title: Fine mapping of the celiac disease-associated LPP locus reveals a potential functional variant.
abstract: Using the Immunochip for genotyping, we identified 39 non-human leukocyte antigen (non-HLA) loci associated to celiac disease (CeD), an immune-mediated disease with a worldwide frequency of ∼1%. The most significant non-HLA signal mapped to the intronic region of 70 kb in the LPP gene. Our aim was to fine map and identify possible functional variants in the LPP locus. We performed a meta-analysis in a cohort of 25 169 individuals from six different populations previously genotyped using Immunochip. Imputation using data from the Genome of the Netherlands and 1000 Genomes projects, followed by meta-analysis, confirmed the strong association signal on the LPP locus (rs2030519, P = 1.79 × 10(-49)), without any novel associations. The conditional analysis on this top SNP-indicated association to a single common haplotype. By performing haplotype analyses in each population separately, as well as in a combined group of the four populations that reach the significant threshold after correction (P < 0.008), we narrowed down the CeD-associated region from 70 to 2.8 kb (P = 1.35 × 10(-44)). By intersecting regulatory data from the ENCODE project, we found a functional SNP, rs4686484 (P = 3.12 × 10(-49)), that maps to several B-cell enhancer elements and a highly conserved region. This SNP was also predicted to change the binding motif of the transcription factors IRF4, IRF11, Nkx2.7 and Nkx2.9, suggesting its role in transcriptional regulation. We later found significantly low levels of LPP mRNA in CeD biopsies compared with controls, thus our results suggest that rs4686484 is the functional variant in this locus, while LPP expression is decreased in CeD.
authors: Department of Genetics, University of Groningen, University Medical Center Groningen, PO Box 30001, Groningen 9700 RB, The Netherlands.
authors: Rodrigo
authors: R
authors: Almeida
authors: Isis
authors: I
authors: Ricaño-Ponce
authors: Vinod
authors: V
authors: Kumar
authors: Patrick
authors: P
authors: Deelen
authors: Agata
authors: A
authors: Szperl
authors: Gosia
authors: G
authors: Trynka
authors: Javier
authors: J
authors: Gutierrez-Achury
authors: Alexandros
authors: A
authors: Kanterakis
authors: Harm-Jan
authors: HJ
authors: Westra
authors: Lude
authors: L
authors: Franke
authors: Morris A
authors: MA
authors: Swertz
authors: Mathieu
authors: M
authors: Platteel
authors: Jose Ramon
authors: JR
authors: Bilbao
authors: Donatella
authors: D
authors: Barisani
authors: Luigi
authors: L
authors: Greco
authors: Luisa
authors: L
authors: Mearin
authors: Victorien M
authors: VM
authors: Wolters
authors: Chris
authors: C
authors: Mulder
authors: Maria Cristina
authors: MC
authors: Mazzilli
authors: Ajit
authors: A
authors: Sood
authors: Bozena
authors: B
authors: Cukrowska
authors: Concepción
authors: C
authors: Núñez
authors: Riccardo
authors: R
authors: Pratesi
authors: Sebo
authors: S
authors: Withoff
authors: Cisca
authors: C
authors: Wijmenga
mesh_terms: D002446:Celiac Disease / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics; D060588:LIM Domain Proteins / Q000235:genetics*; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D000099218:Interferon Regulatory Factor-4
chemical_list: D003598:Cytoskeletal Proteins; D050835:Interferon Regulatory Factors; D060588:LIM Domain Proteins; D014157:Transcription Factors; D000099218:Interferon Regulatory Factor-4; C103594:LPP protein, human