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. 2017 Jul 18;16(1):75.
doi: 10.1186/s12940-017-0283-8.

Association between genome-wide copy number variation and arsenic-induced skin lesions: a prospective study

Muhammad G Kibriya  1 , Farzana Jasmine  2 , Faruque Parvez  3 , Maria Argos  4 , Shantanu Roy  2 , Rachelle Paul-Brutus  2 , Tariqul Islam  5 , Alauddin Ahmed  5 , Muhammad Rakibuz-Zaman  5 , Justin Shinkle  2 , Vesna Slavkovich  3 , Joseph H Graziano  3 , Habibul Ahsan  2   6   7   8
Affiliations

Association between genome-wide copy number variation and arsenic-induced skin lesions: a prospective study

Muhammad G Kibriya et al. Environ Health. .

Abstract

Background: Exposure to arsenic in drinking water is a global health problem and arsenic-induced skin lesions are hallmark of chronic arsenic toxicity. We and others have reported germline genetic variations as risk factors for such skin lesions. The role of copy number variation (CNV) in the germline DNA in this regard is unknown.

Methods: From a large prospectively followed-up cohort, exposed to arsenic, we randomly selected 2171 subjects without arsenic-induced skin lesions at enrollment and genotyped their whole blood DNA samples on Illumina Cyto12v2.1 SNP chips to generate DNA copy number. Participants were followed up every 2 years for a total of 8 years, especially for the development of skin lesions. In Cox regression models, each CNV segment was used as a predictor, accounting for other potential covariates, for incidence of skin lesions.

Result: The presence of genomic deletion(s) in a number of genes (OR5J2, GOLGA6L7P, APBA2, GALNTL5, VN1R31P, PHKG1P2, SGCZ, ZNF658) and lincRNA genes (RP11-76I14.1, CTC-535 M15.2, RP11-73B2.2) were associated with higher risk [HR between 1.67 (CI 1.3-2.1) and 2.15 (CI 1.5-2.9) for different CNVs] for development of skin lesions independent of gender, age, and arsenic exposure. Some deletions had stronger effect in a specific gender (ZNF658 in males, SGCZ in females) and some had stronger effect in higher arsenic exposure (lincRNA CTD-3179P9.1) suggesting a possible gene-environment interaction.

Conclusion: This first genome-wide CNV study in a prospectively followed-up large cohort, exposed to arsenic, suggests that DNA deletion in several genes and lincRNA genes may predispose an individual to a higher risk of development of arsenic-induced skin lesions.

Keywords: Arsenic; Copy number variation; Gene-environment interaction; Skin lesion; Survival analysis; lincRNA.

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Conflict of interest statement

Ethics approval and consent to participate

The study protocol was approved by the Institutional Review board of The University of Chicago, Columbia University, and the Bangladesh Medical Research Council. Informed consent was obtained from all participants.

Consent for publication

Not applicable.

Competing interests

The authors declare they have no actual or potential competing financial interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Copy number variants detected in 8p22 region. Top panel (panel a) shows mapping of the region to Refseq and Ensembl database; middle panel (panel b): y-axis shows the number of samples showing deletion; lower panel (panel c) shows different samples having deletion of different length (shown on x-axis), but the overlap is clearly seen
Fig. 2
Fig. 2
Kaplan-Meier curves: x-axis represents time in months; deletion in chromosome 15q13.1 covering the gene APBA2 did not affect the development of arsenic-induced skin lesions in female subjects (p = 0.117, log rank test; shown on left), but significantly increased the risk in male subjects (p = 3.07E-05, log rank test; shown on right) exposed to arsenic through drinking water
Fig. 3
Fig. 3
Kaplan-Meier curves: x-axis represents time in months; deletion in chromosome 5q23.1 covering the lincRNA CTD-3179P9.1 did not affect the development of arsenic-induced skin lesions in subjects with lower UACR (< median 192 μg/g of creatinine, shown on left; p = 0.771, log rank test), but deletion of the same region significantly increased the risk in subjects with higher UACR (shown on right; p = 0.002, log rank test)
See this image and copyright information in PMC

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