Abstract 1314: Trans-ethnic HLA fine-mapping of the MHC region identified several independent variants influencing susceptibility to lung cancer
Authors: Ferreiro-Iglesias Aida , Lesseur Corina , McKay James , Hung Rayjean J. , Amos Christopher I. , Brennan Paul ,   on behalf of OncoArray consortium
Published: July 2017

Background: Genetic variants within the major histocompatibility complex (MHC) are associated with lung cancer. However, debate persists about the identity of the true causal variants, in part due to the broad linkage disequilibrium (LD) characteristic of the MHC and to the complexity and cost of complete HLA genotyping. Here, we assessed the role of the MHC in modulating lung cancer risk in Asians and Europeans using a broad set of HLA variants to detect the main alleles and the presence of independent effects elsewhere in this genomic region.

Material and methods: Association between the HLA variants and risk of lung cancer was examined in two collections of samples of different ethnicity (18,686 cases / 15,190 controls and 2,324 cases / 1,646 controls of European and Asian ancestry, respectively). Using existing genome-wide SNP data from the lung cancer OncoArray study, we imputed and tested classical alleles and amino acid polymorphisms in HLA-A, HLA-B, HLA-C, HLA-DQA1, HLA-DQB1, HLA-DRB1, HLA-DPA1 and HLA-DPB1, as well as 7,258 SNPs across the MHC. All the analyses were performed assuming an additive genetic model adjusted for sex and principal components as covariates. The study-wide significant threshold was p=6.03 x 10-6.

Results: Conditional, haplotype and stratified analyses identified two independent HLA allele effects associated with lung cancer squamous cell carcinoma in Europeans. One is HLA-DQB1*06 that showed a significant protective effect (OR=0.85, 95%CI 0.80-0.90, p=3.05 x10-8). The other effect is attributed to the long ancestral 8.1 haplotype (OR=1.30, 95%CI 1.18-1.42, p=4.78 x10-8), which contains class I and class II HLA alleles (A*0101 - B*0801 - C*0701 - DRB1*0301 - DQB1*0201 - DQA1*0501). In addition, single-amino-acid polymorphisms in HLA-B (at positions 9, 156, 163 and 178) and HLA-DRB1 (at positions 26, 71 and 74) located in peptide-binding grooves, suggest these proteins as possible functional contributors within the haplotype. In Asians, we observed two independent HLA allele effects associated with lung adenocarcinoma : HLA-DQB1*0401 (OR=1.67, 95% CI 1.35-2.05, p=1.59 x10-6), and HLA-DRB1*0701(OR=1.62, 95% CI 1.31-2.01, p=5.48 x10-6) as well as an intronic SNP in HLA-A (rs2256919) (OR=0.75, 95% CI 0.67-0.83, p=1.75 x10-7).

Conclusions: We established an association between HLA haplotype 8.1 and squamous lung cancer risk in Europeans. In contrast, in Asians we observed associations only with class II HLA alleles and risk of lung adenocarcinoma. We did not observed shared HLA alleles effects between populations. This ethnic heterogeneity in classical HLA allelic associations with lung cancer may be explained by allele frequency differences between populations and also different exposures that interact with HLA. Furthermore, our study illustrates the value of high-resolution imputation for fine-mapping causal variants in the MHC.

Citation Format: Aida Ferreiro-Iglesias, Corina Lesseur, James McKay, Rayjean J. Hung, Christopher I. Amos, Paul Brennan, on behalf of OncoArray consortium. Trans-ethnic HLA fine-mapping of the MHC region identified several independent variants influencing susceptibility to lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1314. doi:10.1158/1538-7445.AM2017-1314