Browsing by Author "Iyengar, Sudha K."

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    Association of Kidney Comorbidities and Acute Kidney Failure With Unfavorable Outcomes After COVID-19 in Individuals With the Sickle Cell Trait
    (American Medical Association, 2022) Verma, Anurag; Huffman, Jennifer E.; Gao, Lina; Minnier, Jessica; Wu, Wen-Chih; Cho, Kelly; Ho, Yuk-Lam; Gorman, Bryan R.; Pyarajan, Saiju; Rajeevan, Nallakkandi; Garcon, Helene; Joseph, Jacob; McGeary, John E.; Suzuki, Ayako; Reaven, Peter D.; Wan, Emily S.; Lynch, Julie A.; Petersen, Jeffrey M.; Meigs, James B.; Freiberg, Matthew S.; Gatsby, Elise; Lynch, Kristine E.; Zekavat, Seyedeh Maryam; Natarajan, Pradeep; Dalal, Sharvari; Jhala, Darshana N.; Arjomandi, Mehrdad; Bonomo, Robert A.; Thompson, Trevor K.; Pathak, Gita A.; Zhou, Jin J.; Donskey, Curtis J.; Madduri, Ravi K.; Wells, Quinn S.; Gelernter, Joel; Huang, Rose D. L.; Polimanti, Renato; Chang, Kyong-Mi; Liao, Katherine P.; Tsao, Philip S.; Sun, Yan V.; Wilson, Peter W. F.; O'Donnell, Christopher J.; Hung, Adriana M.; Gaziano, J. Michael; Hauger, Richard L.; Iyengar, Sudha K.; Luoh, Shiuh-Wen; VA Million Veteran Program COVID-19 Science Initiative; Medicine, School of Medicine
    Importance: Sickle cell trait (SCT), defined as the presence of 1 hemoglobin beta sickle allele (rs334-T) and 1 normal beta allele, is prevalent in millions of people in the US, particularly in individuals of African and Hispanic ancestry. However, the association of SCT with COVID-19 is unclear. Objective: To assess the association of SCT with the prepandemic health conditions in participants of the Million Veteran Program (MVP) and to assess the severity and sequelae of COVID-19. Design, setting, and participants: COVID-19 clinical data include 2729 persons with SCT, of whom 353 had COVID-19, and 129 848 SCT-negative individuals, of whom 13 488 had COVID-19. Associations between SCT and COVID-19 outcomes were examined using firth regression. Analyses were performed by ancestry and adjusted for sex, age, age squared, and ancestral principal components to account for population stratification. Data for the study were collected between March 2020 and February 2021. Exposures: The hemoglobin beta S (HbS) allele (rs334-T). Main outcomes and measures: This study evaluated 4 COVID-19 outcomes derived from the World Health Organization severity scale and phenotypes derived from International Classification of Diseases codes in the electronic health records. Results: Of the 132 577 MVP participants with COVID-19 data, mean (SD) age at the index date was 64.8 (13.1) years. Sickle cell trait was present in 7.8% of individuals of African ancestry and associated with a history of chronic kidney disease, diabetic kidney disease, hypertensive kidney disease, pulmonary embolism, and cerebrovascular disease. Among the 4 clinical outcomes of COVID-19, SCT was associated with an increased COVID-19 mortality in individuals of African ancestry (n = 3749; odds ratio, 1.77; 95% CI, 1.13 to 2.77; P = .01). In the 60 days following COVID-19, SCT was associated with an increased incidence of acute kidney failure. A counterfactual mediation framework estimated that on average, 20.7% (95% CI, -3.8% to 56.0%) of the total effect of SCT on COVID-19 fatalities was due to acute kidney failure. Conclusions and relevance: In this genetic association study, SCT was associated with preexisting kidney comorbidities, increased COVID-19 mortality, and kidney morbidity.
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    Severe vascular calcification and tumoral calcinosis in a family with hyperphosphatemia: a fibroblast growth factor 23 mutation identified by exome sequencing
    (Oxford University Press, 2014-12) Shah, Anuja; Miller, Clinton J.; Nast, Cynthia C.; Adams, Mark D.; Truitt, Barbara; Tayek, John A.; Tong, Lili; Mehtani, Parag; Monteon, Francisco; Sedor, John R.; Clinkenbeard, Erica L.; White, Kenneth; Mehrotra, Rajnish; LaPage, Janine; Dickson, Patricia; Adler, Sharon G.; Iyengar, Sudha K.; Department of Medical & Molecular Genetics, IU School of Medicine
    BACKGROUND: Tumoral calcinosis is an autosomal recessive disorder characterized by ectopic calcification and hyperphosphatemia. METHODS: We describe a family with tumoral calcinosis requiring amputations. The predominant metabolic anomaly identified in three affected family members was hyperphosphatemia. Biochemical and phenotypic analysis of 13 kindred members, together with exome analysis of 6 members, was performed. RESULTS: We identified a novel Q67K mutation in fibroblast growth factor 23 (FGF23), segregating with a null (deletion) allele on the other FGF23 homologue in three affected members. Affected siblings had high circulating plasma C-terminal FGF23 levels, but undetectable intact FGF23 or N-terminal FGF23, leading to loss of FGF23 function. CONCLUSIONS: This suggests that in human, as in experimental models, severe prolonged hyperphosphatemia may be sufficient to produce bone differentiation proteins in vascular cells, and vascular calcification severe enough to require amputation. Genetic modifiers may contribute to the phenotypic variation within and between families.