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Chemotherapeutic-induced apoptosis: a phenotype for pharmacogenomics studies.

ABSTRACT: To determine whether cellular apoptosis is a suitable phenotypic trait for pharmacogenomics studies by evaluating caspase 3/7-mediated activity in lymphoblastoid cell lines after treatment with six chemotherapeutic agents: 5'-deoxyfluorouridine, pemetrexed, cytarabine, paclitaxel, carboplatin, and cisplatin.Using monozygotic twin pair and sibling pair lymphoblastoid cell lines, we identified conditions for measurement of caspase 3/7 activity in lymphoblastoid cell lines. Genome-wide association studies were performed with over 2 million single nucleotide polymorphisms (SNPs) and cisplatin-induced apoptosis in HapMap CEU cell lines (n=77).Although treatment with 5'-deoxyfluorouridine and pemetrexed for up to 24 h resulted in low levels of apoptosis or interindividual variation in caspase-dependent cell death; paclitaxel, cisplatin, carboplatin, and cytarabine treatment for 24 h resulted in 9.4-fold, 9.1-fold, 7.0-fold, and 6.0-fold increases in apoptosis relative to control, respectively. There was a weak correlation between caspase activity and cytotoxicity (r(2)=0.03-0.29) demonstrating that cytotoxicity and apoptosis are two distinct phenotypes that may produce independent genetic associations. Estimated heritability (h(2)) for apoptosis was 0.57 and 0.29 for cytarabine (5 and 40 ?mol/l, respectively), 0.22 for paclitaxel (12.5 nmol/l), and 0.34 for cisplatin (5 ?mol/l). In the genome-wide association study using the HapMap CEU panel, we identified a significant enrichment of cisplatin-induced cytotoxicity SNPs within the significant cisplatin-induced apoptosis SNPs and an enrichment of expression quantitative trait loci (eQTL). Among these eQTLs, we identified several eQTLs with known function related to apoptosis and/or cytotoxicity.Our study identifies apoptosis as a phenotype for pharmacogenomic studies in lymphoblastoid cell lines after treatment with paclitaxel, cisplatin, carboplatin, and cytarabine that may have utility for discovering biomarkers to predict response to certain chemotherapeutics.

SUBMITTER: Wen Y

PROVIDER: S-EPMC3134538 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Chemotherapeutic-induced apoptosis: a phenotype for pharmacogenomics studies.

Wen Yujia Y Gorsic Lidija K LK Wheeler Heather E HE Ziliak Dana M DM Huang Rong Stephanie RS Dolan Mary Eileen ME

Pharmacogenetics and genomics 20110801 8

<h4>Aim</h4>To determine whether cellular apoptosis is a suitable phenotypic trait for pharmacogenomics studies by evaluating caspase 3/7-mediated activity in lymphoblastoid cell lines after treatment with six chemotherapeutic agents: 5'-deoxyfluorouridine, pemetrexed, cytarabine, paclitaxel, carboplatin, and cisplatin.<h4>Materials and methods</h4>Using monozygotic twin pair and sibling pair lymphoblastoid cell lines, we identified conditions for measurement of caspase 3/7 activity in lymphobla ...[more]

PMID: 21642893

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Project description:AimsAntithyroid drug (ATD)-induced agranulocytosis is a life-threatening adverse drug reaction. Previous studies suggested that HLA genotypes may play an important role in ATD-induced agranulocytosis. To examine the associations between HLA genotypes and ATD-induced agranulocytosis, we conducted a systematic review and meta-analysis of pharmacogenomics studies.MethodsWe searched the MEDLINE, Embase and CENTRAL databases on 16 June 2018 for case-control studies on the associations between HLA genotypes with ATD-induced agranulocytosis. The Newcastle-Ottawa scale was used to evaluate the risk of bias of included studies. We conducted random-effects model meta-analysis to obtain pooled odds ratios (ORs) with 95% confidence intervals (CIs) to determine the associations between HLA genotypes and ATD-induced agranulocytosis.ResultsWe included 5 studies with 142 ATD-induced agranulocytosis cases, 1529 matched ATD-tolerant controls and 5945 healthy controls. The risk of bias of included studies was generally low. ATD-induced agranulocytosis was associated with HLA-B*27:05 (OR 10.97; 95% CI 0.75-159.99), HLA-B*38:02 (OR 19.85; 95% CI 7.94-49.57) and HLA-DRB1*08:03 (OR 5.29; 95% CI 3.44-8.14). After excluding propylthiouracil, the associations of ATD-induced agranulocytosis with HLA-B*27:05 and HLA-B*38:02 were strengthened (OR being 20.61 (95% CI 5.21-81.58) and 40.59 (95% CI 13.24-124.47), respectively). The associations of ATD-induced agranulocytosis with HLA-B*27:05, HLA-B*38:02 and HLA-DRB1*08:03 remained significant when compared to population controls (OR being 7.37 (95% CI 3.86-14.07), 36.43 (95% CI 12.80-103.70) and 5.42 (95% CI 2.36-12.47), respectively). HLA-B*27:05, HLA-B*38:02, and HLA-DRB1*08:03 alleles were associated with ATD-induced agranulocytosis, especially in carbimazole/methimazole-induced agranulocytosis.ConclusionsHLA-B*27:05, HLA-B*38:02 and HLA-DRB1*08:03 alleles were associated with ATD-induced agranulocytosis, especially in carbimazole/methimazole-induced agranulocytosis.

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Chemotherapeutic-induced apoptosis: a phenotype for pharmacogenomics studies.

Publications

Chemotherapeutic-induced apoptosis: a phenotype for pharmacogenomics studies.

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