Venous Thromboembolism Risk Assessment in Hospitalized Cancer Patients: A Single Center Study.

This study aimed to identify predictors of venous thromboembolism (VTE) in hospitalized cancer patients and develop a predictive model using demographic, clinical, and laboratory data. Our analysis showed that patient groups categorized under a very high risk, and high risk, patients with low hemoglobin levels and renal disease were at a significantly increased risk of developing VTE. We developed a VTE risk-assessment model (RAM) with moderate discriminatory performance, high specificity, and negative predictive value, indicating its potential utility in identifying patients without VTE risk. However, the model's positive predictive value and sensitivity were low due to the low prevalence of VTE within the analyzed population. Future studies are needed to analyze additional predictive factors, and to validate the effectiveness of our VTE RAM to safely rule out VTE, compare it with other VTE RAMs in hospitalized cancer patients, and address any limitations of our study.

Association of Gout Polygenic Risk Score With Age at Disease Onset and Tophaceous Disease in European and Polynesian Men With Gout.

OBJECTIVE: To determine whether a gout polygenic risk score (PRS) is associated with age at gout onset and tophaceous disease in European, East Polynesian, and West Polynesian men and women with gout. METHODS: A 19-variant gout PRS was produced in 7 European gout cohorts (N = 4,016), 2 East Polynesian gout cohorts (N = 682), and 1 West Polynesian gout cohort (N = 490). Sex-stratified regression models were used to estimate the relationship between the PRS and age at gout onset and tophaceous disease. RESULTS: The PRS was associated with earlier age at gout onset in men (ß = -3.61 in years per unit PRS [95% confidence interval (95% CI) -4.32, -2.90] in European men; ß = -6.35 [95% CI -8.91, -3.80] in East Polynesian men; ß = -3.51 [95% CI -5.46, -1.57] in West Polynesian men) but not in women (ß = 0.07 [95% CI -2.32, 2.45] in European women; ß = 0.20 [95% CI -7.21, 7.62] in East Polynesian women; ß -3.33 [95% CI -9.28, 2.62] in West Polynesian women). The PRS showed a positive association with tophaceous disease in men (odds ratio [OR] for the association 1.15 [95% CI 1.00, 1.31] in European men; OR 2.60 [95% CI 1.66, 4.06] in East Polynesian men; OR 1.53 [95% CI 1.07, 2.19] in West Polynesian men) but not in women (OR for the association 0.68 [95% CI 0.42, 1.10] in European women; OR 1.45 [95% CI 0.39, 5.36] in East Polynesian women). The PRS association with age at gout onset was robust to the removal of ABCG2 variants from the PRS in European and East Polynesian men (ß = -2.42 [95% CI -3.37, -1.46] and ß = -6.80 [95% CI -10.06, -3.55], respectively) but not in West Polynesian men (ß = -1.79 [95% CI -4.74, 1.16]). CONCLUSION: Genetic risk variants for gout also harbor risk for earlier age at gout onset and tophaceous disease in European and Polynesian men. Our findings suggest that earlier gout onset involves the accumulation of gout risk alleles in men but perhaps not in women, and that this genetic risk is shared across multiple ancestral groups.

Local genetic covariance between serum urate and kidney function estimated with Bayesian multitrait models.

Hyperuricemia (serum urate >6.8 mg/dl) is associated with several cardiometabolic and renal diseases, such as gout and chronic kidney disease. Previous studies have examined the shared genetic basis of chronic kidney disease and hyperuricemia in humans either using single-variant tests or estimating whole-genome genetic correlations between the traits. Individual variants typically explain a small fraction of the genetic correlation between traits, thus the ability to map pleiotropic loci is lacking power for available sample sizes. Alternatively, whole-genome estimates of genetic correlation indicate a moderate correlation between these traits. While useful to explain the comorbidity of these traits, whole-genome genetic correlation estimates do not shed light on what regions may be implicated in the shared genetic basis of traits. Therefore, to fill the gap between these two approaches, we used local Bayesian multitrait models to estimate the genetic covariance between a marker for chronic kidney disease (estimated glomerular filtration rate) and serum urate in specific genomic regions. We identified 134 overlapping linkage disequilibrium windows with statistically significant covariance estimates, 49 of which had positive directionalities, and 85 negative directionalities, the latter being consistent with that of the overall genetic covariance. The 134 significant windows condensed to 64 genetically distinct shared loci which validate 17 previously identified shared loci with consistent directionality and revealed 22 novel pleiotropic genes. Finally, to examine potential biological mechanisms for these shared loci, we have identified a subset of the genomic windows that are associated with gene expression using colocalization analyses. The regions identified by our local Bayesian multitrait model approach may help explain the association between chronic kidney disease and hyperuricemia.

Genetic correlations between traits associated with hyperuricemia, gout, and comorbidities.

Hypertension, obesity, chronic kidney disease and type 2 diabetes are comorbidities that have very high prevalence among persons with hyperuricemia (serum urate > 6.8 mg/dL) and gout. Here we use multivariate genetic models to test the hypothesis that the co-association of traits representing hyperuricemia and its comorbidities is genetically based. Using Bayesian whole-genome regression models, we estimated the genetic marker-based variance and the covariance between serum urate, serum creatinine, systolic blood pressure (SBP), blood glucose and body mass index (BMI) from two independent family-based studies: The Framingham Heart Study-FHS and the Hypertension Genetic Epidemiology Network study-HyperGEN. The main genetic findings that replicated in both FHS and HyperGEN, were (1) creatinine was genetically correlated only with urate and (2) BMI was genetically correlated with urate, SBP, and glucose. The environmental covariance among the traits was generally highest for trait pairs involving BMI. The genetic overlap of traits representing the comorbidities of hyperuricemia and gout appears to cluster in two separate axes of genetic covariance. Because creatinine is genetically correlated with urate but not with metabolic traits, this suggests there is one genetic module of shared loci associated with hyperuricemia and chronic kidney disease. Another module of shared loci may account for the association of hyperuricemia and metabolic syndrome. This study provides a clear quantitative genetic basis for the clustering of comorbidities with hyperuricemia.

The Shared Genetic Basis of Hyperuricemia, Gout, and Kidney Function.

Increased urate levels and gout correlate with chronic kidney disease with consensus that the primary driver of this relationship is reduced kidney function. However, a comparison of results of genome-wide association studies in serum urate levels and kidney function indicate a more complex situation. Approximately 20% of loci are shared-comprised of those in which the urate-raising allele associates with reduced kidney function, the vice versa situation, and those in which the signals/alleles are different. Although there is very little known regarding the molecular basis of the shared genetic relationship, it is clear that there is no major role for urate transporters and associated transportasome machinery. Some loci, however, do provide clues. The ATXN2 locus, with a shared signal, is one of only a small number of master regulators of expression by chromatin interaction, regulating expression of genes relevant for cholesterol and blood pressure. This suggests a role for systemic metabolic alteration. At HNF4A there is genetic heterogeneity with different genetic variants conferring risk to hyperuricemia and chronic kidney disease, suggesting different pathways. Interestingly, the shared loci congregate in the olfactory receptor pathway. The genome-wide association studies have generated a range of experimentally testable hypotheses that should provide insights into the shared pathogenesis of hyperuricemia/gout and chronic kidney disease.