engleski

Multiple rare variants in immune genes predict common respiratory infections burden in isolated populations

Introduction: Common respiratory infections are causing a substantial burden of disease, despite numerous infection control measures. The aim of this study was to elucidate the role of host genetic in infections susceptibility. Materials and methods: A follow-up, postal survey was sent to participants from the 10, 001 Dalmatians cohort, focusing on the annual frequency of common cold, influenza and pneumonia, with 1, 082 responses. HRC imputed linear regression GWAS was adjusted for age, gender, years of schooling and socioeconomic status. Participants originated from two different isolated islands, requiring a weighted fixed effects meta- analysis, with Bonferroni adjusted P-value of 3.7E-09. Results: We found 45 significant hits in meta-analysis for the life-time risk of pneumonia, majority of them being rare intron variants. Some of the most interesting results belong to CXCL1, MARCH1, PAX5, and RASA3 genes, which were previously implied in inflammation and infection response processes. Five other genes involved in immunity, including IL12RB1 and C5, were found to be just under the formal significance threshold. We identified 4 marginally suggestive SNPs for cold and influenza frequency, also implied in immunity and infection response. Conclusions: Despite small sample size, genetic architecture underlying host susceptibility to common respiratory infections suggest the role of numerous rare variants. This result could explain high levels of diversity, observed in an individual susceptibility risk and infectious disease outcomes across population. Funding: Medical Research Council UK, Croatian Science Foundation grants 8875 and 8445, FP7 project PREPARE (602525). We gratefully acknowledge contribution from the Institute for Anthropological Research in Zagreb, Croatia.

espiratory infections ; host susceptibility ; GWAS

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