Pharmacogenetic testing and monitoring of complete blood counts among Veterans newly prescribed thiopurine treatments: a retrospective cohort study.

Pharmacogenetic (PGx) testing before initiation of thiopurine treatment and CBC monitoring post-initiation helps avoid adverse events and ensure patient safety. This study aims to evaluate trends in PGx testing and CBC monitoring among Veterans prescribed azathioprine, thioguanine, or mercaptopurine to demonstrate VA's efforts to improve medication safety after an adverse event. To assess testing patterns, we used VA electronic health report data to identify 20,524 Veterans who first began thiopurine treatment between January 1, 2010, to December 31, 2021. Aggregate monthly counts of thiopurine prescriptions and associated lab tests were tabulated, and the trend in the proportion of patients tested was analyzed using the Mann-Kendall test. The proportion of patients undergoing PGx testing rose from 30.0% in 2010 to 47.5% in late 2014 (July-December). However, PGx testing and overall testing only increased slightly after the sentinel event, and orders levelled off over time at slightly lower levels than before the sentinel event. Very little change was seen in the overall proportion of individuals receiving any testing across all patients with new prescriptions from the time of the sentinel event in 2014 to the end of 2021. A large portion of patients prescribed thiopurine drugs did not receive testing that could help prevent the development of potential adverse events, leading to a predominantly reactive approach. Increased PGx testing may result in a more proactive approach to the prevention of adverse events due to genetic interaction.

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.

Polygenic risk of any, metastatic, and fatal prostate cancer in the Million Veteran Program.

BACKGROUND: Genetic scores may provide an objective measure of prostate cancer risk and thus inform screening decisions. We evaluated whether a polygenic hazard score based on 290 genetic variants (PHS290) is associated with prostate cancer risk in a diverse population, including Black men, who have higher average risk of prostate cancer death but are often treated as a homogeneously high-risk group. METHODS: This was a retrospective analysis of the Million Veteran Program, a national, population-based cohort study of US military veterans conducted 2011-2021. Cox proportional hazards analyses tested for association of genetic and other risk factors (including self-reported race and ethnicity and family history) with age at death from prostate cancer, age at diagnosis of metastatic (nodal or distant) prostate cancer, and age at diagnosis of any prostate cancer. RESULTS: A total of 590 750 male participants were included. Median age at last follow-up was 69 years. PHS290 was associated with fatal prostate cancer in the full cohort and for each racial and ethnic group (P < .001). Comparing men in the highest 20% of PHS290 with those in the lowest 20% (based on percentiles from an independent training cohort), the hazard ratio for fatal prostate cancer was 4.42 (95% confidence interval = 3.91 to 5.02). When accounting for guideline-recommended risk factors (family history, race, and ethnicity), PHS290 remained a strong independent predictor of any, metastatic, and fatal prostate cancer. CONCLUSIONS: PHS290 stratified US veterans of diverse ancestry for lifetime risk of prostate cancer, including metastatic and fatal cancer. Predicting genetic risk of lethal prostate cancer with PHS290 might inform individualized decisions about prostate cancer screening.

Impact of COVID-19 on the incidence of localized and metastatic prostate cancer among White and Black Veterans.

The COVID-19 pandemic disrupted prostate-specific antigen (PSA) screening and prostate biopsy procedures. We sought to determine whether delayed screening and diagnostic workup of prostate cancer (PCa) was associated with increased subsequent rates of incident PCa and advanced PCa and whether the rates differed by race. We analyzed data from the Veterans Health Administration to assess the changes in the rates of PSA screening, prostate biopsy procedure, incident PCa, PCa with high-grade Gleason score, and incident metastatic prostate cancer (mPCa) before and after January 2020. While the late pandemic mPCa rate among White Veterans was comparable to the pre-pandemic rate (5.4 pre-pandemic vs 5.2 late-pandemic, p = 0.67), we observed a significant increase in incident mPCa cases among Black Veterans in the late pandemic period (8.1 pre-pandemic vs 11.3 late-pandemic, p < 0.001). Further investigation is warranted to fully understand the impact of the COVID-19 pandemic on the diagnosis of advanced prostate cancer.