CYP3A variation and the evolution of salt-sensitivity variants - PubMed (original) (raw)

Comparative Study

. 2004 Dec;75(6):1059-69.

doi: 10.1086/426406. Epub 2004 Oct 18.

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Comparative Study

CYP3A variation and the evolution of salt-sensitivity variants

E E Thompson et al. Am J Hum Genet. 2004 Dec.

Abstract

Members of the cytochrome P450 3A subfamily catalyze the metabolism of endogenous substrates, environmental carcinogens, and clinically important exogenous compounds, such as prescription drugs and therapeutic agents. In particular, the CYP3A4 and CYP3A5 genes play an especially important role in pharmacogenetics, since they metabolize >50% of the drugs on the market. However, known genetic variants at these two loci are not sufficient to account for the observed phenotypic variability in drug response. We used a comparative genomics approach to identify conserved coding and noncoding regions at these genes and resequenced them in three ethnically diverse human populations. We show that remarkable interpopulation differences exist with regard to frequency spectrum and haplotype structure. The non-African samples are characterized by a marked excess of rare variants and the presence of a homogeneous group of long-range haplotypes at high frequency. The CYP3A5*1/*3 polymorphism, which is likely to influence salt and water retention and risk for salt-sensitive hypertension, was genotyped in >1,000 individuals from 52 worldwide population samples. The results reveal an unusual geographic pattern whereby the CYP3A5*3 frequency shows extreme variation across human populations and is significantly correlated with distance from the equator. Furthermore, we show that an unlinked variant, AGT M235T, previously implicated in hypertension and pre-eclampsia, exhibits a similar geographic distribution and is significantly correlated in frequency with CYP3A5*1/*3. Taken together, these results suggest that variants that influence salt homeostasis were the targets of a shared selective pressure that resulted from an environmental variable correlated with latitude.

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Figures

Figure A1

Figure A1

MultiPipMaker plots that illustrate cross-species conservation at CYP3A4 and CYP3A5. The vertical axis ranges between 50% and 100% sequence identity; areas within the plots shaded in light green and pink correspond to the exons of the CYP3A4 and CYP3A5 genes, respectively. Bars below the plots indicate the segments included in the resequencing survey; red bars indicate the sequence included only because of cross-species conservation, green bars indicate the sequence included because of both cross-species conservation and predicted cluster of transcription-factor-binding sites, and blue bars indicate sequences that contain regulatory elements based on prior functional evidence. Numbers on the horizontal axis indicate the position relative to the reference sequence for each gene (GenBank accession numbers AC069294 and AC005020 for CYP3A4 and CYP3A5, respectively).

Figure A2

Figure A2

Decay of pairwise LD with distance, as measured by |D′| (blue symbols) and r2 (red symbols) across three human population samples. The blackened circles represent the average values of |D′| (blue) and r2 (red) in 10-kb windows.

Figure 1

Figure 1

Inferred haplotypes at CYP3A4 and CYP3A5. Neither singleton sites nor multiallelic indels were included. The chimpanzee sequence was used to infer the ancestral allele at each site. The numbers on the right indicate the number of haplotypes in each population. The asterisk (*) indicates the position of CYP3A5*1/*3. Numbers below the gene names indicate the position of each polymorphic site relative to the reference sequence for each gene (GenBank accession numbers AC069294 and AC005020 for CYP3A4 and CYP3A5, respectively).

Figure 2

Figure 2

Geographic distribution of the CYP3A5*3 and AGT Met235 allele frequencies. A, Plot of CYP3A5*3 and AGT Met235 allele frequencies and distance from the equator (measured in degrees of latitude). B, Plot of CYP3A5*3 versus AGT Met235 allele frequencies, by subpopulation.

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References

Electronic-Database Information

    1. Cluster-Buster, http://zlab.bu.edu/cluster-buster/
    1. Coriell Cell Repositories, http://locus.umdnj.edu/ccr/
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