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

ABSTRACT: SUMMARY: BACKGROUND:The 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. RESULTS:Among 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 (chi2, 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. CONCLUSION:The 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 patient's genotypic information.

SUBMITTER: Branco CC

PROVIDER: S-EPMC2706804 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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

Branco Claudia C CC Pereirinha Tânia T Cabral Rita R Pacheco Paula R PR Mota-Vieira Luisa L

Thrombosis journal 20090618

<h4>Summary</h4><h4>Background</h4>The 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 fift ...[more]

PMID: 19538716

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Project description:BackgroundLeptospirosis is a worldwide zoonotic and recognized neglected infectious disease. It has been observed that only a proportion of individuals exposed to pathogenic species of Leptospira become infected and develop clinically evident disease. Moreover, little information is available in subsequent reinfections. In the present study, we determine if a first infection with leptospirosis protects against subsequent reinfection, and investigate which of the host genetic factors are involved in the susceptibility and resistance to leptospirosis.Methodology and findingsWe conducted, in 2011, a retrospective hospital-based case-control study in the São Miguel Island population (Azores archipelago). In order to determine the seropositivity against pathogenic Leptospira after the first episode of leptospirosis, we performed a serological evaluation in 97 unrelated participants diagnosed with leptospirosis between 1992 and 2011. The results revealed that 46.4% of the 97 participants have circulating anti-Leptospira antibodies, and from these participants 35.6% maintained the seroprevalence for the same serogroup. Moreover, three of them were reinfected with unrelated Leptospira serovars. The genetic study was carried out by adding a control group composed of 470 unrelated healthy blood donors, also from São Miguel Island. Twenty five SNPs among twelve innate immune genes - IL1?, IL1?, IL6, IL10, IL12RB1, TLR2, TLR4, TLR9, CD14, CISH, LTA and TNF - were genotyped, as well as HLA class I (-A and -B) genes. Association analysis indicates that genotypes -511GG (OR=1.6, 95%CI 1.01-2.56, p=0.04) in IL1?, +1196CG (OR=2.0, 95%CI 1.26-3.27, p=0.003) in IL12RB1, -292TA (OR=1.8, 95% CI 1.06-2.1, p=0.03) and +3415CG (OR=1.8, 95% CI 1.08-3.08, p=0.02), both in CISH confer susceptibility to pathogenic Leptospira.ConclusionThe present study suggests some degree of long-term protection against leptospires with an attenuation of symptoms in case of reinfection. Moreover, our data supports the genetic influence of IL1?, IL12RB1 and CISH genes and the susceptibility to leptospirosis infection.

Project description:BackgroundThe macroalgal flora of the Island of São Miguel (eastern group of the Azores Archipelago) has attracted the interest of many researchers in the past, the first publications going back to the nineteenth century. Initial studies were mainly taxonomic, resulting in the publication of a checklist of the Azorean benthic marine algae. Later, the establishment of the University of the Azores on the Island permitted the logistic conditions to develop both temporal studies and long-term research and this resulted in a significant increase on research directed at the benthic marine algae and littoral communities of the Island and consequent publications.Prior to the present paper, the known macroalgal flora of São Miguel Island comprised around 260 species. Despite this richness, a significant amount of the research was never made public, notably Masters and PhD theses encompassing information regarding presence data recorded at littoral and sublittoral levels down to a depth of approximately 40 m around the Island and the many collections made, which resulted in vouchers deposited in the AZB Herbarium Ruy Telles Palhinha and the LSM- Molecular Systematics Laboratory at the Faculty of Sciences and Technology of the University of the Azores.The present publication lists the macroalgal taxonomic records, together with information on their ecology and occurrence around São Miguel Island, improving the knowledge of the Azorean macroalgal flora at local and regional scales.New informationA total of 12,781 specimens (including some identified only to genus) belonging to 431 taxa of macroalgae are registered, comprising 284 Rhodophyta, 59 Chlorophyta and 88 Ochrophyta (Phaeophyceae). Of these, 323 were identified to species level (212 Rhodophyta, 48 Chlorophyta and 63 Ochrophyta), of which 61 are new records for the Island (42 Rhodophyta, 9 Chlorophyta and 10 Ochrophyta), one an Azorean endemic (Predaea feldmannii subsp. azorica Gabriel), five are Macaronesian endemisms (the red algae Botryocladia macaronesica Afonso-Carrillo, Sobrino, Tittley & Neto, Laurencia viridis Gil-Rodríguez & Haroun, Millerella tinerfensis (Seoane-Camba) S.M.Boo & J.M.Rico, Phyllophora gelidioides P.Crouan & H.Crouan ex Karsakoff and the green alga Codium elisabethiae O.C.Schmidt), 19 are introduced species (15 Rhodophyta, two Chlorophyta and two Ochrophyta) and 32 are of uncertain status (21 Rhodophyta, five Chlorophyta and six Ochrophyta).

Project description:ObjectivesTo verify the accuracy of the International Warfarin Pharmacogenetics Consortium (IWPC) algorithm, identify the effects of genetic and clinical factors on warfarin stable dose, and to establish a new warfarin stable dose prediction algorithm for the elderly Han-Chinese population under the guidance of pharmacogenetics.MethodsAccording to the inclusion criteria, 544 non-valvular atrial fibrillation patients taking warfarin for anticoagulation treatment were enrolled. Data information of three groups including the whole population, people under 65 years old and over 65 years old were substituted into the IWPC algorithm respectively to verify its accuracy. The basic data and clinical information of 360 elderly people were collected for statistical analysis and the genotypes of VKORC1-G1639A and CYP2C9 were detected by Sanger sequencing. The new algorithm of the elder pharmacogenetics warfarin dosing was obtained by stepwise multiple regression. The determination coefficient (R2), root mean squared error (RMSE), and the proportion of the predicted value within the true value range of ±20%(20%-p) were used to evaluate the accuracy of the IWPC algorithm and the new algorithm.ResultsAmong the three different age groups, the warfarin stable dose predictive accuracy of IWPC algorithm was the lowest in the elderly patients above 65-year-old. In this study, the important factors influencing the stable dose of warfarin in the elderly Han-Chinese were height, weight, body surface area, serum creatinine level, amiodarone usage, CYP2C9 (*1*2, *1*3), and VKORC1 (GG/GA) genotypes. By means of stepwise multiple regression analysis, we established a new elder warfarin dosing algorithm (R2=0.3714) containing height, creatinine, amiodarone usage, CYP2C9 (*1*2 or *1*3), and VKORC1 (GA or GG) genotypes. The prediction accuracy and clinical availability of the Elderly algorithm was significantly better than that of IWPC algorithm verified by RMSE, R2, and (20%-p) methods.ConclusionsThe IWPC model may not be suitable for the elder Han-Chinese population. Polymorphism of CYP2C9 and VKORC1 obviously affected warfarin stable dose of the elder Han-Chinese. Combination of genetic data with demographic and clinical factors could help to better improve warfarin doses in the elder Han-Chinese population.

Project description:BACKGROUND:Warfarin is a drug with a narrow therapeutic index and large interindividual variability in daily dosing requirements. Patients commencing warfarin treatment are at risk of bleeding due to excessive anticoagulation caused by overdosing. The interindividual variability in dose requirements is influenced by a number of factors, including polymorphisms in genes mediating warfarin pharmacology, co-medication, age, sex, body size and diet. AIMS:To develop population pharmacokinetic models of both R- and S-warfarin using clinical and genetic factors and to identify the covariates which influence the interindividual variability in the pharmacokinetic parameters of clearance and volume of distribution in patients on long-term warfarin therapy. METHODS:Patients commencing warfarin therapy were followed up for 26 weeks. Plasma warfarin enantiomer concentrations were determined in 306 patients for S-warfarin and in 309 patients for R-warfarin at 1, 8 and 26 weeks. Patients were also genotyped for CYP2C9 variants (CYP2C9*1,*2 and *3), two single-nucleotide polymorphisms (SNPs) in CYP1A2, one SNP in CYP3A4 and six SNPs in CYP2C19. A base pharmacokinetic model was developed using NONMEM software to determine the warfarin clearance and volume of distribution. The model was extended to include covariates that influenced the between-subject variability. RESULTS:Bodyweight, age, sex and CYP2C9 genotype significantly influenced S-warfarin clearance. The S-warfarin clearance was estimated to be 0.144?l?h?¹ (95% confidence interval 0.131, 0.157) in a 70?kg woman aged 69.8 years with the wild-type CYP2C9 genotype, and the volume of distribution was 16.6?l (95% confidence interval 13.5, 19.7). Bodyweight and age, along with the SNPs rs3814637 (in CYP2C19) and rs2242480 (in CYP3A4), significantly influenced R-warfarin clearance. The R-warfarin clearance was estimated to be 0.125?l?h?¹ (95% confidence interval 0.115, 0.135) in a 70?kg individual aged 69.8 years with the wild-type CYP2C19 and CYP3A4 genotypes, and the volume of distribution was 10.9?l (95% confidence interval 8.63, 13.2). CONCLUSIONS:Our analysis, based on exposure rather than dose, provides quantitative estimates of the clinical and genetic factors impacting on the clearance of both the S- and R-enantiomers of warfarin, which can be used in developing improved dosing algorithms.

Project description:Multiple linear regression (MLR) and machine learning techniques in pharmacogenetic algorithm-based warfarin dosing have been reported. However, performances of these algorithms in racially diverse group have never been objectively evaluated and compared. In this literature-based study, we compared the performances of eight machine learning techniques with those of MLR in a large, racially-diverse cohort.MLR, artificial neural network (ANN), regression tree (RT), multivariate adaptive regression splines (MARS), boosted regression tree (BRT), support vector regression (SVR), random forest regression (RFR), lasso regression (LAR) and Bayesian additive regression trees (BART) were applied in warfarin dose algorithms in a cohort from the International Warfarin Pharmacogenetics Consortium database. Covariates obtained by stepwise regression from 80% of randomly selected patients were used to develop algorithms. To compare the performances of these algorithms, the mean percentage of patients whose predicted dose fell within 20% of the actual dose (mean percentage within 20%) and the mean absolute error (MAE) were calculated in the remaining 20% of patients. The performances of these techniques in different races, as well as the dose ranges of therapeutic warfarin were compared. Robust results were obtained after 100 rounds of resampling.BART, MARS and SVR were statistically indistinguishable and significantly out performed all the other approaches in the whole cohort (MAE: 8.84-8.96 mg/week, mean percentage within 20%: 45.88%-46.35%). In the White population, MARS and BART showed higher mean percentage within 20% and lower mean MAE than those of MLR (all p values < 0.05). In the Asian population, SVR, BART, MARS and LAR performed the same as MLR. MLR and LAR optimally performed among the Black population. When patients were grouped in terms of warfarin dose range, all machine learning techniques except ANN and LAR showed significantly higher mean percentage within 20%, and lower MAE (all p values < 0.05) than MLR in the low- and high- dose ranges.Overall, machine learning-based techniques, BART, MARS and SVR performed superior than MLR in warfarin pharmacogenetic dosing. Differences of algorithms' performances exist among the races. Moreover, machine learning-based algorithms tended to perform better in the low- and high- dose ranges than MLR.

Dataset Information

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

Publications

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

Similar Datasets

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