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Fine mapping of MHC region in lung cancer highlights independent susceptibility loci by ethnicity.

ABSTRACT: Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA-tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.

SUBMITTER: Ferreiro-Iglesias A

PROVIDER: S-EPMC6156406 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Fine mapping of MHC region in lung cancer highlights independent susceptibility loci by ethnicity.

Ferreiro-Iglesias Aida A Lesseur Corina C McKay James J Hung Rayjean J RJ Han Younghun Y Zong Xuchen X Christiani David D Johansson Mattias M Xiao Xiangjun X Li Yafang Y Qian David C DC Ji Xuemei X Liu Geoffrey G Caporaso Neil N Scelo Ghislaine G Zaridze David D Mukeriya Anush A Kontic Milica M Ognjanovic Simona S Lissowska Jolanta J Szołkowska Małgorzata M Swiatkowska Beata B Janout Vladimir V Holcatova Ivana I Bolca Ciprian C Savic Milan M Ognjanovic Miodrag M Bojesen Stig Egil SE Wu Xifeng X Albanes Demetrios D Aldrich Melinda C MC Tardon Adonina A Fernandez-Somoano Ana A Fernandez-Tardon Guillermo G Le Marchand Loic L Rennert Gadi G Chen Chu C Doherty Jennifer J Goodman Gary G Bickeböller Heike H Wichmann H-Erich HE Risch Angela A Rosenberger Albert A Shen Hongbing H Dai Juncheng J Field John K JK Davies Michael M Woll Penella P Teare M Dawn MD Kiemeney Lambertus A LA van der Heijden Erik H F M EHFM Yuan Jian-Min JM Hong Yun-Chul YC Haugen Aage A Zienolddiny Shanbeh S Lam Stephen S Tsao Ming-Sound MS Johansson Mikael M Grankvist Kjell K Schabath Matthew B MB Andrew Angeline A Duell Eric E Melander Olle O Brunnström Hans H Lazarus Philip P Arnold Susanne S Slone Stacey S Byun Jinyoung J Kamal Ahsan A Zhu Dakai D Landi Maria Teresa MT Amos Christopher I CI Brennan Paul P

Nature communications 20180925 1

Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare r ...[more]

PMID: 30254314

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Project description: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.

Dataset Information

Fine mapping of MHC region in lung cancer highlights independent susceptibility loci by ethnicity.

Publications

Fine mapping of MHC region in lung cancer highlights independent susceptibility loci by ethnicity.

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