Paula R. Pacheco

The Y-chromosomal Heritage of the Azores Islands Population: Y-chromosome in the Azores Islands (Portugal)

The Azores, a Portuguese archipelago located in the north Atlantic Ocean, had no native population when the Portuguese first arrived in the 15th century. The islands were populated mainly by the Portuguese, but Jews, Moorish prisoners, African slaves, Flemish, French and Spaniards also contributed to the initial settlement. To understand the paternal origins and diversity of the extant Azorean population, we typed genomic DNA samples from 172 individuals using a combination of 10 Y‐biallelic markers (YAP, SRY‐1532, SRY‐2627, 92R7, M9, sY81, Tat, SRY‐8299, 12f2 and LLY22g) and the following Y‐chromosomal STR systems: DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393 and DYS385. We identified nine different haplogroups, most of which are frequent in Europe. Haplogroup J* is the second most frequent in the Azores (13.4%), but it is modestly represented in mainland Portugal (6.8%). The other non‐European haplogroups, N3 and E3a, which are prevalent in Asia and sub‐Saharan Africa, respectively, have been found in the Azores (0.6% and 1.2%, respectively) but not in mainland Portugal. Microsatellite data indicate that the mean gene diversity (D) value for all the loci analysed in our sample set is 0.590, while haplotype diversity is 0.9994. Taken together, our analysis suggests that the current paternal pool of the Azorean population is, to a great extent, of Portuguese descent with significant contributions from people with other genetic backgrounds.

Azores Islands: genetic origin, gene flow and diversity pattern.

Background: The Azores are an archipelago located in the North Atlantic Ocean (parallel 38) composed of nine islands, dispersed over three geographical groups: The Eastern group (São Miguel and Santa Maria), the Central group (Terceira, Graciosa, Pico, São Jorge and Faial) and the Western group (Flores and Corvo). Taking into consideration the geographical and settlement history differences of the archipelago, the genetic diversity pattern and the internal migration of the Azorean population were assessed, based on the analysis of 15 STR loci in 592 unrelated individuals. Results: The results of this evaluation reveal that Terceira displays the highest value of gene diversity (0.7979) and Corvo the lowest (0.7717). Gene flow analysis indicates that Corvo has the lowest value for migration, 23.35, where as São Miguel and Terceira have the highest values for emigration, 108.14 and 87.66, respectively. Taken together, the data demonstrate that, despite settlement diversity, no genetic difference between the populations of the nine islands is observable today. This may be explained by internal migration. Conclusion: Overall, the Azorean population can be analysed as a homogeneous genetic group, which consequently, would present, possibly, the same drug-reaction profile. In terms of genomic medicine, these results will have a significant impact on the design of future genetic and pharmacogenomic studies in the Azorean population.

Evaluation of linkage disequilibrium on the Xq13.3 region: comparison between the Azores islands and mainland Portugal.

The design of genetic studies of complex diseases is dependent on the extent and distribution of linkage disequilibrium (LD) across the genome in different populations. Here, we characterize the extent of LD in the Azores (Western, Central, and Eastern island groups) and mainland Portugal populations. LD was evaluated in the Xq13.3 region by genotyping eight STR markers spanning 20.9 Mb. Standardized multiallelic disequilibrium coefficient (D′) analysis indicates that the Western group presents higher values when compared with the Central and Eastern groups. However, all island groups show values of D′ lower than 0.5 and 0.33, suggesting no extensive LD in these populations. Taken together, the data show that the Azorean population presents a lower D′ (0.142) than mainland Portugal (0.226). Although, both populations do not show extensive LD, the easy reconstruction of large pedigrees in the Azorean population is a valuable resource for the fine mapping of disease genes. Am. J. Hum. Biol., 2008.

Thrombotic genetic risk factors and warfarin pharmacogenetic variants in São Miguel's healthy population (Azores)

SummaryBackgroundThe Azorean population presents the highest standardized mortality rate for cardiovascular diseases (CVD) when compared to mainland Portugal and other populations. Since thrombosis is a common cause of CVD, we assessed four polymorphisms in three thrombotic risk genes – F5 (G1691A), F2 (G20210A) and MTHFR (C677T, A1298C), in 469 healthy blood donors from São Miguel Island (Azores). We also analysed the CYP2C9 (C430T, A1075C) and VKORC1 (G1639A) variants in fifty-eight individuals with predisposition to thrombosis (possessing at least one variation in F5 or F2 genes and one in MTHFR) to evaluate their warfarin drug response genetic profiles.ResultsAmong the 469 individuals, the data showed that thrombotic risk allele frequencies – 1691A (4.9%), 20210A (1.8%), 677T (41.7%) and 1298C (24.8%) – were similar to other Caucasians, but significantly different from mainland Portuguese (χ2, p < 0.001). The combined analysis of these variants identified twenty-two different genetic profiles (genotype order: F5, F2, MTHFR C677T and A1298C). Complete homozygosity for all wild-type alleles (GG GG CC AA) was present in 11.7%, being GG GG CT AA (22.4%) the most frequent profile. The results also demonstrated that 12.4% (58 out of 469) of São Miguel islanders have increased genetic predisposition to thrombosis. Subsequently, we evaluated these individuals for their warfarin response genetic profiles. The data showed that seven out of fifty-eight individuals are poor metabolizers (two with CYP2C9*2/*2 and five with CYP2C9*2/*3 genotypes). VKORC1 polymorphism analysis identified twelve individuals (20.7%) with AA genotype, who probably will require lower doses of warfarin. The joint analysis of CYP2C9 and VKORC1 revealed that 79.3% (46 out of 58) of the individuals carry at least one polymorphism in these genes. Within these, twenty-five individuals (43.1%) need intermediate and/or low doses of warfarin, if treatment is started.ConclusionThe present study demonstrated, for the first time, that São Miguel, and possibly the Azores population, shows significant differences on allele frequencies of thrombotic risk factors when compared to mainland Portugal. This research constitutes a primary approach for future studies on CVD, as well as for the implementation of warfarin dosing protocols using the patients genotypic information.

UGT1A1, UGT1A6 and UGT1A7 genetic analysis: repercussion for irinotecan pharmacogenetics in the São Miguel Island Population (Azores, Portugal).

BACKGROUND Glucuronidation reactions, catalyzed by uridine-diphosphate glucuronosyltransferase (UGT) enzymes, constitute a detoxification process that adds glucuronic acid to endogenous and exogenous compounds, aiding their excretion. UGT1A proteins have been implicated as risk factors for both the development of cancer and adverse drug effects. METHODS Here, we assess the genome of 469 individuals from São Miguel Island (Azores, Portugal) in order to determine the frequencies of polymorphisms and haplotypes in UGT1A1, UGT1A6, and UGT1A7, the co-occurrence of reduced enzyme activity UGT1A variants related to irinotecan toxicity, and to calculate the extent of linkage disequilibrium (LD) in the genomic region encompassing these genes. RESULTS Allelic analysis disclosed the presence of rare alleles - UGT1A1*36 and UGT1A1*37--only found in individuals of African descent, and UGT1A7*4. These alleles confirm our previous results on the São Miguel Island genetic background. We identified five different genotypes in UGT1A1 and UGT1A6 and nine in UGT1A7. Haplotype analysis showed that three haplotypes constituted approximately 80% of the allelic variants. Interestingly, haplotype 3 (UGT1A1*28-UGT1A6*2-UGT1A7*3), with a frequency of 0.235, gathers the three alleles encoding the low-function UGT isoforms. Additionally, LD indicates a strong interaction between functional polymorphisms related to the alteration of the UGT enzyme activity. CONCLUSIONS In summary, the results demonstrate a high variability of alleles and haplotypes, which have important roles in modifying expression and activity of UGTs. The data presented here could improve the understanding of the predisposition to cancers and susceptibility to the adverse effects of irinotecan in the São Miguel Island population.

UGT1A1 , UGT1A6 and UGT1A7 Genetic Analysis

AbstractBackground: Glucuronidation reactions, catalyzed by uridine-diphosphate glucuronosyltransferase (UGT) enzymes, constitute a detoxification process that adds glucuronic acid to endogenous and exogenous compounds, aiding their excretion. UGT1A proteins have been implicated as risk factors for both the development of cancer and adverse drug effects. Methods: Here, we assess the genome of 469 individuals from São Miguel Island (Azores, Portugal) in order to determine the frequencies of polymorphisms and haplotypes in UGT1A1, UGT1A6, and UGT1A7, the co-occurrence of reduced enzyme activity UGT1A variants related to irinotecan toxicity, and to calculate the extent of linkage disequilibrium (LD) in the genomic region encompassing these genes. Results: Allelic analysis disclosed the presence of rare alleles — UGT1A1*36 and UGT1A1*37 — only found in individuals of African descent, and UGT1A 7*4. These alleles confirm our previous results on the São Miguel Island genetic background. We identified five different genotypes in UGT1A1 and UGT1A6 and nine in UGT1A7. Haplotype analysis showed that three haplotypes constituted approximately 80% of the allelic variants. Interestingly, haplotype 3 (UGT1A1*28- UGT1A6*2- UGT1A7*3), with a frequency of 0.235, gathers the three alleles encoding the low-function UGT isoforms. Additionally, LD indicates a strong interaction between functional polymorphisms related to the alteration of the UGT enzyme activity. Conclusions: In summary, the results demonstrate a high variability of alleles and haplotypes, which have important roles in modifying expression and activity of UGTs. The data presented here could improve the understanding of the predisposition to cancers and susceptibility to the adverse effects of irinotecan in the São Miguel Island population.

15 STR loci frequencies in the population from Paraná, Southern Brazil

Allele frequencies for 15 short tandem repeats (STR) loci were obtained from a sample of 4076 unrelated individuals undergoing paternity testing. The population is from Paraná, Southern Brazil. The loci are the most commonly used in forensic and paternity testing, being analyzed by the AmpFlSTR((R)) Identifiler (Applied Biosystems) commercial kit. The most polymorphic loci were D2S1338 and D18S51. Excepting the D13S317, all loci were in Hardy-Weinberg equilibrium. Comparative analyses between our population data and other populations are presented.