Fine mapping and identification of serum urate loci in American Indians: The Strong Heart Family Study

While studies have reported genetic loci affecting serum urate (SU) concentrations, few studies have been conducted in minority populations. Our objective for this study was to identify genetic loci regulating SU in a multigenerational family-based cohort of American Indians, the Strong Heart Family Study (SHFS). We genotyped 162,718 single nucleotide polymorphisms (SNPs) in 2000 SHFS participants using an Illumina MetaboChip array. A genome-wide association analysis of SU was conducted using measured genotype analysis approach accounting for kinships in SOLAR, and meta-analysis in METAL. Our results showed strong association of SU with rs4481233, rs9998811, rs7696092 and rs13145758 (minor allele frequency (MAF) = 25–44%; P < 3 × 10−14) of solute carrier family 2, member 9 (SLC2A9) and rs41481455, rs2231142 and rs1481012 (MAF = 29%; p < 3 × 10−9) of ATP-binding cassette protein, subfamily G, member 2 (ABCG2). Carriers of G alleles of rs9998811, rs4148155 and rs1481012 and A alleles of rs4481233, rs7696092 and rs13145758 and rs2231142 had lower SU concentrations as compared to non-carriers. Genetic analysis of SU conditional on significant SLC2A9 and ABCG2 SNPs revealed new loci, nucleobindin 1 (NUCB1) and neuronal PAS domain protein 4 (NPAS4) (p <6× 10−6). To identify American Indian-specific SNPs, we conducted targeted sequencing of key regions of SLC2A9. A total of 233 SNPs were identified of which 89 were strongly associated with SU (p < 7.1 × 10−10) and 117 were American Indian specific. Analysis of key SNPs in cohorts of Mexican-mestizos, European, Indian and East Asian ancestries showed replication of common SNPs, including our lead SNPs. Our results demonstrate the association of SU with uric acid transporters in a minority population of American Indians and potential novel associations of SU with neuronal-related genes which warrant further investigation

Collaborative Cohort of Cohorts for COVID-19 Research (C4R) Study: Study Design

The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a national prospective study of adults comprising 14 established US prospective cohort studies. Starting as early as 1971, investigators in the C4R cohort studies have collected data on clinical and subclinical diseases and their risk factors, including behavior, cognition, biomarkers, and social determinants of health. C4R links this pre-coronavirus disease 2019 (COVID-19) phenotyping to information on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and acute and postacute COVID-related illness. C4R is largely population-based, has an age range of 18-108 years, and reflects the racial, ethnic, socioeconomic, and geographic diversity of the United States. C4R ascertains SARS-CoV-2 infection and COVID-19 illness using standardized questionnaires, ascertainment of COVID-related hospitalizations and deaths, and a SARS-CoV-2 serosurvey conducted via dried blood spots. Master protocols leverage existing robust retention rates for telephone and in-person examinations and high-quality event surveillance. Extensive prepandemic data minimize referral, survival, and recall bias. Data are harmonized with research-quality phenotyping unmatched by clinical and survey-based studies; these data will be pooled and shared widely to expedite collaboration and scientific findings. This resource will allow evaluation of risk and resilience factors for COVID-19 severity and outcomes, including postacute sequelae, and assessment of the social and behavioral impact of the pandemic on long-term health trajectories

Evidence from opiate binding studies that heroin acts through its metabolites

The relative affinity to opiate receptors of heroin, 6-acetylmorphine and morphine was estimated by determining their ability to displace specifically bound 3H-naltrexone from rat brain opiate binding sites. In vitro hydrolysis of heroin to 6-acetylmorphine was monitored in the binding assay filtrate by use of a quantitative HPLC procedure. The rate of heroin hydrolysis was significantly slower at 0°C than at 37°C. The displacement of 1 nM 3H-naltrexone by unlabeled ligand at concentrations ranging from 7 to 500 nM was measured at 0°C for 120 minutes, yielding IC 50 values of heroin = 483 nM, 6-acetylmorphine = 73 nM and morphine = 53 nM. When the binding data for heroin were recalculated to include the displacement that could be attributed to the 6-acetylmorphine derived from heroin degradation during the incubation, all of the apparent heroin binding was accounted for by the 6-acetylmorphine. These results are consistent with previous reports of the low binding affinity of morphine congeners (e.g., codeine) that lack a free phenolic 3-hydroxyl group and support the view that heroin is a prodrug which serves to determine the distribution of its intrinsically active metabolites, 6-acetylmorphine and morphine

PowerPoint Slides for: Acute Kidney Injury and In-Hospital Mortality after Coronary Artery Bypass Graft versus Percutaneous Coronary Intervention: A Nationwide Study

<p><b><i>Background:</i></b> Post-procedural acute kidney injury (AKI) is associated with significantly increased short- and long-term mortalities, and renal loss. Few studies have compared the incidence of post-procedural AKI and in-hospital mortality between 2 major modalities of revascularization - coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) - and results have been inconsistent. <b><i>Methods:</i></b> We generated a propensity score-matched cohort that includes a total of 286,670 hospitalizations with multi-vessel coronary disease undergoing CABG or PCI (2004-2012) from the National Inpatient Sample database. We compared incidence of AKI, AKI requiring renal replacement therapy (RRT), in-hospital mortality, hospital stay, and charges between CABG and PCI groups. <b><i>Results:</i></b> The incidence of AKI after CABG was higher than PCI (8.9 vs. 4.5%, OR 2.05, 95% CI 1.99-2.12, <i>p</i> < 0.001). The incidence of AKI requiring RRT was also higher after CABG (1.1 vs. 0.5%, OR 2.14, 95% CI 1.96-2.34, <i>p</i> < 0.001). Likewise, in-hospital mortality was higher after CABG than PCI (2.0 vs. 1.4%, OR 1.44, 95% CI 1.35-1.52, <i>p</i> < 0.001). Among patients with pre-existing chronic kidney disease (stages I-IV), those undergoing CABG was associated with 2.0-2.3-fold higher odds of developing AKI than those undergoing PCI. The patients treated with CABG had a significantly longer hospital stay and higher hospital charges. <b><i>Conclusions:</i></b> Patients undergoing CABG are associated with (1) increased risk of developing post-procedural AKI, (2) higher likelihood of receiving RRT, and (3) worse short-term survival. Long-term renal outcome remains to be studied.</p

Replication study of 10 genetic polymorphisms associated with coronary heart disease in a specific high-risk population with familial hypercholesterolemia

Aims: Recent large association studies have revealed associations between genetic polymorphisms and myocardial infarction and coronary heart disease (CHD). We performed a replication study of 10 polymorphisms and CHD in a population with familial hypercholesterolemia (FH), individuals at extreme risk of CHD. Methods and results: We genotyped 10 polymorphisms in 2145 FH patients and studied the association between these polymorphisms and CHD in Cox proportional hazards models. We confirmed the associations between four polymorphisms and CHD, the rs1151640 polymorphism in the olfactory receptor family 13 subfamily G member 1 (OR13G1) gene (HR 1.14, 95% CI 1.01-1.28, P = 0.03), the rs11881940 polymorphism in the heterogeneous nuclear ribonucleoprotein U-like 1 (HNRPUL1) gene (HR 1.27, 95% CI 1.07-1.51, P = 0.007), the rs3746731 polymorphism in the complement component 1 q subcomponent receptor 1 (CD93) gene (HR 1.26, 95% CI 1.06-1.49, P = 0.01), and the rs10757274 polymorphism near the cyclin-dependent kinase N2A and N2B (CDKN2A and CDKN2B) genes (HR 1.39, 95% CI 1.15-1.69, P < 0.001). Conclusion: We confirmed previously found associations between four polymorphisms and CHD, but refuted associations for six other polymorphisms in our large FH population. These findings stress the importance of replication before genetic information can be implemented in the prediction of CHD