title: Similarity in recombination rate and linkage disequilibrium at CYP2C and CYP2D cytochrome P450 gene regions among Europeans indicates signs of selection and no advantage of using tagSNPs in population isolates.
abstract: OBJECTIVE
  Linkage disequilibrium (LD) and recombination rate variations are known to vary considerably between human genome regions and populations mostly because of the combined effects of mutation, recombination, and demographic history. Thus, the pattern of LD is a key issue to disentangle variants associated with complex traits. Here, we aim to describe the haplotype structure and LD variation at the pharmacogenetically relevant cytochrome P450 CYP2C and CYP2D gene regions among European populations.
  
  
  METHODS
  To assess the haplotype structure, LD pattern, and recombination rate variations in the clinically significant CYP2C and CYP2D regions, we genotyped 143 single-nucleotide polymorphisms (SNPs) across these two genome regions in a diverse set of 11 European population samples and one sub-Saharan African sample.
  
  
  RESULTS
  Our results showed extended patterns of LD and in general a low rate of recombination at these loci, and a low degree of allele differentiation for the two cytochrome P450 regions among Europeans, with the exception of the Sami and the Finns as European outliers. The Sami sample showed reduced haplotype diversity and higher LD for the two cytochrome P450 regions than the other Europeans, a feature that is proposed to enhance the LD mapping of underlying common complex traits. However, recombination hotspots and LD blocks at these two regions showed highly consistent structures across Europeans including Finns and Sami. Moreover, we showed that the CEPH sample has significantly higher tag transferability among Europeans and a more efficient tagging of both the rare CYP2C9 and the common CYP2C19 functional variants than the Sami. Our data set included CYP2C9*3 (rs1057910) and CYP2C19*2 (rs4244285) enzyme activity-altering variants associated in a recent genome-wide study with acenocoumarol-induced and warfarin-induced anticoagulation or to the antiplatelet effect of clopidogrel, respectively. Including these known activity-altering variants, we showed the haplotype variation and high derived allele frequencies of novel recently identified acenocoumarol genome-wide associated SNPs at CYP2C9 (rs4086116) and CYP2C18 (rs12772169, rs1998591, rs2104543, rs1042194) loci in a comprehensive set of 11 European populations. Furthermore, a significant frequency difference of a CYP2C19*2 gene mutation causing variable drug reactions was observed among Europeans.
  
  
  CONCLUSIONS
  The CEPH sample representing the general European population as such in the HapMap project seems to be the optimal population sample for the LD mapping of common complex traits among Europeans. Nevertheless, it is still argued that the unique pattern of LD in the Sami may offer an advantage for further association mapping, especially if multiple rare variants play a role in disease etiology. However, besides the activity-altering CYP2C9*3 (rs1057910) and CYP2C19*2 (rs4244285) variants, the high derived allele frequencies of novel recently identified acenocoumarol genome-wide associated SNPs at CYP2C9 (rs4086116) and CYP2C18 (rs12772169, rs1998591, rs2104543, rs1042194) loci variants indicated that the CYP2C region may have been influenced by selection. Thus, this fine-scale haplotype map of the CYP2C and CYP2D regions may help to choose markers for further association mapping of complex pharmacogenetic traits at these loci.
authors.affiliation: Laboratory of Forensic Biology, Department of Forensic Medicine, Hjelt-Institute, University of Helsinki, Helsinki, Finland. vnikolai@iconcologia.net
authors.forename: Ville N
authors.initials: VN
authors.lastname: Pimenoff
authors.forename: Guillaume
authors.initials: G
authors.lastname: Laval
authors.forename: David
authors.initials: D
authors.lastname: Comas
authors.forename: Jukka U
authors.initials: JU
authors.lastname: Palo
authors.forename: Ivo
authors.initials: I
authors.lastname: Gut
authors.forename: Howard
authors.initials: H
authors.lastname: Cann
authors.forename: Laurent
authors.initials: L
authors.lastname: Excoffier
authors.forename: Antti
authors.initials: A
authors.lastname: Sajantila
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D044383:Black People; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D014644:Genetic Variation; D005828:Genetics, Population; D015894:Genome, Human; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D011995:Recombination, Genetic; D012641:Selection, Genetic; D044465:White People
chemical_list: C400322:cytochrome P-450 CYP2C subfamily; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19