Susceptibility to Childhood Pneumonia: A Genome-Wide Analysis

Abstract

Previous studies have indicated that in adult smokers, a history of childhood pneumonia is associated with reduced lung function and chronic obstructive pulmonary disease. There have been few previous investigations using genome-wide association studies to investigate genetic predisposition to pneumonia. This study aims to identify the genetic variants associated with the development of pneumonia during childhood and over the course of the lifetime. Study subjects included current and former smokers with and without chronic obstructive pulmonary disease participating in the COPDGene Study. Pneumonia was defined by subject self-report, with childhood pneumonia categorized as having the first episode at <16 years. Genome-wide association studies for childhood pneumonia (843 cases, 9,091 control subjects) and lifetime pneumonia (3,766 cases, 5,659 control subjects) were performed separately in non-Hispanic whites and African Americans. Non-Hispanic white and African American populations were combined in the meta-analysis. Top genetic variants from childhood pneumonia were assessed in network analysis. No single-nucleotide polymorphisms reached genome-wide significance, although we identified potential regions of interest. In the childhood pneumonia analysis, this included variants in NGR1 (P = 6.3 × 10-8), PAK6 (P = 3.3 × 10-7), and near MATN1 (P = 2.8 × 10-7). In the lifetime pneumonia analysis, this included variants in LOC339862 (P = 8.7 × 10-7), RAPGEF2 (P = 8.4 × 10-7), PHACTR1 (P = 6.1 × 10-7), near PRR27 (P = 4.3 × 10-7), and near MCPH1 (P = 2.7 × 10-7). Network analysis of the genes associated with childhood pneumonia included top networks related to development, blood vessel morphogenesis, muscle contraction, WNT signaling, DNA damage, apoptosis, inflammation, and immune response (P ≤ 0.05). We have identified genes potentially associated with the risk of pneumonia. Further research will be required to confirm these associations and to determine biological mechanisms.

Clinical trial registration: NCT00608764.

Keywords: chronic obstructive pulmonary disease; genetic epidemiology; genome-wide association study; pediatrics; pneumonia.

Figures

Figure 1.

Locus plots for top childhood pneumonia variants (Genome build hg19, linkage disequilibrium population 1,000 Genomes Nov 2012 EUR). Regional LocusZoom plots from (A) non-Hispanic whites, near MATN1, 1p35.2 (rs16833920), (B) meta-analysis NRG1, 8p12 (rs188808012), and (C) meta-analysis PAK6, 15q14 (rs77554123). Index single-nucleotide polymorphisms (SNPs) in purple and regional SNPs plotted in colors represent their degree of linkage disequilibrium with the index SNP, as measured by r2, the squared coefficient of correlation. The solid blue lines show the recombination rates. chr, chromosome.

Figure 1.

Locus plots for top childhood pneumonia variants (Genome build hg19, linkage disequilibrium population 1,000 Genomes Nov 2012 EUR). Regional LocusZoom plots from (A) non-Hispanic whites, near MATN1, 1p35.2 (rs16833920), (B) meta-analysis NRG1, 8p12 (rs188808012), and (C) meta-analysis PAK6, 15q14 (rs77554123). Index single-nucleotide polymorphisms (SNPs) in purple and regional SNPs plotted in colors represent their degree of linkage disequilibrium with the index SNP, as measured by r2, the squared coefficient of correlation. The solid blue lines show the recombination rates. chr, chromosome.