Pharmacogenetics in Jewish populations

Abstract

Spanning over 2000 years, the Jewish population has a long history of migration, population bottlenecks, expansions, and geographical isolation, which has resulted in a unique genetic architecture among the Jewish people. As such, many Mendelian disease genes and founder mutations for autosomal recessive diseases have been discovered in several Jewish groups, which have prompted recent genomic studies in the Jewish population on common disease susceptibility and other complex traits. Although few studies on the genetic determinants of drug response variability have been reported in the Jewish population, a number of unique pharmacogenetic variants have been discovered that are more common in Jewish populations than in other major racial groups. Notable examples identified in the Ashkenazi Jewish (AJ) population include the vitamin K epoxide reductase complex subunit 1 (VKORC1) c.106G>T (p.D36Y) variant associated with high warfarin dosing requirements and the recently reported cytochrome P450 2C19 (CYP2C19) allele, CYP2C19*4B, that harbors both loss-of-function [*4 (c.1A>G)] and increased-function [*17 (c.−806C>T)] variants on the same haplotype. These data are encouraging in that like other ethnicities and subpopulations, the Jewish population likely harbors numerous pharmacogenetic variants that are uncommon or absent in other larger racial groups and ethnicities. In addition to unique variants, common multi-ethnic variants in key drug metabolism genes (e.g., ABCB1, CYP2C8, CYP2C9, CYP2C19, CYP2D6, NAT2) have also been detected in the AJ and other Jewish groups. This review aims to summarize the currently available pharmacogenetics literature and discuss future directions for related research with this unique population.

Heterogeneity in the distribution of 159 drug-response related SNPs in world populations and their genetic relatedness

“…There is a global concern to increase pharmacogenetic testing to ensure drug safety and enhance drug efficacy [125,126]. However, most GWAS to identify drug-response related variants have been performed in the western populations and others have lagged behind [7,127,128]. It is important to understand the interpopulation or interethnic variability in drug response so that population/ethnicity-specific guidelines can be produced.…”

Opportunities and Challenges in Cardiovascular Pharmacogenomics

“…45 Nonsynonymous coding region variants in the gene have also been described in specific populations (e.g. Ashkenazi Jewish populations 46 ) and have been associated with relatively high warfarin dose requirements. Studies in registries or in electronic health records (EHRs) have associated the CYP2C9*3 loss of function variant or a variant in CYP4F2 (responsible for vitamin K metabolism) as risk factors for warfarin associated bleeding.…”

“…Some of these are common but only in specific ancestries (e.g. D36Y, an Ashkenazi-specific VKORC1 variant 46 ). Thus, a major challenge facing genomic and pharmacogenomic science is the development of robust methods to identify all such variants across populations, 109–111 and to predict and/or characterize function of these variants – individually and in combination – as they are described.…”

Comparison of CYP2C9 Activity in Ethiopian and Non-Ethiopian Jews Using Phenytoin as a Probe

“…They have arrived to Israel during the last 40 years in several immigration waves and have gradually assimilated into the Israeli society. This population has been the center of several extensive studies that have characterized its unique genetic structure but pharmacogenetics studies are scarce and in particular CYP2C9 has not been evaluated (Britzi et al, 2000;Luo et al, 2004;Ronen et al, 2010;Yang et al, 2014). The purpose of the current study was to compare CYP2C9 genotype and activity as measured by using phenytoin as a probe drug between Ethiopian Jews and a control group consisting of non-Ethiopian Jews.…”