Abstract
ObjectiveLower 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. MethodsWe 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. ResultsA 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). ConclusionA 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.
Highlights
Lower respiratory tract infections (LRTIs) are the sixth leading cause of mortality for all ages, with 2.38 million deaths globally each year [1]
In the UK Biobank and Trøndelag Health Study (HUNT), cases at baseline were older than controls, had higher systolic blood pressure (SBP), and were more likely to be ever-smokers and self-report having diabetes (Table 1)
Using a two-sample Mendelian randomization (MR) framework, we found that increasing body mass index (BMI), lifetime smoking, and SBP were associated with an increased risk of developing LRTI
Summary
Lower respiratory tract infections (LRTIs) are the sixth leading cause of mortality for all ages, with 2.38 million deaths globally each year [1]. There is significant variability in the host response to LRTI, even among individuals considered at low risk, which indicates a genetic component to the pathogenesis and prognosis [2]. Previous genetic studies have focused primarily on sepsis caused by pneumonia [3], childhood pneumonia [4], and viral pneumonia [5e7]. Genome-wide association studies (GWASs) on host susceptibility to bacterial LRTI in adults are scarce. A variety of pathogens can cause LRTIs, the majority are of bacterial origin [8]. Given that smoking is causally related to LRTI [9], it is relevant to estimate whether the effect of genetic variants associated with LRTI risk is modulated by smoking behaviour. Interaction analysis between smoking behaviour and genetic variants can be performed to assess how different risk estimates apply to different genetic predispositions
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