Genome-wide interaction analysis identified low-frequency variants with sex disparity in lung cancer risk

Yafang Li, Xiangjun Xiao, Jianrong Li, Jinyoung Byun, Chao Cheng, Yohan Bossé, James McKay, Demetrios Albanes, Stephen Lam, Adonina Tardon, Chu Chen, Stig E. Bojesen, Maria T. Landi, Mattias Johansson, Angela Risch, Heike Bickeböller, H. Erich Wichmann, David C. Christiani, Gad Rennert, Susanne ArnoldGary Goodman, John K. Field, Michael P.A. Davies, Sanjay S. Shete, Loic Le Marchand, Olle Melander, Hans Brunnström, Geoffrey Liu, Rayjean J. Hung, Angeline S. Andrew, Lambertus A. Kiemeney, Hongbing Shen, Ryan Sun, Shan Zienolddiny, Kjell Grankvist, Mikael Johansson, Neil Caporaso, Dawn M. Teare, Yun Chul Hong, Philip Lazarus, Matthew B. Schabath, Melinda C. Aldrich, Ann G. Schwartz, Ivan Gorlov, Kristen Purrington, Ping Yang, Yanhong Liu, Younghun Han, Joan E. Bailey-Wilson, Susan M. Pinney, INTEGRAL-ILCCO lung cancer consortium

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Abstract

Differences by sex in lung cancer incidence and mortality have been reported which cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lung cancer association studies. By adopting a stringent two-stage analysis strategy, we performed a genome-wide gene-sex interaction analysis using genotypes from a lung cancer cohort including ~ 47 000 individuals with European ancestry. Three low-frequency variants (minor allele frequency < 0.05), rs17662871 [odds ratio (OR) = 0.71, P = 4.29×10-8); rs79942605 (OR = 2.17, P = 2.81×10-8) and rs208908 (OR = 0.70, P = 4.54×10-8) were identified with different risk effect of lung cancer between men and women. Further expression quantitative trait loci and functional annotation analysis suggested rs208908 affects lung cancer risk through differential regulation of Coxsackie virus and adenovirus receptor gene expression in lung tissues between men and women. Our study is one of the first studies to provide novel insights about the genetic and molecular basis for sex disparity in lung cancer development.

OriginalsprogEngelsk
TidsskriftHuman Molecular Genetics
Vol/bind31
Udgave nummer16
Sider (fra-til)2831-2843
Antal sider13
ISSN0964-6906
DOI
StatusUdgivet - 2022

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© The Author(s) 2022. Published by Oxford University Press.

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