Leavy Olivia C, Goemans Anne F, Stockwell Amy D, Allen Richard J, Guillen-Guio Beatriz, Hernandez-Beeftink Tamara, Adegunsoye Ayodeji, Booth Helen L, Cullinan Paul, Fahy William A, Fingerlin Tasha E, Virk Harvinder S, Hall Ian P, Hart Simon P, Hill Mike R, Hirani Nik, Hubbard Richard B, Kaminski Naftali, Ma Shwu-Fan, McAnulty Robin J, Sheng X Rebecca, Millar Ann B, Molina-Molina Maria, Navaratnam Vidya, Neighbors Margaret, Parfrey Helen, Saini Gauri, Sayers Ian, Strek Mary E, Tobin Martin D, Whyte Moira Kb, Zhang Yingze, Maher Toby M, Molyneaux Philip L, Oldham Justin M, Yaspan Brian L, Flores Carlos, Martinez Fernando, Reynolds Carl J, Schwartz David A, Noth Imre, Jenkins R Gisli, Wain Louise V
Department of Population Health Sciences, University of Leicester, Leicester, UK.
NIHR Leicester Biomedical Research Centre, Leicester, UK.
medRxiv. 2024 Jan 15:2024.01.12.24301204. doi: 10.1101/2024.01.12.24301204.
Idiopathic pulmonary fibrosis (IPF) is a chronic lung condition that is more prevalent in males than females. The reasons for this are not fully understood, with differing environmental exposures due to historically sex-biased occupations, or diagnostic bias, being possible explanations. To date, over 20 independent genetic variants have been identified to be associated with IPF susceptibility, but these have been discovered when combining males and females. Our aim was to test for the presence of sex-specific associations with IPF susceptibility and assess whether there is a need to consider sex-specific effects when evaluating genetic risk in clinical prediction models for IPF.
We performed genome-wide single nucleotide polymorphism (SNP)-by-sex interaction studies of IPF risk in six independent IPF case-control studies and combined them using inverse-variance weighted fixed effect meta-analysis. In total, 4,561 cases (1,280 females and 2,281 males) and 23,500 controls (8,360 females and 14,528 males) of European genetic ancestry were analysed. We used polygenic risk scores (PRS) to assess differences in genetic risk prediction between males and females.
Three independent genetic association signals were identified. All showed a consistent direction of effect across all individual IPF studies and an opposite direction of effect in IPF susceptibility between females and males. None had been previously identified in IPF susceptibility genome-wide association studies (GWAS). The predictive accuracy of the PRSs were similar between males and females, regardless of whether using combined or sex-specific GWAS results.
We prioritised three genetic variants whose effect on IPF risk may be modified by sex, however these require further study. We found no evidence that the predictive accuracy of common SNP-based PRSs varies significantly between males and females.
特发性肺纤维化（IPF）是一种慢性肺部疾病，男性比女性更常见。其原因尚不完全清楚，可能的解释包括历史上因性别偏见的职业导致的不同环境暴露，或诊断偏差。迄今为止，已确定超过20个独立的基因变异与IPF易感性相关，但这些都是在合并男性和女性的情况下发现的。我们的目的是测试与IPF易感性是否存在性别特异性关联，并评估在评估IPF临床预测模型中的遗传风险时是否需要考虑性别特异性效应。
我们在六项独立的IPF病例对照研究中进行了全基因组单核苷酸多态性（SNP）与性别的相互作用研究，并使用逆方差加权固定效应荟萃分析将它们合并。总共分析了4561例（1280名女性和2281名男性）和23500名对照（8360名女性和14528名男性）具有欧洲遗传血统的个体。我们使用多基因风险评分（PRS）来评估男性和女性在遗传风险预测方面的差异。
鉴定出三个独立的遗传关联信号。所有信号在所有个体IPF研究中均显示出一致的效应方向，且在女性和男性的IPF易感性中效应方向相反。这些信号在之前的IPF易感性全基因组关联研究（GWAS）中均未被发现。无论使用合并的还是性别特异性的GWAS结果，PRS在男性和女性中的预测准确性相似。
我们确定了三个基因变异，其对IPF风险的影响可能因性别而异，但这些需要进一步研究。我们没有发现基于常见SNP的PRS在男性和女性之间的预测准确性有显著差异的证据。
