Insight on the Genetics of Atrial Fibrillation in Puerto Rican Hispanics.

Non-Hispanic whites present with higher atrial fibrillation (AF) prevalence than other racial minorities living in the mainland USA. In two hospital-based studies, Puerto Rican Hispanics had a lower prevalence of atrial fibrillation of 2.5% than non-Hispanic Whites with 5.7%. This data is particularly controversial because Hispanics possess a higher prevalence of traditional risk factors for developing AF yet have a lower AF prevalence. This phenomenon is known as the atrial fibrillation paradox. Despite recent advancements in understanding AF, its pathogenesis remains unclear. In this study, we compared a genetic dataset of Puerto Rican Hispanics to 111 SNP known to be associated with AF in a large European cohort and determine if they are associated with AF susceptibility in our cohort. To achieve this aim, we performed a secondary analysis of existing data using the following two studies: (1) The Pharmacogenetics of Warfarin in Puerto Ricans study and the (2) A Genomic Approach for Clopidogrel in Caribbean Hispanics, and assess for the presence of European SNPs associated with AF from the genome-wide association study of 1 million people identifies 111 loci for atrial fibrillation. We used data from 555 cardiovascular Puerto Rican Hispanic patients, consisting of 486 control and 69 cases. We found that the following SNPs showed significant association with AF in PHR: rs2834618, rs6462079, rs7508, rs2040862, and rs10458660. Some of these SNPs are proteins involved in lysosomal activities responsible for breaking ceramides to sphingosines and collagen deposition around atrial cardiomyocytes. Furthermore, we performed a machine learning analysis and determined that Native American admixture and heart failure were strongly predictive of AF in PHR. For the first time, this study provides some genetic insight into AF's mechanisms in a Puerto Rican Hispanic cohort.

Cost-Utility Study of Warfarin Genotyping in the VACHS Affiliated Anticoagulation Clinic of Puerto Rico.

OBJECTIVE: To evaluate the cost-utility of the pharmacogenetic-guided dosing of warfarin (PGx), when compared to the current dosing strategy. METHODS: A Markov model was developed to assess the impact of the genotypingguided warfarin dosing in a hypothetical cohort of patients. The model was based on the percentage of time patients spent within the therapeutic international normalized ratio (INR) range (PTTR). PTTR estimates and genotype distribution were derived from a cohort of patients (n = 206) treated in the Veteran Affairs Caribbean Healthcare System (VACHS) and from results of other research study. Costs, utilities and event probability data were obtained from the literature. Probabilistic and one-way sensitivity analyses were performed to explore the range of plausible results. Willingness to pay was established at $50,000 per Quality Adjusted Life Year (QALY) gained. RESULTS: According to our model, the PGx strategy showed a QALY increase of 0.0021, with an increase in total cost of $272. This corresponds to an incremental cost-utility ratio (ICUR) of $127,501, ranging from $95,690 to $148,611. One-way sensitivity analysis revealed that the ICURs were more sensitive to the cost of genotyping and the effect of genotyping on the PTTR. CONCLUSION: Our model suggests that the warfarin PGx was not superior to the standard of care dosing strategy in terms of cost-utility.

Warfarin Anticoagulation Therapy in Caribbean Hispanics of Puerto Rico: A Candidate Gene Association Study.

Existing algorithms account for ~50% of observed variance in warfarin dose requirements after including common polymorphisms. However, they do not perform as well in populations other than Caucasians, in part because some ethno-specific genetic variants are overlooked. The objective of the present study was to identify genetic polymorphisms that can explain variability in warfarin dose requirements among Caribbean Hispanics of Puerto Rico. Next-Generation Sequencing of candidate genes CYP2C9 and VKORC1 and genotyping by DMET® Plus Assay of cardiovascular patients were performed. We also aimed at characterizing the genomic structure and admixture pattern of this study cohort. Our study used the Extreme Discordant Phenotype approach to perform a case-control association analysis. The CYP2C9 variant rs2860905, which was found in all the major haplotypes occurring in the Puerto Rican population, showed stronger association with warfarin sensitivity (<4 mg/day) than common variants CYP2C9*2 and CYP2C9*3. Although, CYP2C9*2 and CYP2C9*3 are separately contained within two of the haplotypes, 10 subjects with the sensitive phenotype were carriers of only the CYP2C9 rs2860905 variant. Other polymorphisms in CES2 and ABCB1 were found to be associated with warfarin resistance. Incorporation of rs2860905 in a regression model (R2 = 0.63, MSE = 0.37) that also includes additional genetics (i.e., VKORC1-1639 G>A; CYP2C9 rs1856908; ABCB1 c.IVS9-44A>G/ rs10276036; CES2 c.269-965A>G/ rs4783745) and non-genetic factors (i.e., hypertension, diabetes and age) showed better prediction of warfarin dose requirements than CYP2C9*2 and CYP2C9*3 combined (partial R2 = 0.132 vs. 0.023 and 0.007, respectively, p < 0.001). The genetic background of Puerto Ricans in the study cohort showed a tri-hybrid admixture pattern, with a slightly higher than expected contribution of Native American ancestry (25%). The genomic diversity of Puerto Ricans is highlighted by the presence of four different major haplotype blocks in the CYP2C9 locus. Although, our findings need further replication, this study contributes to the field by identifying novel genetic variants that increase predictability of stable warfarin dosing among Caribbean Hispanics.

Análisis inferencial de las potencialidades de promoción de absorción de una familia de 1-O-alquil gliceroles / Inferable analysis related to promotion of the absorption potentialities from 1-O-alkyl glycerol family

La interrelación entre las propiedades físico-químicas y la biodisponibilidad de una familia de 1-O-alquil gliceroles son discutidas, se han utilizado como compuestos de referencia, moléculas que presentan una analogía estructural-funcional con estos compuestos, los cuales han sido reconocidos como agentes promotores clase I, de alta capacidad. El enfoque TOPS-MODE (ModesLab) fue utilizado para estimar los momentos espectrales, con diferentes ponderaciones, como descriptores de las propiedades físico-químicas más relevantes utilizadas en los modelos predictivos de permeabilidad intestinal obtenidos, e interpretar estos en términos de contribución de grupos funcionales de los 1-O-alquil gliceroles. A partir de este análisis se establecieron interpretaciones de tipo inferencial sobre las reales potencialidades teóricas de esta familia para su evaluación perspectiva como agentes promotores de absorción clase I. Este enfoque de tamizaje in sílico asistido por computadora permitió postular que los 1-O-alquil gliceroles, en particular el 1-O-hexadecil glicerol y 1-O-octadecil glicerol, son excelentes candidatos para demostrar su elevada capacidad promotora en estudios in vivo, los que han alcanzado altos niveles porcentuales de biodisponibilidad (> 90 por ciento). Se concluye, según análisis por discriminante, que todos los miembros de la familia presentaron potencialidades para la absorción gastrointestinal.

The interrelation among the physical-chemical properties and the bioavailability of a 1-O-alkyl glycerol family is discussed. As reference compounds we used molecules presenting a structural-functional similarity with these compounds, which have been recognized as class I high quality promoting agents. TOPS-MODE approach (ModesLab) was used to estimate spectral moments with different weighing as descriptors of the more relevant physical-chemical properties used in the achieved predictive models of intestinal permeability, and its interpretation in terms of contribution of 1-O-alkyl glycerols functional groups of. From this analysis we established inferred interpretations on the theoretical potentials of this family for its prospective evaluation as promoting agents of class I absorption. This computer-assisted in silico screening approach allowed us to call for that 1-O-alkin glycerols, particularly in the 1-O-hexadecyl glycerol, and 1-O-octadecil glycerol, are excellent candidates to demonstrate its high promotion capacity according to in vivo studies, which have gained percentage high levels of bioavailability (> 90 ). We conclude that according a discriminating analysis, all family members had potentials for gastrointestinal absorption.

Análisis inferencial de las potencialidades de promoción de absorción de una familia de 1-O-alquil gliceroles / Inferable analysis related to promotion of the absorption potentialities from 1-O-alkyl glycerol family

La interrelación entre las propiedades físico-químicas y la biodisponibilidad de una familia de 1-O-alquil gliceroles son discutidas, se han utilizado como compuestos de referencia, moléculas que presentan una analogía estructural-funcional con estos compuestos, los cuales han sido reconocidos como agentes promotores clase I, de alta capacidad. El enfoque TOPS-MODE (ModesLab) fue utilizado para estimar los momentos espectrales, con diferentes ponderaciones, como descriptores de las propiedades físico-químicas más relevantes utilizadas en los modelos predictivos de permeabilidad intestinal obtenidos, e interpretar estos en términos de contribución de grupos funcionales de los 1-O-alquil gliceroles. A partir de este análisis se establecieron interpretaciones de tipo inferencial sobre las reales potencialidades teóricas de esta familia para su evaluación perspectiva como agentes promotores de absorción clase I. Este enfoque de tamizaje in sílico asistido por computadora permitió postular que los 1-O-alquil gliceroles, en particular el 1-O-hexadecil glicerol y 1-O-octadecil glicerol, son excelentes candidatos para demostrar su elevada capacidad promotora en estudios in vivo, los que han alcanzado altos niveles porcentuales de biodisponibilidad (> 90 por ciento). Se concluye, según análisis por discriminante, que todos los miembros de la familia presentaron potencialidades para la absorción gastrointestinal(AU)

The interrelation among the physical-chemical properties and the bioavailability of a 1-O-alkyl glycerol family is discussed. As reference compounds we used molecules presenting a structural-functional similarity with these compounds, which have been recognized as class I high quality promoting agents. TOPS-MODE approach (ModesLab) was used to estimate spectral moments with different weighing as descriptors of the more relevant physical-chemical properties used in the achieved predictive models of intestinal permeability, and its interpretation in terms of contribution of 1-O-alkyl glycerols functional groups of. From this analysis we established inferred interpretations on the theoretical potentials of this family for its prospective evaluation as promoting agents of class I absorption. This computer-assisted in silico screening approach allowed us to call for that 1-O-alkin glycerols, particularly in the 1-O-hexadecyl glycerol, and 1-O-octadecil glycerol, are excellent candidates to demonstrate its high promotion capacity according to in vivo studies, which have gained percentage high levels of bioavailability (> 90 ). We conclude that according a discriminating analysis, all family members had potentials for gastrointestinal absorption(AU)