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A DRD1 polymorphism predisposes to lung cancer among those exposed to secondhand smoke during childhood.

ABSTRACT: Lung cancer has a familial component which suggests a genetic contribution to its etiology. Given the strong evidence linking smoking with lung cancer, we studied miRNA-related loci in genes associated with smoking behavior. CHRNA, CHRNB gene families, CYP2A6, and DRD1 (dopamine receptor D1) were mined for SNPs that fell within the seed region of miRNA binding sites and then tested for associations with risk in a three-stage validation approach. A 3'UTR (untranslated region) SNP in DRD1 was associated with a lower risk of lung cancer among individuals exposed to secondhand smoke during childhood [OR, 0.69; 95% confidence interval (CI), 0.60-0.79; P < 0.0001]. This relationship was evident in both ever (OR, 0.74; 95% CI, 0.62-0.88; P = 0.001) and never smokers (OR, 0.61; 95% CI, 0.47-0.79; P < 0.0001), European American (OR, 0.65; 95% CI, 0.53-0.80; P < 0.0001), and African American (OR, 0.73; 95% CI, 0.62-0.88; P = 0.001) populations. Although much remains undefined about the long-term risks associated with exposure to secondhand smoke and heterogeneity between individuals in regard to their susceptibility to the effects of secondhand smoke, our data show an interaction between an SNP in the 3'UTR of DRD1 and exposure to secondhand smoke during childhood. Further work is needed to explore the mechanistic underpinnings of this SNP and the nature of the interaction between DRD1 and exposure to secondhand smoke during childhood.

SUBMITTER: Robles AI

PROVIDER: S-EPMC4256104 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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A DRD1 polymorphism predisposes to lung cancer among those exposed to secondhand smoke during childhood.

Robles Ana I AI Yang Ping P Jen Jin J McClary Andrew C AC Calhoun Kara K Bowman Elise D ED Vähäkangas Kirsi K Greathouse K Leigh KL Wang Yi Y Olivo-Marston Susan S Wenzlaff Angela S AS Deng Bo B Schwartz Ann G AG Ryan Bríd M BM

Cancer prevention research (Philadelphia, Pa.) 20141003 12

Lung cancer has a familial component which suggests a genetic contribution to its etiology. Given the strong evidence linking smoking with lung cancer, we studied miRNA-related loci in genes associated with smoking behavior. CHRNA, CHRNB gene families, CYP2A6, and DRD1 (dopamine receptor D1) were mined for SNPs that fell within the seed region of miRNA binding sites and then tested for associations with risk in a three-stage validation approach. A 3'UTR (untranslated region) SNP in DRD1 was asso ...[more]

PMID: 25281486

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Project description:BackgroundSecondhand smoke (SHS) exposure has adverse effects on the cardiovascular system. This study aimed to determine the effects of SHS on the cardiovascular disease biomarkers, namely the metabolic, inflammatory, and oxidative stress markers in healthy adult women.MethodsThis comparative cross-sectional study was conducted among healthy women. The cases included those women exposed to SHS, and the controls included those women not exposed to SHS. SHS exposure was defined as being exposed to SHS for at least 15 min for 2 days per week. Venous blood was taken to measure the metabolic markers (high molecular weight adiponectin, insulin level, insulin resistance, and nonesterified fatty acids), oxidative stress markers (oxidized low density lipoprotein cholesterol and 8-isoprostane), and inflammatory markers (high-sensitivity C-reactive protein and interleukin-6). A hair nicotine analysis was also performed. An analysis of covariance and a simple linear regression analysis were conducted.ResultsThere were 101 women in the SHS exposure group and 91 women in the non-SHS exposure group. The mean (with standard deviation) of the hair nicotine levels was significantly higher in the SHS exposure group when compared to the non-SHS exposure group [0.22 (0.62) vs. 0.04 (0.11) ng/mg; P = 0.009]. No significant differences were observed in the high molecular weight adiponectin, insulin and insulin resistance, nonesterified fatty acids, 8-isoprostane, oxidized low density lipoprotein cholesterol, interleukin-6, and high-sensitivity C-reactive protein between the two groups. The serum high molecular weight adiponectin was negatively associated with the insulin level and insulin resistance in the women exposed to SHS. However, no significant relationships were seen between the high molecular weight adiponectin and nonesterified fatty acids, 8-isoprostane, oxidized low density lipoprotein cholesterol, high-sensitivity C-reactive protein in the SHS group.DiscussionThere were no significant differences in the metabolic, oxidative stress, and inflammatory markers between the SHS exposure and non-SHS exposure healthy women. A low serum level of high molecular weight adiponectin was associated with an increased insulin level and resistance in the women exposed to SHS.

Project description:BackgroundMaternal smoking during pregnancy is related to altered DNA methylation in infant umbilical cord blood. The extent to which low levels of smoke exposure among nonsmoking pregnant women relates to offspring DNA methylation is unknown.ObjectiveThis study sought to evaluate relationships between maternal prenatal plasma cotinine levels and DNA methylation in umbilical cord blood in newborns using the Infinium HumanMethylation 450K BeadChip.MethodsParticipants from the Newborn Epigenetics Study cohort who reported not smoking during pregnancy had verified low levels of cotinine from maternal prenatal plasma (0 ng/mL to <4 ng/mL), and offspring epigenetic data from umbilical cord blood were included in this study (n=79). Multivariable linear regression models were fit to the data, controlling for cell proportions, age, race, education, and parity. Estimates represent changes in response to any 1-ng/mL unit increase in exposure.ResultsMultivariable linear regression models yielded 29,049 CpGs that were differentially methylated in relation to increases in cotinine at a 5% false discovery rate. Top CpGs were within or near genes involved in neuronal functioning (PRKG1, DLGAP2, BSG), carcinogenesis (FHIT, HSPC157) and inflammation (AGER). Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses suggest cotinine was related to methylation of gene pathways controlling neuronal signaling, metabolic regulation, cell signaling and regulation, and cancer. Further, enhancers associated with transcription start sites were enriched in altered CpGs. Using an independent sample from the same study population (n=115), bisulfite pyrosequencing was performed with infant cord blood DNA for two genes within our top 20 hits (AGER and PRKG1). Results from pyrosequencing replicated epigenome results for PRKG1 (cg17079497, estimate=-1.09, standard error (SE)=0.45, p=0.018) but not for AGER (cg09199225; estimate=-0.16, SE=0.21, p=0.44).DiscussionSecondhand smoke exposure among nonsmoking women may alter DNA methylation in regions involved in development, carcinogenesis, and neuronal functioning. These novel findings suggest that even low levels of smoke exposure during pregnancy may be sufficient to alter DNA methylation in distinct sites of mixed umbilical cord blood leukocytes in pathways that are known to be altered in cord blood from pregnant active smokers. https://doi.org/10.1289/EHP8099.

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A DRD1 polymorphism predisposes to lung cancer among those exposed to secondhand smoke during childhood.

Publications

A DRD1 polymorphism predisposes to lung cancer among those exposed to secondhand smoke during childhood.

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