Abstract
CYP2D6 is a highly polymorphic gene whose variations affect its enzyme activity. To assess whether the specific population history of Roma, characterized by constant migrations and endogamy, influenced the distribution of alleles and thus phenotypes, the CYP2D6 gene was sequenced using NGS (Next Generation Sequencing) method-targeted sequencing in three groups of Croatian Roma (N = 323) and results were compared to European and Asian populations. Identified single nucleotide polymorphisms (SNPs) were used to reconstruct haplotypes, which were translated into the star-allele nomenclature and later into phenotypes. A total of 43 polymorphic SNPs were identified. The three Roma groups differed significantly in the frequency of alleles of polymorphisms 6769 A > G, 6089 G > A, and 5264 A > G (p < 0.01), as well as in the prevalence of the five most represented star alleles: *1, *2, *4, *10, and *41 (p < 0.0001). Croatian Roma differ from the European and Asian populations in the accumulation of globally rare SNPs (6089 G > A, 4589 C > T, 4622 G > C, 7490 T > C). Our results also show that demographic history influences SNP variations in the Roma population. The three socio-culturally different Roma groups studied differ significantly in the distribution of star alleles, which confirms the importance of a separate study of different Roma groups.
Highlights
The CYP2D6 gene encodes the phase I drug-metabolizing homonymous enzyme and is located in tandem with pseudogenes CYP2D7P and CYP2D8P on chromosome 22q13.1, at the 3 end of the CYP2D cluster [1,2]
Due to low heterozygosity, only 21 single nucleotide polymorphisms (SNPs) could be tested for Hardy–Weinberg equilibrium (HWE) in all three Croatian Roma groups
The remaining 22 SNPs were tested for HWE in only one or two Croatian Roma groups
Summary
The CYP2D6 gene encodes the phase I drug-metabolizing homonymous enzyme and is located in tandem with pseudogenes CYP2D7P and CYP2D8P on chromosome 22q13.1, at the 3 end of the CYP2D cluster [1,2]. It contains nine exons consisting of 1461 codons and is highly polymorphic, with more than a hundred genetic variations and numerous subvariants that differ in single nucleotide polymorphisms (SNPs) or copy number variations (CNV); the latter resulting from CYP2D6 gene deletion or multiplication. The most important consequence of CYP2D6 genetic variations is their influence on the metabolizing activity of the CYP2D6 enzyme. Variations in the CYP2D6 gene have been studied as a risk factor for a number of diseases: Parkinson’s disease [19–21], schizophrenia and other psychiatric diseases [15,22], Alzheimer’s disease [23,24], and several forms of cancer [25,26]
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