2.1 Cross-sectional study
A cross-sectional survey was conducted in Shimen county during November 2016. Residents from three villages in the mining region were recruited through cluster sampling. Details can be found in our previous publications11 12. In brief, demographic information, behavioral characteristics with respect to bath and skin care, history of diseases and medications, and history of occupational arsenic exposure were inquired through a face-to-face questionnaire interview. Height, weight, and waist circumference were measured using a standardized procedure. Body mass index (BMI) was calculated as weight [kg] / (height [m])2.
Skin examinations were performed by certificated dermatologists from Xiangya Hospital, Central South University. Skin disorders were diagnosed according to skin lesions and symptoms, and dermatoscope or skin biopsy when necessary. Participants were asked to record their current intensity of itch on a numerical rating scale (NRS) from 0 to 10. Participants were grouped by NRS: no itch or mild itch (0–2), moderate itch (3–6), and severe itch (7–10) in data analysis13.
2.2 Mendelian randomization study
To confirm the causal relationship between arsenic exposure and pruritus, we conducted a Mendelian randomization (MR) analysis using external data from the UK Biobank, a prospective cohort that recruited 500,000 participants in the United Kingdom during 2007 and 2010. The percentages of monomethylated arsenic (MMA%) and dimethylated arsenic (DMA%) in total urinary arsenic are established indicators for the toxicity of arsenic, as high MMA% and low DMA% represent insufficient detoxication and vulnerability to arsenic exposure. Therefore, we constructed the polygenic risk scores (PRSs) for MMA% and DMA% according to a published genome-wide association study (GWAS) using data on urinary arsenic metabolite concentrations and genome-wide single nucleotide polymorphisms (SNPs) from 1,313 arsenic-exposed individuals14. They identified significant associations (P <5×10–8) for both MMA% and DMA% near the AS3MT gene (arsenite methyltransferase; 10q24.32), with five SNPs showing independent associations. The number of alleles (0, 1, or 2) for each individual was then summed after multiplication with the β coefficients between the SNPs and MMA% or DMA% to derive the PRSMMA% and PRSDMA% for each participant in the UK Biobank. The outcome variable was the diagnosis of pruritus from either primary care or hospital admissions, based on 10th revision of the International Statistical Classification of Diseases and Related Health Problems (code: L29). To reduce heterogeneity, the MR analysis was restricted to individuals whose ethnic backgrounds were White (including British, Irish, and other White backgrounds), with genetic information available.