Browsing by Author "Robinson-Cohen, Cassianne"

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    APOL1 G3 variant is associated with cardiovascular mortality and sudden cardiac death in patients receiving maintenance hemodialysis of European Ancestry
    (Karger, 2022) Schwantes-An, Tae-Hwi; Robinson-Cohen, Cassianne; Liu, Sai; Zheng, Neil; Stedman, Margaret; Wetherill, Leah; Edenberg, Howard J.; Vatta, Matteo; Foroud, Tatiana M.; Chertow, Glenn M.; Moe, Sharon M.; Medical and Molecular Genetics, School of Medicine
    Introduction: The G1 and G2 variants in the APOL1 gene convey high risk for the progression of chronic kidney disease in African Americans. The G3 variant in APOL1 is more common in patients of European ancestry (EA); outcomes associated with this variant have not been explored previously in EA patients receiving dialysis. Methods: DNA was collected from approximately half of the patients enrolled in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial and genotyped for the G3 variants. We utilized an additive genetic model to test associations of G3 with the EVOLVE adjudicated endpoints of all-cause mortality, cardiovascular mortality, sudden cardiac death (SCD), and heart failure. EA and African ancestry samples were analyzed separately. Validation was done in the Vanderbilt BioVU using ICD codes for cardiovascular events that parallel the adjudicated endpoints in EVOLVE. Results: In EVOLVE, G3 in EA patients was associated with the adjudicated endpoints of cardiovascular mortality and SCD. In a validation cohort from the Vanderbilt BioVU, cardiovascular events and cardiovascular mortality defined by ICD codes showed similar associations in EA participants who had been on dialysis for 2 to <5 years. Discussion/conclusions: G3 in APOL1 variant was associated with cardiovascular events and cardiovascular mortality in the EA patients receiving dialysis. This suggests that variations in the APOL1 gene that differ in populations of different ancestry may contribute to cardiovascular disease.
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    APOL1 Risk Variants, Acute Kidney Injury, and Death in Participants With African Ancestry Hospitalized With COVID-19 From the Million Veteran Program
    (American Medical Association, 2022) Hung, Adriana M.; Shah, Shailja C.; Bick, Alexander G.; Yu, Zhihong; Chen, Hua-Chang; Hunt, Christine M.; Wendt, Frank; Wilson, Otis; Greevy, Robert A.; Chung, Cecilia P.; Suzuki, Ayako; Ho, Yuk-Lam; Akwo, Elvis; Polimanti, Renato; Zhou, Jin; Reaven, Peter; Tsao, Philip S.; Gaziano, J. Michael; Huffman, Jennifer E.; Joseph, Jacob; Luoh, Shiuh-Wen; Iyengar, Sudha; Chang, Kyong-Mi; Casas, Juan P.; Matheny, Michael E.; O'Donnell, Christopher J.; Cho, Kelly; Tao, Ran; Susztak, Katalin; Robinson-Cohen, Cassianne; Tuteja, Sony; Siew, Edward D.; VA Million Veteran Program COVID-19 Science Initiative; Medicine, School of Medicine
    Importance: Coronavirus disease 2019 (COVID-19) confers significant risk of acute kidney injury (AKI). Patients with COVID-19 with AKI have high mortality rates. Objective: Individuals with African ancestry with 2 copies of apolipoprotein L1 (APOL1) variants G1 or G2 (high-risk group) have significantly increased rates of kidney disease. We tested the hypothesis that the APOL1 high-risk group is associated with a higher-risk of COVID-19-associated AKI and death. Design, setting, and participants: This retrospective cohort study included 990 participants with African ancestry enrolled in the Million Veteran Program who were hospitalized with COVID-19 between March 2020 and January 2021 with available genetic information. Exposures: The primary exposure was having 2 APOL1 risk variants (RV) (APOL1 high-risk group), compared with having 1 or 0 risk variants (APOL1 low-risk group). Main outcomes and measures: The primary outcome was AKI. The secondary outcomes were stages of AKI severity and death. Multivariable logistic regression analyses adjusted for preexisting comorbidities, medications, and inpatient AKI risk factors; 10 principal components of ancestry were performed to study these associations. We performed a subgroup analysis in individuals with normal kidney function prior to hospitalization (estimated glomerular filtration rate ≥60 mL/min/1.73 m2). Results: Of the 990 participants with African ancestry, 905 (91.4%) were male with a median (IQR) age of 68 (60-73) years. Overall, 392 (39.6%) patients developed AKI, 141 (14%) developed stages 2 or 3 AKI, 28 (3%) required dialysis, and 122 (12.3%) died. One hundred twenty-five (12.6%) of the participants were in the APOL1 high-risk group. Patients categorized as APOL1 high-risk group had significantly higher odds of AKI (adjusted odds ratio [OR], 1.95; 95% CI, 1.27-3.02; P = .002), higher AKI severity stages (OR, 2.03; 95% CI, 1.37-2.99; P < .001), and death (OR, 2.15; 95% CI, 1.22-3.72; P = .007). The association with AKI persisted in the subgroup with normal kidney function (OR, 1.93; 95% CI, 1.15-3.26; P = .01). Data analysis was conducted between February 2021 and April 2021. Conclusions and relevance: In this cohort study of veterans with African ancestry hospitalized with COVID-19 infection, APOL1 kidney risk variants were associated with higher odds of AKI, AKI severity, and death, even among individuals with prior normal kidney function.
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    Genetic Variants Associated With Mineral Metabolism Traits in Chronic Kidney Disease
    (Oxford University Press, 2022) Laster, Marciana L.; Rowan, Bryce; Chen, Hua-Chang; Schwantes-An, Tae-Hwi; Sheng, Xin; Friedman, Peter A.; Ikizler, T. Alp; Sinshiemer, Janet S.; Ix, Joachim H.; Susztak, Katalin; de Boer, Ian H.; Kestenbaum, Bryan; Hung, Adriana; Moe, Sharon M.; Perwad, Farzana; Robinson-Cohen, Cassianne; Medicine, School of Medicine
    Context: Chronic kidney disease (CKD) causes multiple interrelated disturbances in mineral metabolism. Genetic studies in the general population have identified common genetic variants associated with circulating phosphate, calcium, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23). Objective: In this study we aimed to discover genetic variants associated with circulating mineral markers in CKD. Methods: We conducted candidate single-nucleotide variation (SNV) analysis in 3027 participants in the multiethnic Chronic Renal Insufficiency Cohort (CRIC) to determine the associations between SNVs and circulating levels of mineral markers. Results: SNVs adjacent to or within genes encoding the regulator of G protein-coupled signaling 14 (RGS14) and the calcium-sensing receptor (CASR) were associated with levels of mineral metabolites. The strongest associations (P < .001) were at rs4074995 (RGS14) for phosphate (0.09 mg/dL lower per minor allele) and FGF23 (8.6% lower), and at rs1801725 (CASR) for calcium (0.12 mg/dL higher). In addition, the prevalence of hyperparathyroidism differed by rs4074995 (RGS14) genotype (chi-square P < .0001). Differential inheritance by race was noted for the minor allele of RGS14. Expression quantitative loci (eQTL) analysis showed that rs4074995 was associated with lower RGS14 gene expression in glomeruli (P = 1.03 × 10-11) and tubules (P = 4.0 × 10-4). Conclusion: We evaluated genetic variants associated with mineral metabolism markers in a CKD population. Participants with CKD and the minor allele of rs4074995 (RGS14) had lower phosphorus, lower plasma FGF23, and lower prevalence of hyperparathyroidism. The minor allele of RGS14 was also associated with lower gene expression in the kidney. Further studies are needed to elucidate the effect of rs4074995 on the pathogenesis of disordered mineral metabolism in CKD.
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    Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels
    (Nature Publishing Group, 2018-01-17) Jiang, Xia; O’Reilly, Paul F.; Aschard, Hugues; Hsu, Yi-Hsiang; Richards, J. Brent; Dupuis, Josée; Ingelsson, Erik; Karasik, David; Pilz, Stefan; Berry, Diane; Kestenbaum, Bryan; Zheng, Jusheng; Luan, Jianan; Sofianopoulou, Eleni; Streeten, Elizabeth A.; Albanes, Demetrius; Lutsey, Pamela L.; Yao, Lu; Tang, Weihong; Econs, Michael J.; Wallaschofski, Henri; Völzke, Henry; Zhou, Ang; Power, Chris; McCarthy, Mark I.; Michos, Erin D.; Boerwinkle, Eric; Weinstein, Stephanie J.; Freedman, Neal D.; Huang, Wen-Yi; Van Schoor, Natasja M.; Velde, Nathalie van der; de Groot, Lisette C. P. G. M.; Enneman, Anke; Cupples, L. Adrienne; Booth, Sarah L.; Vasan, Ramachandran S.; Liu, Ching-Ti; Zhou, Yanhua; Ripatti, Samuli; Ohlsson, Claes; Vandenput, Liesbeth; Lorentzon, Mattias; Eriksson, Johan G.; Shea, M. Kyla; Houston, Denise K.; Kritchevsky, Stephen B.; Liu, Yongmei; Lohman, Kurt K.; Ferrucci, Luigi; Peacock, Munro; Gieger, Christian; Beekman, Marian; Slagboom, Eline; Deelen, Joris; Heemst, Diana van; Kleber, Marcus E.; März, Winfried; de Boer, Ian H.; Wood, Alexis C.; Rotter, Jerome I.; Rich, Stephen S.; Robinson-Cohen, Cassianne; Heijer, Martin den; Jarvelin, Marjo-Riitta; Cavadino, Alana; Joshi, Peter K.; Wilson, James F.; Hayward, Caroline; Lind, Lars; Michaëlsson, Karl; Trompet, Stella; Zillikens, M. Carola; Uitterlinden, Andre G.; Rivadeneira, Fernando; Broer, Linda; Zgaga, Lina; Campbell, Harry; Theodoratou, Evropi; Farrington, Susan M.; Timofeeva, Maria; Dunlop, Malcolm G.; Valdes, Ana M.; Tikkanen, Emmi; Lehtimäki, Terho; Lyytikäinen, Leo-Pekka; Kähönen, Mika; Raitakari, Olli T.; Mikkilä, Vera; Ikram, M. Arfan; Sattar, Naveed; Jukema, J. Wouter; Wareham, Nicholas J.; Langenberg, Claudia; Forouhi, Nita G.; Gundersen, Thomas E.; Khaw, Kay-Tee; Butterworth, Adam S.; Danesh, John; Spector, Timothy; Wang, Thomas J.; Hyppönen, Elina; Kraft, Peter; Kiel, Douglas P.; Medicine, School of Medicine
    Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10-9 at rs8018720 in SEC23A, and P = 1.9×10-14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels