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Genetic variation in the cysteine biosynthesis pathway causes sensitivity to pharmacological compounds.

ABSTRACT: Complex traits are the product of multiple genes with effects that depend on both the genetic and environmental background. Although this complexity makes a comprehensive genetic analysis difficult, identification of even a single gene provides insight into the biochemical and/or signaling pathway underlying a trait. However, it is unknown whether multiple pathways, and consequently multiple genes, must be identified to adequately understand a trait's molecular basis. Using crosses between three natural isolates of Saccharomyces cerevisiae, we mapped sensitivity to a number of pharmacologically active compounds to a single nonsynonymous polymorphism in cystathione-beta-synthase (CYS4), which is required for the first committed step in the cysteine biosynthesis pathway. Drug sensitivity is mediated by a deficiency in cysteine and consequently glutathione production, because drug sensitivity is abrogated by cysteine or glutathione supplementation. Within a diverse panel of 60 natural yeast isolates, the drug-sensitive CYS4 allele is rare, and glutathione supplementation failed to alleviate drug-dependent growth defects in two other drug-sensitive strains. These results implicate the cysteine/glutathione biosynthesis pathway as a significant, but not the sole contributor to pharmacological variation in yeast.

SUBMITTER: Kim HS

PROVIDER: S-EPMC2148299 | biostudies-literature | 2007 Dec

REPOSITORIES: biostudies-literature

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Genetic variation in the cysteine biosynthesis pathway causes sensitivity to pharmacological compounds.

Kim Hyun Seok HS Fay Justin C JC

Proceedings of the National Academy of Sciences of the United States of America 20071127 49

Complex traits are the product of multiple genes with effects that depend on both the genetic and environmental background. Although this complexity makes a comprehensive genetic analysis difficult, identification of even a single gene provides insight into the biochemical and/or signaling pathway underlying a trait. However, it is unknown whether multiple pathways, and consequently multiple genes, must be identified to adequately understand a trait's molecular basis. Using crosses between three ...[more]

PMID: 18042712

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Project description:Background: Single nucleotide polymorphisms in the 9p21 region have been associated with cardiovascular disease and to a lesser extent insulin sensitivity. Previous studies have focused on older populations, and few have examined the impact of gene-diet interactions. The objective of this study was to determine the interaction between dietary patterns and 9p21 genotypes on insulin sensitivity in young adults from different ethnic groups. Methods: Subjects were 1,333 participants aged 20-29 years from the Toronto Nutrigenomics and Health Study (405 men and 928 women; 776 Caucasians and 557 East Asians). Fasting blood was collected to measure glucose, insulin, c-reactive protein and serum lipids, as well as to isolate DNA for genotyping subjects for five SNPs in 9p21 (rs10757274, rs10757278, rs1333049, rs2383206, and rs4977574). Insulin resistance (HOMA-IR) and beta-cell dysfunction (HOMA-Beta) were calculated from fasting insulin and glucose concentrations. The Toronto-modified Harvard 196-item semi-quantitative food frequency questionnaire was used to measure dietary intake over 1 month and principal components analysis was used to identify three dietary patterns (Prudent, Western and Eastern). ANOVA and ANCOVA were used to examine gene-diet interactions on markers of insulin sensitivity. Results: Significant gene-diet interactions on insulin sensitivity using HOMA-IR were observed with all five SNPs, which remained significant after adjusting for covariates (p < 0.05). Among those who were homozygous for the 9p21 risk allele (rs1333049), fasting insulin was 40% higher in those who were consuming a low-prudent diet compared to those consuming a high-prudent diet (p < 0.05). No differences were observed between those following a low versus high-prudent diet among those who did not carry a 9p21 risk allele. Similar findings were observed with HOMA-Beta, however, the association was only significant for rs10757274 (p = 0.04). Conclusion: Our findings suggest that a prudent dietary pattern may protect against the effects of 9p21 risk genotypes on insulin sensitivity.

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Genetic variation in the cysteine biosynthesis pathway causes sensitivity to pharmacological compounds.

Publications

Genetic variation in the cysteine biosynthesis pathway causes sensitivity to pharmacological compounds.

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