Risk of lower respiratory tract infections: a genome-wide association study with Mendelian randomization analysis in three independent European populations

Objective Lower respiratory tract infections (LRTIs) are a leading cause of morbidity and mortality worldwide. Few studies have previously investigated genetic susceptibility and potential risk factors for LRTI. Methods We used data from the UK Biobank, Trøndelag Health Study (HUNT), and FinnGen to conduct a genome-wide association study (GWAS). Cases were subjects hospitalized with LRTI, and controls were subjects with no such hospitalization. We conducted stratification and interaction analyses to evaluate whether the genetic effect of LRTI differed by sex or smoking. Mendelian randomization (MR) analyses were conducted to identify the unconfounded relationship between cardiometabolic risk factors and LRTI. Results A total of 25 320 cases and 575 294 controls were included. The 15q25.1 locus reached genome-wide significance in the meta-analysis (rs10519203: OR 0.94, p 3.87e-11). The protective effect of effect allele of rs10519203 was present among smokers (OR 0.90, 95%CI 0.87–0.92, p 1.38e-15) but not among never-smokers (OR 1.01, 95%CI 0.97–1.06, p 5.20e-01). In MR analyses, we found that increasing body mass index (OR 1.31, 95%CI 1.24–1.40, p 3.78e-18), lifetime smoking (OR 2.83, 95%CI 2.34–3.42, p 6.56e-27), and systolic blood pressure robustly increased the risk of LRTIs (OR 1.11, 95%CI 1.02–1.22, p 1.48e-02). Conclusion A region in 15q25.1 was strongly associated with LRTI susceptibility. Reduction in the prevalence of smoking, overweight, obesity, and hypertension may reduce the disease burden of LRTIs.