TY - JOUR
T1 - High-density SNP mapping of the HLA region identifies multiple independent susceptibility loci associated with selective IgA deficiency
AU - Ferreira, Ricardo C.
AU - Pan-Hammarström, Qiang
AU - Graham, Robert R.
AU - Fontán, Gumersindo
AU - Lee, Annette T.
AU - Ortmann, Ward
AU - Wang, Ning
AU - Urcelay, Elena
AU - Fernández-Arquero, Miguel
AU - Núñez, Concepción
AU - Jorgensen, Gudmundur
AU - Ludviksson, Björn R.
AU - Koskinen, Sinikka
AU - Haimila, Katri
AU - Padyukov, Leonid
AU - Gregersen, Peter K.
AU - Hammarström, Lennart
AU - Behrens, Timothy W.
PY - 2012/1
Y1 - 2012/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84857496758&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1002476
DO - 10.1371/journal.pgen.1002476
M3 - Article
C2 - 22291608
AN - SCOPUS:84857496758
SN - 1553-7390
VL - 8
JO - PLoS Genetics
JF - PLoS Genetics
IS - 1
M1 - e1002476
ER -