title: High-density SNP mapping of the HLA region identifies multiple independent susceptibility loci associated with selective IgA deficiency.
abstract: Selective IgA deficiency (IgAD; serum IgA<0.07 g/l) is the most common form of human primary immune deficiency, affecting approximately 1∶600 individuals in populations of Northern European ancestry. The polygenic nature of IgAD is underscored by the recent identification of several new risk genes in a genome-wide association study. Among the characterized susceptibility loci, the association with specific HLA haplotypes represents the major genetic risk factor for IgAD. Despite the robust association, the nature and location of the causal variants in the HLA region remains unknown. To better characterize the association signal in this region, we performed a high-density SNP mapping of the HLA locus and imputed the genotypes of common HLA-B, -DRB1, and -DQB1 alleles in a combined sample of 772 IgAD patients and 1,976 matched controls from 3 independent European populations. We confirmed the complex nature of the association with the HLA locus, which is the result of multiple effects spanning the entire HLA region. The primary association signal mapped to the HLA-DQB1*02 allele in the HLA Class II region (combined P = 7.69×10(-57); OR = 2.80) resulting from the combined independent effects of the HLA-B*0801-DRB1*0301-DQB1*02 and -DRB1*0701-DQB1*02 haplotypes, while additional secondary signals were associated with the DRB1*0102 (combined P = 5.86×10(-17); OR = 4.28) and the DRB1*1501 (combined P = 2.24×10(-35); OR = 0.13) alleles. Despite the strong population-specific frequencies of HLA alleles, we found a remarkable conservation of these effects regardless of the ethnic background, which supports the use of large multi-ethnic populations to characterize shared genetic association signals in the HLA region. We also provide evidence for the location of association signals within the specific extended haplotypes, which will guide future sequencing studies aimed at characterizing the precise functional variants contributing to disease pathogenesis.
authors.affiliation: Genentech, South San Francisco, California, USA. ricardo.ferreira@cimr.cam.ac.uk
authors.forename: Ricardo C
authors.initials: RC
authors.lastname: Ferreira
authors.forename: Qiang
authors.initials: Q
authors.lastname: Pan-Hammarström
authors.forename: Robert R
authors.initials: RR
authors.lastname: Graham
authors.forename: Gumersindo
authors.initials: G
authors.lastname: Fontán
authors.forename: Annette T
authors.initials: AT
authors.lastname: Lee
authors.forename: Ward
authors.initials: W
authors.lastname: Ortmann
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.forename: Elena
authors.initials: E
authors.lastname: Urcelay
authors.forename: Miguel
authors.initials: M
authors.lastname: Fernández-Arquero
authors.forename: Concepción
authors.initials: C
authors.lastname: Núñez
authors.forename: Gudmundur
authors.initials: G
authors.lastname: Jorgensen
authors.forename: Björn R
authors.initials: BR
authors.lastname: Ludviksson
authors.forename: Sinikka
authors.initials: S
authors.lastname: Koskinen
authors.forename: Katri
authors.initials: K
authors.lastname: Haimila
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: Lennart
authors.initials: L
authors.lastname: Hammarström
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Behrens
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D002874:Chromosome Mapping; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015235:HLA-B Antigens / Q000235:genetics*; D059866:HLA-DQ beta-Chains / Q000235:genetics*; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006239:Haplotypes; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D017098:IgA Deficiency / Q000235:genetics*; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
chemical_list: D015235:HLA-B Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D059811:HLA-DRB1 Chains; D000949:Histocompatibility Antigens Class II