One of the goals of the Environmental Genome Project is to develop a framework for assessing individual risk of disease due to the interplay of environmental exposure and genetic susceptibility. In one research Project in the Mount Sinai Children's Environmental Health Center, the researchers have been investigating the relationship between functional polymorphisms in the paraoxonase-1 (PON1) gene and neurodevelopment in children born to mothers exposed to organophosphate pesticides. The paraoxonase gene includes single nucleotide polymorphisms (SNPs) in the promoter affecting the level of expression of the enzyme, as well as a SNP in the coding region affecting the spectrum of specific activity of the enzyme with different substrates. If an individual is heterozygous for both classes of polymorphisms, a complete understanding of the effect of genotype on enzymatic activity requires not only the SNP data, but also the haplotypes. Haplotypes can sometimes be determined by using allele-specific polymerase chain reaction (PCR), often involving walking along longer genes. The investigators propose instead to develop a robust allele-enrichment procedure that may be used prior to carrying out high throughput genotyping using standard primers and readouts. Because the enrichment will take place before PCR, the haplotype may be extended over the full length of isolated DNA molecules to include not only single genes, but tandomly-repeated members of gene families, such as paraoxonase-1, -2, and -3; cytochrome P450 gene families and histocompatibility genes. Such a method may reveal haplotype-specific effects that point to the need to study the biochemistry of additional polymorphisms in linkage disequilibrium. They will apply the method to the PON and CYP3A families. Additional studies include: (1) enumeration of additional polymorphic genes and gene families of importance in studies of gene-environment interactions; (2) determination for which genes, populations, and gene-environment interactions that inclusion of haplotype analysis will improve the study design; and (3) identification of potential populations for future molecular epidemiologic studies.
| Wallenstein, Sylvan; Chen, Jia; Wetmur, James G (2006) Comparison of statistical models for analyzing genotype, inferred haplotype, and molecular haplotype data. Mol Genet Metab 89:270-3 |
| Chen, Jia; Chan, Wendy; Wallenstein, Sylvan et al. (2005) Haplotype-phenotype relationships of paraoxonase-1. Cancer Epidemiol Biomarkers Prev 14:731-4 |
| Wetmur, James G; Kumar, Madhu; Zhang, Li et al. (2005) Molecular haplotyping by linking emulsion PCR: analysis of paraoxonase 1 haplotypes and phenotypes. Nucleic Acids Res 33:2615-9 |
| Chen, Jia; Kumar, Madhu; Chan, Wendy et al. (2003) Increased influence of genetic variation on PON1 activity in neonates. Environ Health Perspect 111:1403-9 |
