From dietary adaptation in the past to drug metabolism of today: An example of NAT genes in the Croatian Roma

Abstract

Objectives: The evolutionary mechanisms that shape the genetic structure of a population left their mark on genes that metabolize drugs. The Roma are an example of a population in which the migrations, isolation, and multiple founder effects have affected its genetic structure. In this study, we investigated NAT1 and NAT2 genes, members of the xenobiotic-metabolizing NAT gene family in three Roma groups from Croatia to explore the specificities of the Roma population in relation to other populations.Materials and Methods: Seven SNPs in the NAT1 gene and seven in the NAT2 gene were genotyped in 439 Roma from Croatia, members of three socio-culturally different and geographically distant groups (two groups of Vlax/Bayash Roma and one Balkan Roma group). Intra-and inter-population variation was assessed in the Roma and 2504 individuals from the 1000 Genomes project database. Results:The distribution of haplotypes differed significantly between the Roma groups for NAT2, but not for NAT1. Translation of NAT2 diplotypes into acetylation phenotypes showed significant differences between populations. The Roma from Balkan had the highest frequency of slow acetylators among the studied populations.In the overall worldwide sample, population differentiation was higher for NAT2 than for NAT1 haplotypes consistent with pairwise genetic distances that were smaller for NAT1 than for NAT2. The Ewens-Watterson test results suggest that NAT1 is subjected to directional selection, while NAT2 is evolving neutrally. Conclusion:The distribution of variations within NAT genes in the Croatian Roma population is similar to that in the surrounding European populations. The significantly different distribution of NAT2 gene haplotypes and consequent phenotypes between the three investigated Roma groups is probably the result of genetic drift due to different demographic history and socio-cultural isolation. The highest frequency of slow acetylators in Balkan Roma compared to the world populations makes them more prone to develop a NAT gene-related adverse drug reaction than other populations.

From Croatian Roma to 1000 Genomes: The Story of the CYP2D6 Gene Promoter and Enhancer SNPs

“…The pharmacogenomics of the Roma minority population has been studied for the last few years [ 33 ]. These studies included SNPs in several ADME genes, such as ABCB1 [ 34 , 35 ], CYP2B6 [ 36 , 37 , 38 ], CYP2C19 [ 39 , 40 , 41 , 42 ], CYP2D6 [ 24 , 37 , 38 , 41 ] and NAT [ 42 , 43 ].…”

Relevance of CYP2D6 Gene Variants in Population Genetic Differentiation

“…The genomic diversity of modern populations reflects former demographic and evolutionary changes. In isolated populations with minimal gene exchange, genetic distinctiveness is especially evident (e.g., Jewish populations, Saami, Roma, Basque), which can also be seen in pharmacogene research [60][61][62][63][64][65][66].…”