Association of Pharmacogenomic Phenotypes in CYP2D6, CYP2C9, CYP2C19, and CYP3A5 on Polypharmacy in Veterans.

The Department of Veterans Affairs (VA) utilizes a pharmacogenomic (PGx) program that analyzes specific "pharmacogenes." This study evaluates the effect that pharmacogenes may have on prevalence of polypharmacy. This retrospective cohort study included patients with VA prescriptions who underwent PGx testing. We quantified prescriptions active or recently expired at the time of PGx testing. We constructed two co-primary polypharmacy (≥10 medications) end points: (i) based on all medications and (ii) requiring that at least one medication was affected by a pharmacogene of interest. Pharmacogenes and actionable phenotypes of interest included poor and ultrarapid metabolizers for CYP2D6, CYP2C9, and CYP2C19 and intermediate and normal metabolizers for CYP3A5. Patients were classified as having 0, 1, and 2+ total phenotypes across all genes. Of the 15,144 patients screened, 13,116 met eligibility criteria. Across phenotype cohorts, there was no significant association with polypharmacy using all medications, number of total medications, or number of medications affected by phenotypes. However, there was a significant difference in patients with polypharmacy prescribed ≥1 medication impacted by PGx across phenotype groups: 2,514/4,949 (51%), 1,349/2,595 (52%), 204/350 (58%) (P = 0.03, OR 1.31, 95% CI 1.02-1.67). The median number of medications affected by PGx phenotypes with ≥1 PGx-impacted medication across phenotype groups was a median of 0 (IQR 0, 0), 0 (IQR 0, 0), and 1 (IQR 0, 1) (P < 0.001). In patients prescribed ≥1 medication impacted by PGx, those with more actionable pharmacogenomic phenotypes were more likely to meet polypharmacy criteria.

Factors Associated with Delayed Care Among Women Veterans Actively Engaged in Primary Care.

Background: Delaying needed medical care contributes to greater health risks and higher long-term medical costs. Women Veterans with complex medical and mental health needs face increased barriers to timely care access. Objectives: In a sample of women Veterans with recent engagement in Veterans Administration (VA) primary care, we aimed to compare characteristics of women Veterans who delayed care in the past 6 months with those who did not and examine factors associated with self-reported delayed care. Our study aims to inform interventions focused on eliminating health care access disparities among women Veterans. Materials and Methods: An innovation to improve women Veterans' engagement and retention in evidence-based health care for cardiovascular (CV) risk reduction (CV Toolkit) was implemented across five primary care sites within the VA. Women Veterans who were exposed to at least one CV Toolkit component participated in a mailed survey (n = 253). We used multivariate logistic regression to model factors associated with delaying care, including trust in VA providers, positive mental health screening (i.e., positive screen for either depression or anxiety), traumatic experience, self-rated health, and age. Results: Women with any mental health symptoms (odds ratio [OR] 2.42, 95% confidence interval [CI]: 1.23-4.74) and women who had experienced a traumatic event (OR 2.61, 95%CI: 1.11-6.14) were significantly more likely to report delaying care. Conclusions: Our study identified high rates of delayed care-over one-third of respondents-among women Veterans with recent primary care engagement. Mental health symptoms were the most common reported reason for delay among those who delayed care. Clinical Trial registration: NCT02991534.

Investigation of genomic and transcriptomic risk factors in clopidogrel response in African Americans.

Clopidogrel, an anti-platelet drug, used to prevent thrombosis after percutaneous coronary intervention. Clopidogrel resistance results in recurring ischemic episodes, with African Americans suffering disproportionately. The aim of this study was to identify biomarkers of clopidogrel resistance in African American patients. We conducted a genome-wide association study, including local ancestry adjustment, in 141 African Americans on clopidogrel to identify associations with high on-treatment platelet reactivity (HTPR). We validated genome-wide and suggestive hits in an independent cohort of African American clopidogrel patients (N = 823) from the Million Veteran's Program (MVP) along with in vitro functional follow up. We performed differential gene expression (DGE) analysis in whole blood with functional follow-up in MEG-01 cells. We identified rs7807369, within thrombospondin 7A (THSD7A), as significantly associated with increasing risk of HTPR (p = 4.56 × 10-9). Higher THSD7A expression was associated with HTPR in an independent gene expression cohort of clopidogrel treated patients (p = 0.004) and supported by increased gene expression on THSD7A in primary human endothelial cells carrying the risk haplotype. Two SNPs (rs1149515 and rs191786) were validated in the MVP cohort. DGE analysis identified an association with decreased LAIR1 expression to HTPR. LAIR1 knockdown in a MEG-01 cells resulted in increased expression of SYK and AKT1, suggesting an inhibitory role of LAIR1 in the Glycoprotein VI pathway. Notably, the CYP2C19 variants showed no association with clopidogrel response in the discovery or MVP cohorts. In summary, these finding suggest that other variants outside of CYP2C19 star alleles play an important role in clopidogrel response in African Americans.

African ancestry GWAS of dementia in a large military cohort identifies significant risk loci.

While genome wide association studies (GWASs) of Alzheimer's Disease (AD) in European (EUR) ancestry cohorts have identified approximately 83 potentially independent AD risk loci, progress in non-European populations has lagged. In this study, data from the Million Veteran Program (MVP), a biobank which includes genetic data from more than 650,000 US Veteran participants, was used to examine dementia genetics in an African descent (AFR) cohort. A GWAS of Alzheimer's disease and related dementias (ADRD), an expanded AD phenotype including dementias such as vascular and non-specific dementia that included 4012 cases and 18,435 controls age 60+ in AFR MVP participants was performed. A proxy dementia GWAS based on survey-reported parental AD or dementia (n = 4385 maternal cases, 2256 paternal cases, and 45,970 controls) was also performed. These two GWASs were meta-analyzed, and then subsequently compared and meta-analyzed with the results from a previous AFR AD GWAS from the Alzheimer's Disease Genetics Consortium (ADGC). A meta-analysis of common variants across the MVP ADRD and proxy GWASs yielded GWAS significant associations in the region of APOE (p = 2.48 × 10-101), in ROBO1 (rs11919682, p = 1.63 × 10-8), and RNA RP11-340A13.2 (rs148433063, p = 8.56 × 10-9). The MVP/ADGC meta-analysis yielded additional significant SNPs near known AD risk genes TREM2 (rs73427293, p = 2.95 × 10-9), CD2AP (rs7738720, p = 1.14 × 10-9), and ABCA7 (rs73505251, p = 3.26 × 10-10), although the peak variants observed in these genes differed from those previously reported in EUR and AFR cohorts. Of the genes in or near suggestive or genome-wide significant associated variants, nine (CDA, SH2D5, DCBLD1, EML6, GOPC, ABCA7, ROS1, TMCO4, and TREM2) were differentially expressed in the brains of AD cases and controls. This represents the largest AFR GWAS of AD and dementia, finding non-APOE GWAS-significant common SNPs associated with dementia. Increasing representation of AFR participants is an important priority in genetic studies and may lead to increased insight into AD pathophysiology and reduce health disparities.

Women Veterans' Healthcare Needs, Utilization, and Preferences in Veterans Affairs Primary Care Settings.

BACKGROUND: The Veterans Health Administration (VA) is the largest integrated health system in the US and provides access to comprehensive primary care. Women Veterans are the fastest growing segment of new VA users, yet little is known about the characteristics of those who routinely access VA primary care in general or by age group. OBJECTIVE: Describe healthcare needs, utilization, and preferences of women Veterans who routinely use VA primary care. PARTICIPANTS: 1,391 women Veterans with 3+ primary care visits within the previous year in 12 VA medical centers (including General Primary Care Clinics, General Primary Care Clinics with designated space for women, and Comprehensive Women's Health Centers) in nine states. METHODS: Cross-sectional survey (45% response rate) of sociodemographic characteristics, health status (including chronic disease, mental health, pain, and trauma exposure), utilization, care preferences, and satisfaction. Select utilization data were extracted from administrative data. Analyses were weighted to the population of routine users and adjusted for non-response in total and by age group. KEY RESULTS: While 43% had health coverage only through VA, 62% received all primary care in VA. In the prior year, 56% used VA mental healthcare and 78% used VA specialty care. Common physical health issues included hypertension (42%), elevated cholesterol (39%), pain (35%), and diabetes (16%). Many screened positive for PTSD (41%), anxiety (32%), and depression (27%). Chronic physical and mental health burdens varied by age. Two-thirds (62%) had experienced military sexual trauma. Respondents reported satisfaction with VA women's healthcare and preference for female providers. CONCLUSIONS: Women Veterans who routinely utilize VA primary care have significant multimorbid physical and mental health conditions and trauma histories. Meeting women Veterans' needs across the lifespan will require continued investment in woman-centered primary care, including integrated mental healthcare and emphasis on trauma-informed, age-specific care, guided by women's provider preferences.

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

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.

The Relationship Between Sexual Assault History and Cervical Cancer Screening Completion Among Women Veterans in the Veterans Health Administration.

Background: Sexual assault affects one in three U.S. women and may have lifelong consequences for women's health, including potential barriers to completing cervical cancer screening and more than twofold higher cervical cancer risk. The objective of this study was to determine whether a history of sexual assault is associated with reduced cervical cancer screening completion among women Veterans. Materials and Methods: We analyzed data from a 2015 survey of women Veterans who use primary care or women's health services at 12 Veterans Health Administration facilities (VA's) in nine states. We linked survey responses with VA electronic health record data and used logistic regression to examine the association of lifetime sexual assault with cervical cancer screening completion within a guideline-concordant interval. Results: The sample included 1049 women, of whom 616 (58.7%) reported lifetime sexual assault. Women with a history of sexual assault were more likely to report a high level of distress related to pelvic examinations, and to report ever delaying a gynecologic examination due to distress. However, in the final adjusted model, lifetime sexual assault was not significantly associated with reduced odds of cervical cancer screening completion (OR 1.35, 95% CI 0.93-1.97). Conclusions: Contrary to our expectations, sexual assault was not significantly associated with gaps in cervical cancer screening completion. Three- to five-year screening intervals may provide sufficient time to complete screening, despite barriers. Trauma-sensitive care practices promoted in the VA may allow women to overcome the distress and discomfort of pelvic examinations to complete needed screening. ClinicalTrials.gov (#NCT02039856).

Approaches to rationing antiretroviral treatment: ethical and equity implications.

Despite a growing global commitment to the provision of antiretroviral therapy (ART), its availability is still likely to be less than the need. This imbalance raises ethical dilemmas about who should be granted access to publicly-subsidized ART programmes. This paper reviews the eligibility and targeting criteria used in four case-study countries at different points in the scale-up of ART, with the aim of drawing lessons regarding ethical approaches to rationing. Mexico, Senegal, Thailand and Uganda have each made an explicit policy commitment to provide antiretrovirals to all those in need, but are achieving this goal in steps--beginning with explicit rationing of access to care. Drawing upon the case-studies and experiences elsewhere, categories of explicit rationing criteria have been identified. These include biomedical factors, adherence to treatment, prevention-driven factors, social and economic benefits, financial factors and factors driven by ethical arguments. The initial criteria for determining eligibility are typically clinical criteria and assessment of adherence prospects, followed by a number of other factors. Rationing mechanisms reflect several underlying ethical theories and the ethical underpinnings of explicit rationing criteria should reflect societal values. In order to ensure this alignment, widespread consultation with a variety of stakeholders, and not only policy-makers or physicians, is critical. Without such explicit debate, more rationing will occur implicitly and this may be more inequitable. The effects of rationing mechanisms upon equity are critically dependent upon the implementation processes. As antiretroviral programmes are implemented it is crucial to monitor who gains access to these programmes.