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Prediction of individual variation in thiopurine response phenotypes from genome‐wide association studies
Author(s) -
Li Fang,
Kalari Krishna R.,
Fridley Brooke L.,
Batzler Anthony,
Jenkins Gregory D.,
Schaid Daniel J.,
Wang Liewei
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1134.8
Subject(s) - thiopurine methyltransferase , single nucleotide polymorphism , gene , biology , phenotype , genome wide association study , genetics , copy number variation , gene expression , mercaptopurine , pharmacogenomics , genetic variation , candidate gene , genotype , microbiology and biotechnology , genome , azathioprine , medicine , pharmacology , disease
Thiopurine drugs such as 6‐mercaptopurine (6‐MP) and 6‐thioguanine (6‐TG) are effective immunosuppressants and antineoplastic agents. We used a genome‐wide approach to identify genes that might contribute to individual variation in thiopurine response. Basal gene expression profiles, genome‐wide SNP data, and 6‐MP and 6‐TG Cell growth inhibition (GI50) values were generated for 200 Coriell Institute “Human Variation Panel” lymphoblastoid cell lines. Gene expression and genome‐wide SNPs were correlated with GI50 values to identify candidate genes that might contribute to thiopurine response. We identified 104 expression probes and 161 SNPs, as well as 315 gene probes and 579 SNPs that correlated significantly with GI50 values for 6‐MP and 6‐TG, respectively (P<10 −5 and 10 −6 , respectively). Three genes, CD83 , TXNDC13 and SNAP23 , contained SNPs that contributed significantly to both 6‐MP and 6‐TG cytotoxicity and were also significantly associated with expression levels (P<10 −4 ), suggesting a “three‐way model” involving genotype, gene expression and cytotoxicity. GBP5 , a gene with an expression level that correlated negatively with 6‐MP and 6‐TG GI50 values, sensitized leukemia cells when overexpressed. Functional studies of the remainder of the candidate genes are being performed. These results may enhance our ability to predict thiopurine response phenotypes. NIH GM28157.