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Pharmacogenetic variants and risk of remdesivir-associated liver enzyme elevations in Million Veteran Program participants hospitalized with COVID-19.

ABSTRACT: Remdesivir is the first US Food and Drug Administration (FDA)-approved drug for the treatment of coronavirus disease 2019 (COVID-19). We conducted a retrospective pharmacogenetic study to examine remdesivir-associated liver enzyme elevation among Million Veteran Program participants hospitalized with COVID-19 between March 15, 2020, and June 30, 2021. Pharmacogene phenotypes were assigned using Stargazer. Linear regression was performed on peak log-transformed enzyme values, stratified by population, adjusted for age, sex, baseline liver enzymes, comorbidities, and 10 population-specific principal components. Patients on remdesivir had higher peak alanine aminotransferase (ALT) values following treatment initiation compared with patients not receiving remdesivir. Remdesivir administration was associated with a 33% and 24% higher peak ALT in non-Hispanic White (NHW) and non-Hispanic Black (NHB) participants (p < 0.001), respectively. In a multivariable model, NHW CYP2C19 intermediate/poor metabolizers had a 9% increased peak ALT compared with NHW normal/rapid/ultrarapid metabolizers (p = 0.015); this association was not observed in NHB participants. In summary, remdesivir-associated ALT elevations appear to be multifactorial, and further studies are needed.

SUBMITTER: Tuteja S

PROVIDER: S-EPMC9347806 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Pharmacogenetic variants and risk of remdesivir-associated liver enzyme elevations in Million Veteran Program participants hospitalized with COVID-19.

Tuteja Sony S Yu Zhihong Z Wilson Otis O Chen Hua-Chang HC Wendt Frank F Chung Cecilia P CP Shah Shailja C SC Hunt Christine M CM Suzuki Ayako A Chanfreau Catherine C Gorman Bryan R BR Joseph Jacob J Luoh Shiuh-Wen SW Napolioni Valerio V Robinson-Cohen Cassianne C Tao Ran R Zhou Jin J Chang Kyong-Mi KM Hung Adriana M AM

Clinical and translational science 20220609 8

Remdesivir is the first US Food and Drug Administration (FDA)-approved drug for the treatment of coronavirus disease 2019 (COVID-19). We conducted a retrospective pharmacogenetic study to examine remdesivir-associated liver enzyme elevation among Million Veteran Program participants hospitalized with COVID-19 between March 15, 2020, and June 30, 2021. Pharmacogene phenotypes were assigned using Stargazer. Linear regression was performed on peak log-transformed enzyme values, stratified by popula ...[more]

PMID: 35684976

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Project description:ImportanceCoronavirus disease 2019 (COVID-19) confers significant risk of acute kidney injury (AKI). Patients with COVID-19 with AKI have high mortality rates.ObjectiveIndividuals 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 participantsThis 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.ExposuresThe 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 measuresThe 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).ResultsOf 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 relevanceIn 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.

Project description:PurposePrimary open-angle glaucoma (POAG) is a degenerative eye disease for which early treatment is critical to mitigate visual impairment and irreversible blindness. POAG-associated loci individually confer incremental risk. Genetic risk score(s) (GRS) could enable POAG risk stratification. Despite significantly higher POAG burden among individuals of African ancestry (AFR), GRS are limited in this population. A recent large-scale, multi-ancestry meta-analysis identified 127 POAG-associated loci and calculated cross-ancestry and ancestry-specific effect estimates, including in European ancestry (EUR) and AFR individuals. We assessed the utility of the 127-variant GRS for POAG risk stratification in EUR and AFR Veterans in the Million Veteran Program (MVP). We also explored the association between GRS and documented invasive glaucoma surgery (IGS).DesignCross-sectional study.ParticipantsMVP Veterans with imputed genetic data, including 5830 POAG cases (445 with IGS documented in the electronic health record) and 64 476 controls.MethodsWe tested unweighted and weighted GRS of 127 published risk variants in EUR (3382 cases and 58 811 controls) and AFR (2448 cases and 5665 controls) Veterans in the MVP. Weighted GRS were calculated using effect estimates from the most recently published report of cross-ancestry and ancestry-specific meta-analyses. We also evaluated GRS in POAG cases with documented IGS.Main outcome measuresPerformance of 127-variant GRS in EUR and AFR Veterans for POAG risk stratification and association with documented IGS.ResultsGRS were significantly associated with POAG (P < 5 × 10-5) in both groups; a higher proportion of EUR compared with AFR were consistently categorized in the top GRS decile (21.9%-23.6% and 12.9%-14.5%, respectively). Only GRS weighted by ancestry-specific effect estimates were associated with IGS documentation in AFR cases; all GRS types were associated with IGS in EUR cases.ConclusionsVaried performance of the GRS for POAG risk stratification and documented IGS association in EUR and AFR Veterans highlights (1) the complex risk architecture of POAG, (2) the importance of diverse representation in genomics studies that inform GRS construction and evaluation, and (3) the necessity of expanding diverse POAG-related genomic data so that GRS can equitably aid in screening individuals at high risk of POAG and who may require more aggressive treatment.

Project description:BackgroundAbdominal aortic aneurysm (AAA) is an important cause of cardiovascular mortality; however, its genetic determinants remain incompletely defined. In total, 10 previously identified risk loci explain a small fraction of AAA heritability.MethodsWe performed a genome-wide association study in the Million Veteran Program testing ≈18 million DNA sequence variants with AAA (7642 cases and 172 172 controls) in veterans of European ancestry with independent replication in up to 4972 cases and 99 858 controls. We then used mendelian randomization to examine the causal effects of blood pressure on AAA. We examined the association of AAA risk variants with aneurysms in the lower extremity, cerebral, and iliac arterial beds, and derived a genome-wide polygenic risk score (PRS) to identify a subset of the population at greater risk for disease.ResultsThrough a genome-wide association study, we identified 14 novel loci, bringing the total number of known significant AAA loci to 24. In our mendelian randomization analysis, we demonstrate that a genetic increase of 10 mm Hg in diastolic blood pressure (odds ratio, 1.43 [95% CI, 1.24-1.66]; P=1.6×10-6), as opposed to systolic blood pressure (odds ratio, 1.06 [95% CI, 0.97-1.15]; P=0.2), likely has a causal relationship with AAA development. We observed that 19 of 24 AAA risk variants associate with aneurysms in at least 1 other vascular territory. A 29-variant PRS was strongly associated with AAA (odds ratioPRS, 1.26 [95% CI, 1.18-1.36]; PPRS=2.7×10-11 per SD increase in PRS), independent of family history and smoking risk factors (odds ratioPRS+family history+smoking, 1.24 [95% CI, 1.14-1.35]; PPRS=1.27×10-6). Using this PRS, we identified a subset of the population with AAA prevalence greater than that observed in screening trials informing current guidelines.ConclusionsWe identify novel AAA genetic associations with therapeutic implications and identify a subset of the population at significantly increased genetic risk of AAA independent of family history. Our data suggest that extending current screening guidelines to include testing to identify those with high polygenic AAA risk, once the cost of genotyping becomes comparable with that of screening ultrasound, would significantly increase the yield of current screening at reasonable cost.

Project description:BackgroundMany psychiatric outcomes are thought to share a common etiological pathway reflecting behavioral disinhibition, generally referred to as externalizing disorders (EXT). Recent genome-wide association studies (GWAS) have demonstrated the overlap between EXT and important aspects of veterans' health, such as suicide-related behaviors, substance use disorders, and other medical conditions.MethodsWe conducted a series of phenome-wide association studies (PheWAS) of polygenic scores (PGS) for EXT, and comorbid psychiatric problems (depression, schizophrenia, and suicide attempt) in an ancestrally diverse cohort of U.S. veterans (N = 560,824), using diagnostic codes from electronic health records. We conducted ancestry-specific PheWASs of EXT PGS in the European, African, and Hispanic/Latin American ancestries. To determine if associations were driven by risk for other comorbid problems, we performed a conditional PheWAS, covarying for comorbid psychiatric problems (European ancestries only). Lastly, to adjust for unmeasured confounders we performed a within-family analysis of significant associations from the main PheWAS in full-siblings (N = 12,127, European ancestries only).ResultsThe EXT PGS was associated with 619 outcomes across all bodily systems, of which, 188 were independent of risk for comorbid problems of PGS. Effect sizes ranged from OR = 1.02 (95% CI = 1.01, 1.03) for overweight/obesity to OR = 1.44 (95% CI = 1.42, 1.47) for viral hepatitis C. Of the significant outcomes 73 (11.9%) and 26 (4.5%) were significant in the African and Hispanic/Latin American results, respectively. Within-family analyses uncovered robust associations between EXT and consequences of substance use disorders, including liver disease, chronic airway obstruction, and viral hepatitis C.ConclusionOur results demonstrate a shared polygenic basis of EXT across populations of diverse ancestries and independent of risk for other psychiatric problems. The strongest associations with EXT were for diagnoses related to substance use disorders and their sequelae. Overall, we highlight the potential negative consequences of EXT for health and functioning in the US veteran population.

Dataset Information

Pharmacogenetic variants and risk of remdesivir-associated liver enzyme elevations in Million Veteran Program participants hospitalized with COVID-19.

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Pharmacogenetic variants and risk of remdesivir-associated liver enzyme elevations in Million Veteran Program participants hospitalized with COVID-19.

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