Dataset Information

Population-based in vitro hazard and concentration-response assessment of chemicals: the 1000 genomes high-throughput screening study.

ABSTRACT: Understanding of human variation in toxicity to environmental chemicals remains limited, so human health risk assessments still largely rely on a generic 10-fold factor (10½ each for toxicokinetics and toxicodynamics) to account for sensitive individuals or subpopulations.We tested a hypothesis that population-wide in vitro cytotoxicity screening can rapidly inform both the magnitude of and molecular causes for interindividual toxicodynamic variability.We used 1,086 lymphoblastoid cell lines from the 1000 Genomes Project, representing nine populations from five continents, to assess variation in cytotoxic response to 179 chemicals. Analysis included assessments of population variation and heritability, and genome-wide association mapping, with attention to phenotypic relevance to human exposures.For about half the tested compounds, cytotoxic response in the 1% most "sensitive" individual occurred at concentrations within a factor of 10½ (i.e., approximately 3) of that in the median individual; however, for some compounds, this factor was > 10. Genetic mapping suggested important roles for variation in membrane and transmembrane genes, with a number of chemicals showing association with SNP rs13120371 in the solute carrier SLC7A11, previously implicated in chemoresistance.This experimental approach fills critical gaps unaddressed by recent large-scale toxicity testing programs, providing quantitative, experimentally based estimates of human toxicodynamic variability, and also testable hypotheses about mechanisms contributing to interindividual variation.

SUBMITTER: Abdo N

PROVIDER: S-EPMC4421772 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Population-based in vitro hazard and concentration-response assessment of chemicals: the 1000 genomes high-throughput screening study.

Abdo Nour N Xia Menghang M Brown Chad C CC Kosyk Oksana O Huang Ruili R Sakamuru Srilatha S Zhou Yi-Hui YH Jack John R JR Gallins Paul P Xia Kai K Li Yun Y Chiu Weihsueh A WA Motsinger-Reif Alison A AA Austin Christopher P CP Tice Raymond R RR Rusyn Ivan I Wright Fred A FA

Environmental health perspectives 20150113 5

<h4>Background</h4>Understanding of human variation in toxicity to environmental chemicals remains limited, so human health risk assessments still largely rely on a generic 10-fold factor (10½ each for toxicokinetics and toxicodynamics) to account for sensitive individuals or subpopulations.<h4>Objectives</h4>We tested a hypothesis that population-wide in vitro cytotoxicity screening can rapidly inform both the magnitude of and molecular causes for interindividual toxicodynamic variability.<h4>M ...[more]

PMID: 25622337

Similar Datasets

Project description:Genotype imputation, used in genome-wide association studies to expand coverage of single nucleotide polymorphisms (SNPs), has performed poorly in African Americans compared to less admixed populations. Overall, imputation has typically relied on HapMap reference haplotype panels from Africans (YRI), European Americans (CEU), and Asians (CHB/JPT). The 1000 Genomes project offers a wider range of reference populations, such as African Americans (ASW), but their imputation performance has had limited evaluation. Using 595 African Americans genotyped on Illumina's HumanHap550v3 BeadChip, we compared imputation results from four software programs (IMPUTE2, BEAGLE, MaCH, and MaCH-Admix) and three reference panels consisting of different combinations of 1000 Genomes populations (February 2012 release): (1) 3 specifically selected populations (YRI, CEU, and ASW); (2) 8 populations of diverse African (AFR) or European (AFR) descent; and (3) all 14 available populations (ALL). Based on chromosome 22, we calculated three performance metrics: (1) concordance (percentage of masked genotyped SNPs with imputed and true genotype agreement); (2) imputation quality score (IQS; concordance adjusted for chance agreement, which is particularly informative for low minor allele frequency [MAF] SNPs); and (3) average r2hat (estimated correlation between the imputed and true genotypes, for all imputed SNPs). Across the reference panels, IMPUTE2 and MaCH had the highest concordance (91%-93%), but IMPUTE2 had the highest IQS (81%-83%) and average r2hat (0.68 using YRI+ASW+CEU, 0.62 using AFR+EUR, and 0.55 using ALL). Imputation quality for most programs was reduced by the addition of more distantly related reference populations, due entirely to the introduction of low frequency SNPs (MAF≤2%) that are monomorphic in the more closely related panels. While imputation was optimized by using IMPUTE2 with reference to the ALL panel (average r2hat = 0.86 for SNPs with MAF>2%), use of the ALL panel for African American studies requires careful interpretation of the population specificity and imputation quality of low frequency SNPs.

Dataset Information

Population-based in vitro hazard and concentration-response assessment of chemicals: the 1000 genomes high-throughput screening study.

Publications

Population-based in vitro hazard and concentration-response assessment of chemicals: the 1000 genomes high-throughput screening study.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets