Evidence for gene-smoking interactions for hearing loss and deafness in Japanese American families

Abstract

Background: This study investigated the relationship between smoking and hearing loss and deafness (HLD) and whether the relationship is modified by genetic variation. Data for these analyses was from the subset of Japanese American families collected as part of the American Diabetes Association Genetics of Non-insulin Dependent Diabetes Mellitus study. Logistic regression with generalized estimating equations assessed the relationship between HLD and smoking. Nonparametric linkage analysis identified genetic regions harboring HLD susceptibility genes and ordered subset analysis was used to identify regions showing evidence for gene-smoking interactions. Genetic variants within these candidate regions were then each tested for interaction with smoking using logistic regression models.

Results: After adjusting for age, sex, diabetes status and smoking duration, for each pack of cigarettes smoked per day, risk of HLD increased 4.58 times (odds ratio (OR) = 4.58; 95% Confidence Interval (CI): (1.40,15.03)), and ever smokers were over 5 times more likely than nonsmokers to report HLD (OR = 5.22; 95% CI: (1.24, 22.03)). Suggestive evidence for linkage for HLD was observed in multiple genomic regions (Chromosomes 5p15, 8p23 and 17q21), and additional suggestive regions were identified when considering interactions with smoking status (Chromosomes 7p21, 11q23, 12q32, 15q26, and 20q13) and packs-per-day (Chromosome 8q21).

Conclusions: To our knowledge this was the first report of possible gene-by-smoking interactions in HLD using family data. Additional work, including independent replication, is needed to understand the basis of these findings. HLD are important public health issues and understanding the contributions of genetic and environmental factors may inform public health messages and policies.

Keywords: Family; Gene-environment interaction; Genome-wide linkage; Hearing loss; Linkage; Smoking.

Figure 1:

Evidence of of GxE (PDE7A, MTFR1 genes by smoking packs per day) interaction (circle points of -log10(p-values) on lefthand vertical axis) with underlying recombination rate (blue lines with right hand vertical axis) on chromosome 8. The linkage disequilibrium (LD) or correlation between each SNV and the SNV with the highest evidence of GxE (i.e., highest -log10(p-value) and denoted by a purple dot) is described by r² with legend in the box located in the right upper corner. The red demotes high LD/correlation and dark blue denotes low LD/correlation. All variants involved in the interaction with smoking packs-per-day to modify HLD risk are all in high LD. Reference panel is hg19/1000G Nov 2014 ASN. Plot was made using Locus Zoom (Prium et al., 2010).