Abstract for presentation at 11th International Congress of Human Genetics

Low linkage disequilibrium among 1840 SNPs in 203 drug metabolizing enzymes underlines the necessity of directly genotyping putative functional variants

  • Fiona Hyland, Applied Biosystems, Foster City, CA, USA, United States
  • Katherine Lazaruk, Applied Biosystems, Foster City, CA, USA, United States
  • Daniel Ingber, Applied Biosystems, Foster City, CA, USA, United States
  • Francisco De La Vega, Applied Biosystems, Foster City, CA, USA, United States

    • We examined patterns of linkage disequilibrium (LD) among polymorphisms in drug-metabolizing enzyme (DME) genes. Polymorphisms within DME genes have been shown to alter drug responses in individuals. We have developed and wet-lab validated thousands of specific and robust TaqMan(R) drug metabolism genotyping assays for putatively functional SNPs in 203 DME genes, were the high degree of homology is a challenge for assay development. These variants were extensively annotated including names from locus-specific allele nomenclature committees. We genotyped 180 DNA samples from European, African-American, Chinese and Japanese populations with 1840 DME SNPs. These variants show low heterozygosity as expected for alleles likely to be under strong purifying or directional selection. Missense, and especially nonsense SNPs were more likely to appear monomorphic than the other types of variants. Among polymorphic variants, coding SNPs showed lower frequency than intronic or intergenic SNPs. Rare alleles are less likely to be in high LD with a set of common ‘tagging SNPs’, such as those selected using HapMap data. We thus investigated the extent of pairwise LD among the DME SNPs. Few SNPs are in high or perfect linkage disequilibrium with each other: among 300 SNP pairs within 500 kb on chromosome 1, only 2.4% of the pairs have r2 > 0.85. The low frequency variants (MAF < 0.05) showed less LD with the other polymorphisms. As expected, there was less LD between the SNPs in the African American population than in the other populations. Our results suggest that investigators interested in DME SNPs, and particularly in putative functional polymorphisms, should use caution in relying solely on tagging SNPs for research on disease association or drug efficacy, toxicity, metabolism, and should consider typing directly the relevant variants in their studies.

    Conference Organiser - ICMS Pty Ltd