Genome-Wide Association Study Identifies Chromosome 10q24.32 Variants Associated with Arsenic Metabolism and Toxicity Phenotypes in Bangladesh
Arsenic contamination of drinking water is a major public health issue in many countries, increasing risk for a wide array of diseases, including cancer. There is inter-individual variation in arsenic metabolism efficiency and susceptibility to arsenic toxicity; however, the basis of this variation is not well understood. Here, we have performed the first genome-wide association study (GWAS) of arsenic-related metabolism and toxicity phenotypes to improve our understanding of the mechanisms by which arsenic affects health. Using data on urinary arsenic metabolite concentrations and approximately 300,000 genome-wide single nucleotide polymorphisms (SNPs) for 1,313 arsenic-exposed Bangladeshi individuals, we identified genome-wide significant association signals (P<5×10−8) for percentages of both monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) near the AS3MT gene (arsenite methyltransferase; 10q24.32), with five genetic variants showing independent associations. In a follow-up analysis of 1,085 individuals with arsenic-induced premalignant skin lesions (the classical sign of arsenic toxicity) and 1,794 controls, we show that one of these five variants (rs9527) is also associated with skin lesion risk (P = 0.0005). Using a subset of individuals with prospectively measured arsenic (n = 769), we show that rs9527 interacts with arsenic to influence incident skin lesion risk (P = 0.01). Expression quantitative trait locus (eQTL) analyses of genome-wide expression data from 950 individual's lymphocyte RNA suggest that several of our lead SNPs represent cis-eQTLs for AS3MT (P = 10−12) and neighboring gene C10orf32 (P = 10−44), which are involved in C10orf32-AS3MT read-through transcription. This is the largest and most comprehensive genomic investigation of arsenic metabolism and toxicity to date, the only GWAS of any arsenic-related trait, and the first study to implicate 10q24.32 variants in both arsenic metabolism and arsenical skin lesion risk. The observed patterns of associations suggest that MMA% and DMA% have distinct genetic determinants and support the hypothesis that DMA is the less toxic of these two methylated arsenic species. These results have potential translational implications for the prevention and treatment of arsenic-associated toxicities worldwide.
Vyšlo v časopise:
Genome-Wide Association Study Identifies Chromosome 10q24.32 Variants Associated with Arsenic Metabolism and Toxicity Phenotypes in Bangladesh. PLoS Genet 8(2): e32767. doi:10.1371/journal.pgen.1002522
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002522
Souhrn
Arsenic contamination of drinking water is a major public health issue in many countries, increasing risk for a wide array of diseases, including cancer. There is inter-individual variation in arsenic metabolism efficiency and susceptibility to arsenic toxicity; however, the basis of this variation is not well understood. Here, we have performed the first genome-wide association study (GWAS) of arsenic-related metabolism and toxicity phenotypes to improve our understanding of the mechanisms by which arsenic affects health. Using data on urinary arsenic metabolite concentrations and approximately 300,000 genome-wide single nucleotide polymorphisms (SNPs) for 1,313 arsenic-exposed Bangladeshi individuals, we identified genome-wide significant association signals (P<5×10−8) for percentages of both monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) near the AS3MT gene (arsenite methyltransferase; 10q24.32), with five genetic variants showing independent associations. In a follow-up analysis of 1,085 individuals with arsenic-induced premalignant skin lesions (the classical sign of arsenic toxicity) and 1,794 controls, we show that one of these five variants (rs9527) is also associated with skin lesion risk (P = 0.0005). Using a subset of individuals with prospectively measured arsenic (n = 769), we show that rs9527 interacts with arsenic to influence incident skin lesion risk (P = 0.01). Expression quantitative trait locus (eQTL) analyses of genome-wide expression data from 950 individual's lymphocyte RNA suggest that several of our lead SNPs represent cis-eQTLs for AS3MT (P = 10−12) and neighboring gene C10orf32 (P = 10−44), which are involved in C10orf32-AS3MT read-through transcription. This is the largest and most comprehensive genomic investigation of arsenic metabolism and toxicity to date, the only GWAS of any arsenic-related trait, and the first study to implicate 10q24.32 variants in both arsenic metabolism and arsenical skin lesion risk. The observed patterns of associations suggest that MMA% and DMA% have distinct genetic determinants and support the hypothesis that DMA is the less toxic of these two methylated arsenic species. These results have potential translational implications for the prevention and treatment of arsenic-associated toxicities worldwide.
Zdroje
1. SmithAHLingasEORahmanM 2000 Contamination of drinking-water by arsenic in Bangladesh: a public health emergency. Bull World Health Organ 78 1093 1103
2. United States Environmental Protection Agency 2009 Fact Sheet: drinking water standard for arsenic. EPI815-R-00-015. www.epa.gov/safewater/arsenic/regulations_factsheet.html
3. CelikIGallicchioLBoydKLamTKMatanoskiG 2008 Arsenic in drinking water and lung cancer: a systematic review. Environ Res 108 48 55
4. MinkPJAlexanderDDBarrajLMKelshMATsujiJS 2008 Low-level arsenic exposure in drinking water and bladder cancer: a review and meta-analysis. Regul Toxicol Pharmacol 52 299 310
5. LiuJWaalkesMP 2008 Liver is a target of arsenic carcinogenesis. Toxicol Sci 105 24 32
6. YuHSLiaoWTChaiCY 2006 Arsenic carcinogenesis in the skin. J Biomed Sci 13 657 666
7. ChenCJChenCWWuMMKuoTL 1992 Cancer potential in liver, lung, bladder and kidney due to ingested inorganic arsenic in drinking water. Br J Cancer 66 888 892
8. YuanYMarshallGFerreccioCSteinmausCLiawJ 2010 Kidney cancer mortality: fifty-year latency patterns related to arsenic exposure. Epidemiology 21 103 108
9. BrinkelJKhanMHKraemerA 2009 A systematic review of arsenic exposure and its social and mental health effects with special reference to Bangladesh. Int J Environ Res Public Health 6 1609 1619
10. VahidniaAvan der VoetGBde WolffFA 2007 Arsenic neurotoxicity–a review. Hum Exp Toxicol 26 823 832
11. StatesJCSrivastavaSChenYBarchowskyA 2009 Arsenic and cardiovascular disease. Toxicol Sci 107 312 323
12. ArgosMKalraTRathouzPJChenYPierceB 2010 Arsenic exposure from drinking water, and all-cause and chronic-disease mortalities in Bangladesh (HEALS): a prospective cohort study. Lancet 376 252 258
13. SohelNPerssonLARahmanMStreatfieldPKYunusM 2009 Arsenic in drinking water and adult mortality: a population-based cohort study in rural Bangladesh. Epidemiology 20 824 830
14. ArgosMKalraTPierceBLChenYParvezF 2011 A prospective study of arsenic exposure from drinking water and incidence of skin lesions in Bangladesh. Am J Epidemiol 174 185 194
15. YangCYChiuHFChangCCHoSCWuTN 2005 Bladder cancer mortality reduction after installation of a tap-water supply system in an arsenious-endemic area in southwestern Taiwan. Environ Res 98 127 132
16. ChangCCHoSCTsaiSSYangCY 2004 Ischemic heart disease mortality reduction in an arseniasis-endemic area in southwestern Taiwan after a switch in the tap-water supply system. J Toxicol Environ Health A 67 1353 1361
17. AhsanHChenYKibriyaMGSlavkovichVParvezF 2007 Arsenic metabolism, genetic susceptibility, and risk of premalignant skin lesions in Bangladesh. Cancer Epidemiol Biomarkers Prev 16 1270 1278
18. KileMLHoffmanERodriguesEGBretonCVQuamruzzamanQ 2011 A pathway-based analysis of urinary arsenic metabolites and skin lesions. Am J Epidemiol 173 778 786
19. LindbergALRahmanMPerssonLAVahterM 2008 The risk of arsenic induced skin lesions in Bangladeshi men and women is affected by arsenic metabolism and the age at first exposure. Toxicol Appl Pharmacol 230 9 16
20. ValenzuelaOLBorja-AburtoVHGarcia-VargasGGCruz-GonzalezMBGarcia-MontalvoEA 2005 Urinary trivalent methylated arsenic species in a population chronically exposed to inorganic arsenic. Environ Health Perspect 113 250 254
21. DrobnaZWatersSBWaltonFSLeCluyseELThomasDJ 2004 Interindividual variation in the metabolism of arsenic in cultured primary human hepatocytes. Toxicol Appl Pharmacol 201 166 177
22. ChungJSKalmanDAMooreLEKosnettMJArroyoAP 2002 Family correlations of arsenic methylation patterns in children and parents exposed to high concentrations of arsenic in drinking water. Environ Health Perspect 110 729 733
23. HernandezAMarcosR 2008 Genetic variations associated with interindividual sensitivity in the response to arsenic exposure. Pharmacogenomics 9 1113 1132
24. KangHMSulJHServiceSKZaitlenNAKongSY 2010 Variance component model to account for sample structure in genome-wide association studies. Nat Genet 42 348 354
25. ThorntonTMcPeekMS 2010 ROADTRIPS: case-control association testing with partially or completely unknown population and pedigree structure. Am J Hum Genet 86 172 184
26. ChenYvan GeenAGrazianoJHPfaffAMadajewiczM 2007 Reduction in urinary arsenic levels in response to arsenic mitigation efforts in Araihazar, Bangladesh. Environ Health Perspect 115 917 923
27. SongXGengZLiXHuXBianN 2010 New insights into the mechanism of arsenite methylation with the recombinant human arsenic (+3) methyltransferase (hAS3MT). Biochimie 92 1397 1406
28. EngstromKVahterMMlakarSJConchaGNermellB 2011 Polymorphisms in arsenic(+III oxidation state) methyltransferase (AS3MT) predict gene expression of AS3MT as well as arsenic metabolism. Environ Health Perspect 119 182 188
29. Gomez-RubioPMeza-MontenegroMMCantu-SotoEKlimeckiWT 2010 Genetic association between intronic variants in AS3MT and arsenic methylation efficiency is focused on a large linkage disequilibrium cluster in chromosome 10. J Appl Toxicol 30 260 270
30. Schlawicke EngstromKNermellBConchaGStrombergUVahterM 2009 Arsenic metabolism is influenced by polymorphisms in genes involved in one-carbon metabolism and reduction reactions. Mutat Res 667 4 14
31. ChungCJHsuehYMBaiCHHuangYKHuangYL 2009 Polymorphisms in arsenic metabolism genes, urinary arsenic methylation profile and cancer. Cancer Causes Control 20 1653 1661
32. AgusaTIwataHFujiharaJKunitoTTakeshitaH 2009 Genetic polymorphisms in AS3MT and arsenic metabolism in residents of the Red River Delta, Vietnam. Toxicol Appl Pharmacol 236 131 141
33. HwangYHChenYHSuYNHsuCCYuanTH 2010 Genetic polymorphism of As3MT and delayed urinary DMA excretion after organic arsenic intake from oyster ingestion. J Environ Monit 12 1247 1254
34. Sampayo-ReyesAHernandezAEl-YamaniNLopez-CamposCMayet-MachadoE 2010 Arsenic induces DNA damage in environmentally exposed Mexican children and adults. Influence of GSTO1 and AS3MT polymorphisms. Toxicol Sci 117 63 71
35. AgusaTFujiharaJTakeshitaHIwataH 2011 Individual Variations in Inorganic Arsenic Metabolism Associated with AS3MT Genetic Polymorphisms. Int J Mol Sci 12 2351 2382
36. StuiverMLainezSWillCTerrynSGunzelD 2011 CNNM2, encoding a basolateral protein required for renal Mg2+ handling, is mutated in dominant hypomagnesemia. Am J Hum Genet 88 333 343
37. StachowiczMHiemstraTvan RiemsdijkWH 2008 Multi-competitive interaction of As(III) and As(V) oxyanions with Ca(2+), Mg(2+), PO(3−)(4), and CO(2−)(3) ions on goethite. J Colloid Interface Sci 320 400 414
38. SrivastavaDSubramanianRBMadamwarDFloraSJ 2010 Protective effects of selenium, calcium, and magnesium against arsenic-induced oxidative stress in male rats. Arh Hig Rada Toksikol 61 153 159
39. WoodTCSalavagionneOEMukherjeeBWangLKlumppAF 2006 Human arsenic methyltransferase (AS3MT) pharmacogenetics: gene resequencing and functional genomics studies. J Biol Chem 281 7364 7373
40. FujiharaJYasudaTKatoHYuasaIPanduroA 2011 Genetic variants associated with arsenic metabolism within human arsenic (+3 oxidation state) methyltransferase show wide variation across multiple populations. Arch Toxicol 85 119 125
41. AhsanHChenYParvezFArgosMHussainAI 2006 Health Effects of Arsenic Longitudinal Study (HEALS): description of a multidisciplinary epidemiologic investigation. J Expo Sci Environ Epidemiol 16 191 205
42. VerretWJChenYAhmedAIslamTParvezF 2005 A randomized, double-blind placebo-controlled trial evaluating the effects of vitamin E and selenium on arsenic-induced skin lesions in Bangladesh. J Occup Environ Med 47 1026 1035
43. AhsanHChenYParvezFZablotskaLArgosM 2006 Arsenic exposure from drinking water and risk of premalignant skin lesions in Bangladesh: baseline results from the Health Effects of Arsenic Longitudinal Study. Am J Epidemiol 163 1138 1148
44. NixonDEMussmannGVEckdahlSJMoyerTP 1991 Total arsenic in urine: palladium-persulfate vs nickel as a matrix modifier for graphite furnace atomic absorption spectrophotometry. Clin Chem 37 1575 1579
45. NermellBLindbergALRahmanMBerglundMPerssonLA 2008 Urinary arsenic concentration adjustment factors and malnutrition. Environ Res 106 212 218
46. PurcellSNealeBTodd-BrownKThomasLFerreiraMA 2007 PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81 559 575
47. PriceALPattersonNJPlengeRMWeinblattMEShadickNA 2006 Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38 904 909
48. PruimRJWelchRPSannaSTeslovichTMChinesPS 2010 LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26 2336 2337
49. LiYWillerCJDingJScheetPAbecasisGR 2010 MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol 34 816 834
50. BarrettJC 2009 Haploview: Visualization and analysis of SNP genotype data. Cold Spring Harb Protoc 2009 pdb ip71
51. XuZTaylorJA 2009 SNPinfo: integrating GWAS and candidate gene information into functional SNP selection for genetic association studies. Nucleic Acids Res 37 W600 605
52. HafemanDM 2009 “Proportion explained”: a causal interpretation for standard measures of indirect effect? Am J Epidemiol 170 1443 1448
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
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