Pneumonia: host susceptibility and shared genetics with pulmonary function and other traits

Area of Science:

• Genetics and Genomics
• Infectious Diseases
• Pulmonary Medicine

Background:

• Pneumonia is a severe infectious lung disease with susceptibility influenced by host genetics and underlying conditions.
• Genome-wide association studies (GWAS) are crucial for identifying genetic variants associated with complex diseases like pneumonia.
• Understanding genetic underpinnings of pneumonia can reveal shared pathways with other pulmonary and systemic conditions.

Purpose of the Study:

• To conduct a secondary analysis of genome-wide association studies (GWAS) for pneumonia in large cohorts.
• To investigate the correlation between genetic variants and gene expression in lung and blood tissues using expression quantitative trait loci (eQTL) data.
• To identify shared genetic loci between pneumonia and pulmonary function (PF) and explore their biological relevance.

Main Methods:

• Secondary analysis of GWAS data from 23andMe and UK Biobank participants for pneumonia.
• Correlation of single nucleotide polymorphisms (SNPs) with eQTL data from the GTEx database in lung and whole blood.
• Comparison of pneumonia GWAS loci with published GWAS data for pulmonary function (PF) and enrichment analysis using dbGaP and NHGRI-EBI Catalog.

Main Results:

• 177 SNPs in the human leukocyte antigen (HLA) region met genome-wide significance for pneumonia risk.
• Several genes (C4A, VARS2, SFTA2, HLA-C, HLA-DQA2) showed unidirectional regulation by HLA eSNPs associated with pneumonia risk.
• Significant overlap was found between genetic loci for pneumonia and pulmonary function (28.8% in UK Biobank, 49.2% in 23andMe).
• Enrichment analysis revealed overlap between pneumonia/PF genes and those related to inflammatory, developmental, neuropsychiatric, cardiovascular, and obesity traits.

Conclusions:

• Host genetics, particularly within the HLA region, play a significant role in pneumonia susceptibility.
• Shared genetic loci between pneumonia and pulmonary function suggest common etiological pathways.
• Genetic factors influencing pneumonia risk are associated with a range of other complex traits, highlighting pleiotropy.