Autoimmune polyglandular syndrome (APS) type 2 is defined by the manifestation of at least two autoimmune endocrine diseases. Only few data exist on genetic associations of APS type 2. In this controlled study, 98 patients with APS type 2, 96 patients with type 1 diabetes (T1D), and 92 patients with autoimmune thyroid disease, both as a single autoimmune endocrinopathy, were tested for association with alleles of the human leukocyte antigen (HLA) class II loci DRB1, DQA1, and DQB1. Patients with APS type 2 had significantly more often the alleles DRB1*03 (P(c) < 0.0001), DRB1*04 (P(c) < 0.000005), DQA1*03 (P(c) < 0.0001), and DQB1*02 (P(c) < 0.05), when compared with controls. Less frequent in APS were DRB1*15 (P(c) < 0.05), DQA1*01 (P(c) < 0.0005), and DQB1*05 (P(c) < 0.005). With regard to frequency and linkage of these alleles, the susceptible haplotypes DRB1*0301-DQA1*0501-DQB1*0201 and DRB1*0401/04-DQA1*0301-DQB1*0302 were deduced. Protective haplotypes in this study were DRB1*1501-DQA1*0102-DQB1*0602 and DRB1*0101-DQA1*0101-DQB1*0501. Comparing APS patients with vs without AD, no significant differences regarding HLA class II alleles were noted in our collective. Patients with T1D as a singular disease had the same susceptible and protective HLA alleles and haplotypes. The prevalence of DRB1*03 and DRB1*04 in APS patients was not because of the presence of diabetes, as the APS type 2 patients without diabetes had the same allele distribution. In conclusion, these data suggest a common immunogenetic pathomechanism for T1D and APS type 2, which might be different from the immunogenetic pathomechanism of other autoimmune endocrine disease.
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.
Longevity is a hallmark of successful ageing and a complex trait with a significant genetic component. In this study, 43 single nucleotide polymorphisms (SNPs) were chosen from the literature and genotyped in a Croatian oldest-old sample (85+ years, sample size (N) = 314), in order to determine whether any of these SNPs have a significant effect on reaching the age thresholds for longevity (90+ years, N = 212) and extreme longevity (95+ years, N = 84). The best models were selected for both survival ages using multivariate logistic regression. In the model for reaching age 90, nine SNPs explained 20% of variance for survival to that age, while the 95-year model included five SNPs accounting for 9.3% of variance. The two SNPs that showed the most significant association (p ≤ 0.01) with longevity were TERC rs16847897 and GHRHR rs2267723. Unweighted and weighted Genetic Longevity Scores (uGLS and wGLS) were calculated and their predictive power was tested. All four scores showed significant correlation with age at death (p ≤ 0.01). They also passed the ROC curve test with at least 50% predictive ability, but wGLS90 stood out as the most accurate score, with a 69% chance of accurately predicting survival to the age of 90.
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.
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