Browsing by Subject "genome wide association study"

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    Urinary cadmium and lung cancer risk in smokers from the Multiethnic Cohort Study
    (2019-08) Cigan, Shannon
    Abstract Objective: The overall objective of this research is to investigate the effects of smoking, occupational exposures, demographics (e.g. race/ethnicity and education) and common genetic variants on the levels of urinary cadmium (Cd), a validated biomarker of long-term Cd exposure, in current smokers from the Multiethnic Cohort (MEC) Study. In addition, test whether this biomarker in smokers is associated with lung cancer risk. The overall objective of this research was accomplished in three separate dissertation chapters (chapter 2, 3 and 4) and set up as three sequential papers. Specific Aim 1: Aim: To investigate the relationship between self-reported occupation and urinary Cd levels in 1,956 current smokers at time of urine collection from five race/ethnicity groups from the MEC Study with complete covariate data. Methods: Urinary Cd was measured by inductively coupled plasma mass spectrometry (ICP-MS). Internal smoking dose was estimated by the biomarker urinary total nicotine equivalents (TNE). A censored multiple linear regression model (tobit regression) was used to estimate the percent adjusted change in the association between occupational exposure categories and levels of urinary Cd, while adjusting for confounding variables, with estimated 95% confidence intervals (CI) to characterize precision. Occupational exposure categories were based on the combined response to questions regarding the industry and occupation the participant worked the longest. Results: Participants categorized as ‘Likely exposed’ to Cd based on their occupations had 12.1% (95%CI: 1.2%, 24.3%) higher levels of urinary Cd as compared to those ‘Not likely exposed’ to Cd in the workplace, after adjusting for age, sex, race/ethnicity, creatinine (natural-log), education, smoking dose (TNE), and duration (years of smoking). Similarly, participants categorized as ‘Possibly exposed’ to Cd in the workplace had 7.7% (95%CI: 0.1%, 16.0%) higher levels of urinary Cd as compared to workers ‘Not likely exposed’ to Cd in the workplace. Specific Aim 2: Aim: To conduct a genome-wide association study to identify common genetic variants that may be associated with urinary Cd in smokers (N=1,977). In addition, evaluate the association between urinary Cd and single nucleotide polymorphisms (SNPs) previously reported in literature to be associated with Cd and located within genes that have biological plausibility to be associated with Cd absorption, distribution, metabolism and elimination. Methods: Linear regression was used to test the association of each genetic variant with urinary Cd levels, adjusted for age at urine collection, sex, self-reported race/ethnicity, creatinine (natural log), smoking dose (urinary TNE), and the top 10 leading PCs. Allele dosage was used as the explanatory variable of most interest in the analysis. Genome-wide significance was based on a Bonferroni-corrected 5% significant threshold of p < 8.4 x 10-9 (0.05/5,944,091 SNPs for analyses). In addition, a candidate SNP approach was used to identify associations in 1,169 single nucleotide polymorphisms (SNPs) comprised from 15 SNPs reported in literature to be associated with Cd biomarkers and SNPs within 29 candidate genes identified a priori that have biological plausibility to be involved in transport of Cd; Metallothionein (MT) gene family, metal-regulatory factor 1 (MTF1), and Glutathione S-transferase (GST) gene family. Results: No single SNP was associated with urinary Cd in the genome-wide association study. The SNP with the lowest p-value for the association with urinary Cd was rs673456 on chromosome 11, an intron variant close to the TENM4 gene (p=3.47 x 10-7). The candidate SNP analyses also did not reach statistically significance (lowest p-values 3.89 x 10-4). After adjusting for age at urine collection, sex, creatinine (natural log), and total nicotine equivalents, geometric mean levels of urinary Cd were significantly different across the five race/ethnicity groups (p<0.001). Latinos and Native Hawaiians had the highest geometric mean urinary Cd (0.87 and 0.84 ng/mL) followed by Japanese Americans (0.81 ng/mL), African Americans (0.80 ng/mL), and Whites (0.74 ng/mL). Geometric means were also higher in females than males across all race/ethnicity groups. Specific Aim 3: Aim: To investigate the association of urinary Cd and lung cancer risk in a subset of 1,956 MEC current smokers at the time of urine collection. Methods: Cd was analyzed by ICP-MS in urine samples collected between 1997 and 2006. Lung cancer incidence was identified by linkages with the statewide Surveillance, Epidemiology and End Results (SEER) registries of Hawaii and California through December 31, 2016. Cox proportional hazards regression was used to estimate multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (95% CI) for lung cancer. Urinary Cd was modelled as (1) continuous urinary Cd levels (natural log) and (2) quartiles of urinary Cd levels. Results: A total of 89 lung cancer cases were diagnosed in our subset of 1,956 current smokers with a median follow-up time of 12.4 years. Higher urinary Cd was associated with increased lung cancer risk after adjustment for age, sex, race/ethnicity, creatinine (natural log), education, smoking dose (urinary total nicotine equivalents), smoking duration (years of smoking), and occupational Cd exposure (HR: 1.69; 95% CI: 1.26, 2.26). Categorical analysis by quartiles of urinary Cd levels showed the multivariable-adjusted HR for lung cancer increased by increasing quartile of urinary Cd. Relative to the lowest quartile of urinary Cd levels, the adjusted HR for the fourth (highest) quartile was 3.45 (95% CI: 1.73, 6.89), third quartile was 2.02 (95% CI: 1.05, 3.89) and second quartile was 1.21 (95% CI: 0.62, 2.36). Overall Conclusions: Overall, our results indicate that urinary Cd is an important determinant of lung cancer risk in current smokers at the time of urine collection from the MEC Study and future studies investigating lung cancer risk will benefit from these findings. Specific Aim 1 demonstrated that at similar levels of smoking, smokers in occupations that have a potential for Cd exposure had higher levels of urinary Cd. This suggest workers in these types of occupations who also smoke may be at an increased risk for lung cancer and should be targeted for intervention measures. In Specific Aim 2, no common genetic variants were associated with urinary Cd at a genome-wide level. In addition, the candidate SNP analyses also did not demonstrate a statistically significant association with urinary Cd levels. Specific Aim 3 demonstrated that levels of urinary Cd were associated with lung cancer incidence in smokers from the MEC study and this association persisted after adjustment for occupational Cd exposure, smoking dose (TNE), duration (years of smoking) and other potential risk factors. Replication of findings in a larger sample size and/or studies with well-characterized measures of occupational Cd exposure, dietary and environmental exposures are warranted. The findings of this study were consistent with literature, confirm Cd is a risk factor for lung cancer and this relationship can be detected in current smokers at the time of urine collection. Public health efforts to reduce Cd exposure including tobacco cessation programs, reducing the environmental and industrial impact of Cd, and the implementation of educating smokers in occupations that pose a high risk for Cd exposure, may contribute to the reduction of lung cancer in the future.