Pair 1; D002882:Chromosomes, Human, Pair 13; D002897:Chromosomes, Human, Pair 7; D004843:Epistasis, Genetic; D005787:Gene Frequency; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000235:genetics* / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide
chemical_list: D006680:HLA Antigens