engleski

NAT2 polymorphisms suggest that isoniazid tuberculosis treatment might cause adverse drug reaction in Croatian Roma

Roma population is a transnational minority present in many countries around the world. They originated in India, and reached Europe around the 11th century following a path through central Asia and present-day Turkey. Some of the Roma settled in the Balkans area, while others kept migrating for centuries to come. It is estimated that today Roma population consists of 15 million people, with 12 million living in Europe. The social structure of Roma groups is deeply influenced by the traditional endogamy which, together with their unique ancestry, shaped Roma genetic structure. It is well known that pharmacological outcome of drug use extensively depends on the patient’s DNA profile, which is largely influenced by the ancestry. Due to poor living conditions, Roma have a higher prevalence of infectious diseases, which is especially pronounced in tuberculosis incidence. It is several times higher than in the general population in southern Europe, and there has been no reduction in the incidence of tuberculosis among the Roma within the last few decades. The first line drug in tuberculosis treatment is isoniazid or isonicotinylhydrazide (INH) which is metabolized by NAT2 gene, one of the most polymorphic drug-metabolizing genes. Due to the importance of NAT2 gene polymorphisms in inter-individual variation in responses to anti-tubercular therapies, we analyzed 439 DNA samples of Roma from Croatia, who come from three culturally and geographically different regions (Baranja, Međimurje, Zagreb). Six SNP loci in NAT2 gene (rs1801279, rs1041983, rs1801280, rs1799929, rs1799930, and rs1208) were genotyped using Kompetitive Allele Specific PCR (KASP) method. Population specific haplotypes were inferred from analyzed SNP loci using Phase ver. 2.1. To determine pharmacogenetic phenotype, haplotypes were translated to the star nomenclature on the basis of the haplotype set translational table from PharmGKB (https://www.pharmgkb.org/). Inter- and intra- population statistical methods were used to analyze differences in phenotype distribution among the three investigated Roma groups. The analyses revealed six distinct haplotypes. When translated to the pharmacogenomic nomenclature, out of the haplotypes present in all three subpopulations, the most frequent was *5B haplotype (42%), followed by *6A haplotype (33.9%), the wild haplotype *4 (21.8%) and *5A haplotype (0.9%). Translating star diplotypes into metabolizing phenotypes revealed that 61% of the investigated subjects were slow and 39% were fast acetylators. Significant difference was found between the three subpopulations after testing the prevalence of metabolizers. Slow metabolizers were more frequently present in Baranja, and Balkan subpopulations. Since slow acetylators have been associated with an increased risk of adverse drug reaction caused by tuberculosis treatment with isoniazid, we can conclude that subpopulations of Baranja and Balkan are at a higher risk when treated by isoniazid. The specific distribution of haplotypes, resulting from socio-cultural isolation, suggests the need for further systematic pharmacogenetic research in this large, transnationally isolated population.

NAT2 gene ; isoniazid ; tuberculosis ; Roma population ; Croatia

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