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

Muhammad G Kibriya,Faruque Parvez,Habibul Ahsan,Muhammad Rakibuz-Zaman,Vesna Slavkovich,Tariqul Islam,Joseph H Graziano,Shantanu Roy,Farzana Jasmine,Maria Argos,Rachelle Paul-Brutus,Justin Shinkle,Alauddin Ahmed

doi:10.1186/s12940-017-0283-8

Abstract

BackgroundExposure 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.MethodsFrom 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.ResultThe 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.ConclusionThis 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.

Highlights

Exposure to arsenic in drinking water is a global health problem and arsenic-induced skin lesions are hallmark of chronic arsenic toxicity
This first genome-wide copy number variation (CNV) study in a prospectively followed-up large cohort, exposed to arsenic, suggests that DNA deletion in several genes and Long intervening noncoding RNA (lincRNA) genes may predispose an individual to a higher risk of development of arsenic-induced skin lesions
We present the first paper addressing the role of germ line CNVs in the development of arsenic-induced skin lesions in a population exposed to arsenic through drinking water

Summary

Introduction

Exposure to arsenic in drinking water is a global health problem and arsenic-induced skin lesions are hallmark of chronic arsenic toxicity. Using clinical follow-up data of one of the largest cohorts exposed to arsenic through drinking water, our group presented evidence that a higher risk of arsenic-induced skin lesions was found in the male gender, higher age and higher arsenic exposure [16]. A copy number variant (CNV) is a term collectively used to describe gains or losses of DNA sequence >1 kb in length. These may have a direct effect on transcription and transcriptional regulation, which in turn may be a cause for disease susceptibility and phenotypic variation [29]

Methods

Findings

Discussion

Conclusion