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Science/Tech See other Science/Tech Articles Title: Gene Expression Differences Affect Drug Response Gene Expression Differences Affect Drug Response Thursday, February 28, 2008; 12:00 AM THURSDAY, Feb. 28 (HealthDay News) -- People of European and African ancestry have differences in gene expression levels that affect how they respond to certain kinds of drugs and fight off specific types of infections, says a new U.S. study. Researchers studied 30 white families from Utah and 30 Yoruban families from Nigeria, and found significant variations in nearly 5 percent of the 9,156 genes they analyzed. The findings were published online in theAmerican Journal of Human Geneticsand are expected to be published in the March 7 print issue of the journal. "Our primary interest is the genes that regulate how people respond to medicines, such as cancer chemotherapy," senior study author Eileen Dolan, a professor of medicine at the University of Chicago, said in a prepared statement. "We want to understand why different populations experience different degrees of toxicity when taking certain drugs and learn how to predict who might be most at risk for drug side effects." In this study, Dolan and her colleagues found expected variations in immune system response to microbial invaders. Previous studies have shown that black Americans may be more susceptible than whites to infection by certain kinds of bacteria, such as the kind that cause periodontitis. But they also made some unexpected findings of major differences in expression levels of genes involved in a communication system that governs basic cellular activities and coordinates cell actions. "Population differences in gene expression have only recently begun to be investigated. We believe they play a significant role in susceptibility to disease and in regulating drug response. Our current research focuses on how these genetic and expression differences play a role in sensitivity to adverse effects associated with chemotherapy," Dolan said. Learning more about how a person's genetics affects their response to drugs may help lead to improvements in treatment. Gene Expression Study of African, European-Descended Populations May Provide Clues on Drug Response [February 28, 2008] By a GenomeWeb staff reporter NEW YORK (GenomeWeb News) – African and European-descended populations have different levels of gene expression, particularly for genes linked to ribosome biogenesis and antimicrobial immunity, according to new research. Researchers from the University of Chicago and Affymetrix used microarrays and SNP data to compare cell lines from individuals in Utah and Nigeria. They found gene expression differences related to immune response to microbial intruders as well as ribosome biogenesis and other basic cellular functions. The findings, which appeared in the American Journal of Human Genetics today, may eventually contribute to a population-based or individualized understanding of medicine, the authors suggest. “We want to understand why different populations experience different degrees of toxicity when taking certain drugs and learn how to predict who might be most at risk for drug side effects,” University of Chicago oncology researcher Eileen Dolan, senior author on the paper, said in a statement. Suspecting that gene expression differences could be behind such variable drug responses, Dolan and her colleagues compared gene expression between two populations from different parts of the world. They used Affymetrix GeneChip Human Exon 1.0 ST arrays to examine 176 HapMap lymphoblastoid cell lines, created from blood samples from healthy people from 60 nuclear families — 30 Caucasian families from Utah and 30 Yoruban families from Nigeria. From the 17,879 genes targeted initially, they then focused on the 9,156 that were reliably expressed in all the samples. Almost five percent of those genes were expressed differently in those descended from Europeans than they were in African individuals. On average, the differences in gene expression were approximately 1.26-fold and, based on subsequent experiments, did not seem to stem from copy number variation. They also looked at whether the genes with the 383 most statistically significant expression differences belonged to certain biological processes. Indeed, the genes tended to cluster to two main processes: ribosome biogenesis and antimicrobial humoral immune response. When they analyzed their results using less rigorous cutoffs, they also detected expression differences in clusters of genes linked to cell-cell adhesion, mRNA catabolism, and tRNA processing. The team also used genotype information from the International HapMap Project database to look for SNPs that might be contributing to the gene expression differences they detected. That analysis suggested that genetic variation — both in cis-acting and distant trans-acting regulators — contributes to the gene expression differences they observed. “[I]t is possible that various cis- and trans-acting elements interact as part of a complete network of regulation of complex traits,” the authors wrote. “Our findings of significant SNP and transcript cluster associations, therefore, can be targets for further functional validation to investigate these regulation mechanisms.”
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