Person:

Su, Li

Background: Occupational exposure to endotoxin is associated with decrements in pulmonary function, but how much variation in this association is explained by genetic variants is not well understood. Objective: We aimed to identify single nucleotide polymorphisms (SNPs) that are associated with the rate of forced expiratory volume in one second (FEV1) decline by a large scale genetic association study in newly-hired healthy young female cotton textile workers. Methods: DNA samples were genotyped using the Illumina Human CVD BeadChip. Change rate in FEV1 was modeled as a function of each SNP genotype in linear regression model with covariate adjustment. We controlled the type 1 error in study-wide level by permutation method. The false discovery rate (FDR) and the family-wise error rate (FWER) were set to be 0.10 and 0.15 respectively. Results: Two SNPs were found to be significant (P<6.29×(10^{−5})), including rs1910047 (P = 3.07×(10^{−5}), FDR = 0.0778) and rs9469089 (P = 6.19×(10^{−5}), FDR = 0.0967), as well as other eight suggestive (P<5×(10^{−4})) associated SNPs. Gene-gene and gene-environment interactions were also observed, such as rs1910047 and rs1049970 (P = 0.0418, FDR = 0.0895); rs9469089 and age (P = 0.0161, FDR = 0.0264). Genetic risk score analysis showed that the more risk loci the subjects carried, the larger the rate of FEV1 decline occurred (Ptrend = 3.01×(10^{−18})). However, the association was different among age subgroups (P = 7.11×(10^{−6})) and endotoxin subgroups (P = 1.08×(10^{−2})). Functional network analysis illustrates potential biological connections of all interacted genes. Conclusions: Genetic variants together with environmental factors interact to affect the rate of FEV1 decline in cotton textile workers.

Rationale: Adiponectin is an anti-inflammatory adipokine that is the most abundant gene product of adipose tissue. Lower levels have been observed in obesity, insulin resistance, and in critical illness. However, elevated levels early in acute respiratory failure have been associated with mortality. Polymorphisms in adiponectin-related genes (ADIPOQ, ADIPOR1, ADIPOR2) have been examined for relationships with obesity, insulin resistance and diabetes, cardiovascular disease, and to circulating adipokine levels, but many gaps in knowledge remain. The current study aims to assess the association between potentially functional polymorphisms in adiponectin-related genes with acute respiratory distress syndrome (ARDS) risk and mortality. Methods: Consecutive patients with risk factors for ARDS admitted to the ICU were enrolled and followed prospectively for development of ARDS. ARDS cases were followed through day 60 for all-cause mortality. 2067 patients were successfully genotyped using the Illumina CVD BeadChip high-density platform. Of these, 567 patients developed ARDS. Forty-four single nucleotide polymorphisms (SNPs) on ADIPOQ, ADIPOR1 and ADIPOR2 were successfully genotyped. Of these, 9 SNPs were hypothesized to be functional based on their location (promoter, exon, or 3′ untranslated region). These 9 SNPs were analyzed for association with ARDS case status and mortality among ARDS cases. Results: After multivariable analysis and adjustment for multiple comparisons, no SNPs were significantly associated with ARDS case status. Among ARDS cases, homozygotes for the minor allele of rs2082940 (ADIPOQ) had increased mortality (hazard ratio 2.61, 95% confidence interval 1.36–5.00, p = 0.0039) after adjustment for significant covariates. The significance of this association persisted after adjustment for multiple comparisons (FDR_q = 0.029). Conclusions: A common and potentially functional polymorphism in ADIPOQ may impact survival in ARDS. Further studies are required to replicate these results and to correlate genotype with circulating adiponectin levels.

Background: An inverse association between socioeconomic status and pulmonary function has emerged in many studies. However, the mediating factors in this relationship are poorly understood, and might be expected to differ between countries. We sought to investigate the relationship between socioeconomic status and lung function in China, a rapidly industrializing nation with unique environmental challenges, and to identify potentially-modifiable environmental mediators. Methods: We used data from the Shanghai Putuo Study, a cross-sectional study performed in Shanghai, China. Participants completed a questionnaire and spirometry. The primary exposure was socioeconomic status, determined by education level. The primary outcomes were FEV1 and FVC percent predicted. Multiple linear regressions were used to test this association, and the percent explained by behavioral, environmental, occupational, and dietary variables was determined by adding these variables to a base model. Results: The study population consisted of a total of 22,878 study subjects that were 53.3 % female and had a mean age of 48. In the final multivariate analysis, the effect estimates for FEV1 and FVC percent predicted for low socioeconomic status (compared to high) were statistically significant at a p-value of <0.01. Smoking, biomass exposure, mode of transportation to work, a diet low in fruits or vegetables, and occupational category partially attenuated the relationship between SES and lung function. In a fully-adjusted age-stratified analysis, the socioeconomic disparity in lung function widened with increasing age. Conclusions: We found cross-sectional evidence of socioeconomic disparities in pulmonary function in Shanghai. These differences increased with age and were partially explained by potentially modifiable exposures.