Gene-Gene and Gene-Environmental Interactions of Childhood Asthma: A Multifactor Dimension Reduction Approach

Abstract

BackgroundThe importance of gene-gene and gene-environment interactions on asthma is well documented in literature, but a systematic analysis on the interaction between various genetic and environmental factors is still lacking.Methodology/Principal FindingsWe conducted a population-based, case-control study comprised of seventh-grade children from 14 Taiwanese communities. A total of 235 asthmatic cases and 1,310 non-asthmatic controls were selected for DNA collection and genotyping. We examined the gene-gene and gene-environment interactions between 17 single-nucleotide polymorphisms in antioxidative, inflammatory and obesity-related genes, and childhood asthma. Environmental exposures and disease status were obtained from parental questionnaires. The model-free and non-parametrical multifactor dimensionality reduction (MDR) method was used for the analysis. A three-way gene-gene interaction was elucidated between the gene coding glutathione S-transferase P (GSTP1), the gene coding interleukin-4 receptor alpha chain (IL4Ra) and the gene coding insulin induced gene 2 (INSIG2) on the risk of lifetime asthma. The testing-balanced accuracy on asthma was 57.83% with a cross-validation consistency of 10 out of 10. The interaction of preterm birth and indoor dampness had the highest training-balanced accuracy at 59.09%. Indoor dampness also interacted with many genes, including IL13, beta-2 adrenergic receptor (ADRB2), signal transducer and activator of transcription 6 (STAT6). We also used likelihood ratio tests for interaction and chi-square tests to validate our results and all tests showed statistical significance.Conclusions/SignificanceThe results of this study suggest that GSTP1, INSIG2 and IL4Ra may influence the lifetime asthma susceptibility through gene-gene interactions in schoolchildren. Home dampness combined with each one of the genes STAT6, IL13 and ADRB2 could raise the asthma risk.

Genetic Susceptibility to Asthma and Genetic Interactions in the 5q31-q33 and 16p11 Regions in Sudanese Families

“…The strongest association was between SNPs in IL9 and IL4R (P-value<0.0001). Our results are consistent with previous studies which identified gene-gene interactions as a major component in the pathogenesis of asthma [18]. These results can be explained by the fact that these interleukins share many signaling pathways and some can cross activate others' receptors [19].…”

Gene-gene and gene-sex epistatic interactions of <i>DNMT1</i>, <i>DNMT3A</i> and <i>DNMT3B</i> in autoimmune thyroid disease

“…It is optimal to combine several analytical methods to detect epistasis effects [35,36]. Because gene-gene interactions may occur through different pathophysiological pathways [36,37], we examined gene-gene interactions for each SNP pair of the three genes. The data showed multiple tendencies toward interactions in the above genes.…”

Oxidative stress at high altitude: genotype&ndash;phenotype correlations

“…In such studies, genotyping is done in a case-control format, which tells about the risk or minor genotype (found more in cases) or protective or major genotype (found more in controls) of a gene. SPSS 49,50 (IBM Corporation, Armonk, NY, USA) and MDR (Vanderbilt University Medical School, Nashville, TN, USA) 51,52 are two well-known software programs that can be used to study such interactions. The input file format depends on the software being used.…”