Correspondence to: Timothy Rebbeck, Ph.D., University of Pennsylvania School of Medicine, Department of Biostatistics and Epidemiology, 904 Blockley Hall, 423 Guardian Dr., Philadelphia, PA 191046021 (e-mail: trebbeck{at}cceb.med.upenn.edu).
Wojnowski et al. provide a welcome and provocative insight into the conflicting data regarding the functional relevance of CYP3A4*1B and its effect on disease endpoints. As these authors suggest, two explanations are commonly given when a genotypedisease association is observed. First, the allele under study may be in linkage disequilibrium (LD) with a truly causative allele. Wojnowski et al. suggest that this may be the case for CYP3A4. This finding is consistent with the report by Chang et al. (1), who showed that alleles at CYP3A3, CYP3A4, CYP3A5, CYP3A7, CYP3A43, CYP3AP1, and CYP3AP2 on chromosome 7q21q22 are in LD. Therefore, the effects suggested by Wojnowski et al. may not be limited to CYP3A4 and CYP3A5 but could involve multiple genes in the CYP3A family. Second, associations (and the lack of consistency among reports) may be explained by the fact that relevant interactions among genes and between genes and exposures have not been studied. Wojnowski et al. suggest that CYP3A4*1B is associated with CYP3A5 expression. This finding is also analogous to that of Chang et al. (1), who reported that the CYP3AP1-t369g variant is associated with increased CYP3A5 activity. Given overlap in substrate specificities, induction of expression, and other biologically relevant events that may be shared among members of the CYP3A family, studies that consider complex interactions among these genes may be required to understand their effects in disease etiology and drug metabolism.
The reports of Wojnowski et al. and Chang et al. (1) do not fully explain whether associations involving the CYP3A multigene family are a result of LD alone, of multigene interactions in overlapping metabolic pathways, or of some combination of LD and multigene interactions. To evaluate these hypotheses, a complete characterization of LD between the CYP3A alleles on chromosome 7 should be undertaken. This should include formal statistical evaluation of multilocus genotypes or haplotypes. In addition, relationships of multilocus genotypes or haplotypes with phenotypic characteristics must be studied. These studies should consider the effect of potential confounders such as exogenous exposures. In each situation, large sample sizes may be required to evaluate the potential interaction effects among multilocus CYP3A genotypes. Finally, it will be of interest to evaluate these effects across ethnic groups because allele frequencies at CYP3A4 vary significantly more by race than allele frequencies at CYP3A5 (2,3). These studies could help to clarify the effects of LD versus functionally relevant interactions involving CYP3A genes.
The phenomena discussed here not only may be of interest to those who study the CYP3A multigene family but also may represent a paradigm for genotypedisease association studies involving germline variants more generally in complex metabolic pathways. It is possible that both LD and multigene interactions may influence associations. These issues will only be resolved by appropriate molecular epidemiologic investigations that include careful characterization of LD among loci; knowledge of genotypephenotype relationships; and well-designed, adequately powered association studies.
REFERENCES
1 Chang BL, Zheng SL, Hawkins GA, Isaacs SD, Wiley KE, Turner A, et al. Association between CYP3AP1 gene polymorphisms and the risk of hereditary prostate cancer. Am J Hum Genet 2001;69:265.
2 Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 2001;27:38391.[Medline]
3 Walker AH, Jaffe JM, Gunasegaram S, Cummings SA, Huang CS, Chern HD, et al. Characterization of an allelic variant in the nifedipine-specific element of CYP3A4: ethnic distribution and implications for prostate cancer risk. Hum Mutat 1998;12:28993.[Medline]
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