Invited Commentary: On Studying the Joint Effects of Candidate Genes and Exposures

Received for publication July 7, 2000, and accepted for publication July 11, 2000. From the Biostatistics Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC. Correspondence to Dr. David M. Umbach, Biostatistics Branch, Mail Drop A3-03, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, NC 27709-2233 (email: umbach@niehs.nih.gov). For a long time, epidemiologists have recognized that human disease arises from the interplay of environmental exposures and host susceptibilities. With recent advances in molecular biology, assessment of genetic contributions to susceptibility has progressed from indirect measures based on family history to direct measures of an individual’s genotype at particular loci. With a draft sequence for the entire human genome in hand, medical science is poised for rapid advances in the study of how genetic susceptibility modulates risk from environmental exposures. The goal of gene-environment studies in epidemiology is to learn how the risk of a disease changes as a joint function of genotype and exposure. Such studies promise new insights into etiology. They also promise the eventual capability to tailor interventions more precisely, whether at a clinical level, where the therapeutic agent prescribed or its dose may be chosen in light of an individual’s genetic makeup, or at a public health level, where programs may be targeted at high-risk subpopulations. Of course, the study of candidate genes and exposures presents methodological challenges. This commentary reviews some of these issues and indicates how successfully the report by Wang et al. (1) has addressed them. These authors study the interrelation of benzene exposure, maternal polymorphisms in the CYP1A1 and GSTT1 genes, and length of gestation and find that lowdose maternal benzene exposure is associated with shortened pregnancy among a genetically defined subset of mothers.