Deciphering Distinct Genetic Risk Factors for FTLD-TDP Pathological Subtypes via Whole-Genome Sequencing.

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 cases and 3,153 controls, and meta-analysis with the Dementia-seq cohort, compiled from 26 institutions/brain banks in the United States, Europe and Australia. We confirm UNC13A as the strongest overall FTLD-TDP risk factor and identify TNIP1 as a novel FTLD-TDP risk factor. In subgroup analyses, we further identify for the first time genome-wide significant loci specific to each of the three main FTLD-TDP pathological subtypes (A, B and C), as well as enrichment of risk loci in distinct tissues, brain regions, and neuronal subtypes, suggesting distinct disease aetiologies in each of the subtypes. Rare variant analysis confirmed TBK1 and identified VIPR1 , RBPJL , and L3MBTL1 as novel subtype specific FTLD-TDP risk genes, further highlighting the role of innate and adaptive immunity and notch signalling pathway in FTLD-TDP, with potential diagnostic and novel therapeutic implications.

Primary human papillomavirus testing by clinician- versus self-collection: Awareness and acceptance among cervical cancer screening-eligible women.

OBJECTIVES: Primary human papillomavirus (HPV) testing by clinician-collection is endorsed by U.S. guideline organizations for cervical cancer screening, but uptake remains low and insights into patients' understanding are limited. This study aims to primarily address patient awareness of primary HPV screening by clinician-collection and acceptance of primary HPV screening by clinician- and self-collection, and secondarily assess factors associated with awareness and acceptance. SETTING: Primary care practices affiliated with an academic medical center. METHODS: A cross-sectional survey study of screening-eligible women aged 30-65 years was conducted to assess awareness and acceptability of primary HPV screening. We analyzed bivariate associations of respondent characteristics with awareness of primary HPV screening by clinician-collection, willingness to have clinician- or self-collected primary HPV testing, and reasons for self-collection preference. RESULTS: Respondents (n = 351; response rate = 23.4%) reported cervical cancer screening adherence of 82.8% but awareness of clinician-collected primary HPV as an option was low (18.9%) and only associated with HPV testing with recent screening (p = 0.003). After reviewing a description of primary HPV screening, willingness for clinician-collected (81.8%) or home self-collected (76.1%) HPV testing was high, if recommended by a provider. Acceptability of clinician-collected HPV testing was associated with higher income (p = 0.009) and for self-collection was associated with higher income (p = 0.002) and higher education (p = 0.02). Higher education was associated with reporting self-collection as easier than clinic-collection (p = 0.02). Women expected self-collection to be more convenient (94%), less embarrassing (85%), easier (85%), and less painful (81%) than clinician-collection. CONCLUSIONS: Educational interventions are needed to address low awareness about the current clinician-collected primary HPV screening option and to prepare for anticipated federal licensure of self-collection kits. Informing women about self-collection allows them to recognize benefits which could address screening barriers.

Primary Human Papillomavirus Test Uptake and Cervical Cancer Screening Trends in the Midwest, United States.

INTRODUCTION/OBJECTIVES: Despite U.S. Preventive Services Task Force and American Cancer Society endorsement of primary HPV screening, limited published data shows low uptake. PRIMARY AIM: Assess cervical cancer screening rates over time, particularly primary HPV test uptake, among patients in a midwestern practice. SECONDARY AIM: Evaluate associations between sociodemographics and screening adherence. METHODS: Cross-sectional study. Qualifying subjects and type of screening test used were identified by applying ICD-9, ICD-10, lab test, and CPT codes to the Unified Data Platform. Sociodemographics were found through the electronic health record. RESULTS: Primary HPV uptake represented <1% of annual screening from 1/2017 to 1/2022. On 1/1/2022, only 55% of 21 to 29 year old and 63% of 30 to 65 year old were up to date with screening among the studied population. For 21 to 29 year old, compared with White women, Black women were 28% less likely to be screened [RR = 0.72 (0.66-0.79)]. Compared with never-smokers, current smokers were 9% less likely to be screened [RR = 0.91 (0.87-0.96)], past smokers were 14% more likely [RR = 1.14 (1.09-1.2)]. Among 30 to 65 year old, compared with White women, Black women were 14% less likely to be screened [RR = 0.86 (0.81-0.9)]. Compared with never-smokers, current smokers were 21% less likely to be screened [RR = 0.79 (0.77-0.81)], past smokers were 6% less likely [RR = 0.94 (0.92-0.95)]. Jointly considering race, ethnicity, smoking status, Charlson score, and rurality, findings were similar for 21 to 29 year old; Black women were screened less than White women [RR = 0.73 (0.67-0.79)]; current smokers [RR = 0.9 (0.85-0.94)] and past smokers [RR = 1.12 (1.06-1.17)] were screened less than never smokers. For 30 to 65 year old, Black women were screened less than White women [RR = 0.83 (0.79-0.88)]; current smokers [RR = 0.8 (0.78-0.81)] and past smokers [RR = 0.95 (0.93-0.96)] were screened less than never smokers. CONCLUSIONS: Screening rates remained below the Healthy People 2030 goal of 79.2% over time, particularly for younger Black women and current smokers, with minimal use of primary HPV screening.

Age-Dependent Sex Differences in the Prevalence of Selective Serotonin Reuptake Inhibitor Treatment: A Retrospective Cohort Analysis.

Background: Antidepressants are among the most prescribed medications in the United States. The aim of this study was to explore the prevalence of antidepressant prescriptions and investigate sex differences and age-sex interactions in adults enrolled in the Right Drug, Right Dose, Right Time: Using Genomic Data to Individualize Treatment (RIGHT) study. Materials and Methods: We conducted a retrospective analysis of the RIGHT study. Using electronic prescriptions, we assessed 12-month prevalence of antidepressant treatment. Sex differences and age-sex interactions were evaluated using multivariable logistic regression and flexible recursive smoothing splines. Results: The sample consisted of 11,087 participants (60% women). Antidepressant prescription prevalence was 22.24% (27.96% women, 13.58% men). After adjusting for age and enrollment year, women had significantly greater odds of antidepressant prescription (odds ratio = 2.29; 95% confidence interval = 2.07, 2.54). Furthermore, selective serotonin reuptake inhibitors (SSRIs) had a significant age-sex interaction. While SSRI prescriptions in men showed a sustained decrease with age, there was no such decline for women until after reaching ∼50 years of age. There are important limitations to consider in this study. Electronic prescription data were cross-sectional; information on treatment duration or adherence was not collected; this cohort is not nationally representative; and enrollment occurred over a broad period, introducing confounding by changes in temporal prescribing practices. Conclusions: Underscored by the significant interaction between age and sex on odds of SSRI prescription, our results warrant age to be incorporated as a mediator when investigating sex differences in mental illness, especially mood disorders and their treatment.

Myocardial Recovery in Recent Onset Dilated Cardiomyopathy: Role of CDCP1 and Cardiac Fibrosis.

BACKGROUND: Dilated cardiomyopathy (DCM) is a major cause of heart failure and carries a high mortality rate. Myocardial recovery in DCM-related heart failure patients is highly variable, with some patients having little or no response to standard drug therapy. A genome-wide association study may agnostically identify biomarkers and provide novel insight into the biology of myocardial recovery in DCM. METHODS: A genome-wide association study for change in left ventricular ejection fraction was performed in 686 White subjects with recent-onset DCM who received standard pharmacotherapy. Genome-wide association study signals were subsequently functionally validated and studied in relevant cellular models to understand molecular mechanisms that may have contributed to the change in left ventricular ejection fraction. RESULTS: The genome-wide association study identified a highly suggestive locus that mapped to the 5'-flanking region of the CDCP1 (CUB [complement C1r/C1s, Uegf, and Bmp1] domain containing protein 1) gene (rs6773435; P=7.12×10-7). The variant allele was associated with improved cardiac function and decreased CDCP1 transcription. CDCP1 expression was significantly upregulated in human cardiac fibroblasts (HCFs) in response to the PDGF (platelet-derived growth factor) signaling, and knockdown of CDCP1 significantly repressed HCF proliferation and decreased AKT (protein kinase B) phosphorylation. Transcriptomic profiling after CDCP1 knockdown in HCFs supported the conclusion that CDCP1 regulates HCF proliferation and mitosis. In addition, CDCP1 knockdown in HCFs resulted in significantly decreased expression of soluble ST2 (suppression of tumorigenicity-2), a prognostic biomarker for heart failure and inductor of cardiac fibrosis. CONCLUSIONS: CDCP1 may play an important role in myocardial recovery in recent-onset DCM and mediates its effect primarily by attenuating cardiac fibrosis.

Myocardial Fibrosis and Cardiomyopathy Risk: A Genetic Link in the MESA.

BACKGROUND: Common genetic variants are associated with risk for hypertrophic cardiomyopathy and dilated cardiomyopathy and with left ventricular (LV) traits. Whether these variants are associated with myocardial fibrosis, an important pathophysiological mediator of cardiomyopathy, is unknown. METHODS: Multi-Ethnic Study of Atherosclerosis participants with T1-mapping cardiac magnetic resonance imaging in-whom extracellular volume was assessed, and genotyping information was available were included (N=1255). Log extracellular volume (%) was regressed on 50 candidate single nucleotide polymorphisms (previously identified to be associated with hypertrophic cardiomyopathy, dilated cardiomyopathy, and LV traits) adjusting for age, sex, diabetes, blood pressure, and principal components of ancestry. Ancestry-specific results were pooled by fixed-effect meta-analyses. Gene knockdown experiments were performed in human cardiac fibroblasts. RESULTS: The SMARCB1 rs2186370 intronic variant (minor allele frequency: 0.18 in White and 0.50 in Black participants), previously identified as a risk variant for dilated cardiomyopathy and hypertrophic cardiomyopathy, was significantly associated with increased extracellular volume (P=0.0002) after adjusting for confounding clinical variables. The SMARCB1 rs2070458 locus previously associated with increased LV wall thickness and mass was similarly significantly associated with increased extracellular volume (P=0.0002). The direction of effect was similar in all 4 ancestry groups, but the effect was strongest in Black participants. The variants are strong expression quantitative loci in human LV tissue and associated with genotype-dependent decreased expression of SMARCB1 (P=7.3×10-22). SMARCB1 knockdown in human cardiac fibroblasts resulted in increased TGF (transforming growth factor)-ß1-mediated α-smooth muscle actin and collagen expression. CONCLUSIONS: Common genetic variation in SMARCB1 previously associated with risk for cardiomyopathies and increased LV wall thickness is associated with increased cardiac magnetic resonance imaging-based myocardial fibrosis and increased TGF-ß1 mediated myocardial fibrosis in vitro. Whether these findings suggest a pathophysiologic link between myocardial fibrosis and cardiomyopathy risk remains to be proven.

The importance of social activity to risk of major depression in older adults.

BACKGROUND: Several social determinants of health (SDoH) have been associated with the onset of major depressive disorder (MDD). However, prior studies largely focused on individual SDoH and thus less is known about the relative importance (RI) of SDoH variables, especially in older adults. Given that risk factors for MDD may differ across the lifespan, we aimed to identify the SDoH that was most strongly related to newly diagnosed MDD in a cohort of older adults. METHODS: We used self-reported health-related survey data from 41 174 older adults (50-89 years, median age = 67 years) who participated in the Mayo Clinic Biobank, and linked ICD codes for MDD in the participants' electronic health records. Participants with a history of clinically documented or self-reported MDD prior to survey completion were excluded from analysis (N = 10 938, 27%). We used Cox proportional hazards models with a gradient boosting machine approach to quantify the RI of 30 pre-selected SDoH variables on the risk of future MDD diagnosis. RESULTS: Following biobank enrollment, 2073 older participants were diagnosed with MDD during the follow-up period (median duration = 6.7 years). The most influential SDoH was perceived level of social activity (RI = 0.17). Lower level of social activity was associated with a higher risk of MDD [hazard ratio = 2.27 (95% CI 2.00-2.50) for highest v. lowest level]. CONCLUSION: Across a range of SDoH variables, perceived level of social activity is most strongly related to MDD in older adults. Monitoring changes in the level of social activity may help identify older adults at an increased risk of MDD.

Employment Characteristics and Risk of Hospitalization Among Older Adults Participating in the Mayo Clinic Biobank.

Objective: To determine the relationship between characteristics of employment and future hospitalization in older adults. Patients and Methods: We conducted a survey of adults aged 65 years or older participating in the Mayo Clinic Biobank. Using a frequency-matched, case-control design, we compared patients who were hospitalized within 5 years of biobank enrollment (cases) with those who were not hospitalized (controls). We assessed the duration of work, age at first job, number of jobs, disability, retirement, and reasons for leaving work. We performed logistic regression analysis to assess the association of these factors with hospitalization, accounting for age, sex, comorbid conditions, and education level. Results: Among 3536 participants (1600 cases and 1936 controls; median age, 68.5 years; interquartile range, 63.4-73.9 years), cases were older, more likely to be male, and had lower education levels. Comorbid illnesses had the largest association with hospitalization (odds ratio [OR], 4.09; 95% CI, 3.37-4.97 [highest vs lowest quartile]). On adjusted analyses, odds of hospitalization increased with the presence of disability (OR, 1.31; 95% CI, 1.01-1.69) and decreased with having 1 or 2 lifetime jobs vs no employment (OR, 0.77; 95% CI, 0.60-1.00). The length of work, furlough, age of retirement, childcare issues, and reasons for leaving a job were not associated with hospitalization. Conclusion: This study reports an association between disability during work and hospitalization. On the basis of our findings, it may be important to obtain a more detailed work history from patients because it may provide further insight into their future health.

Identification of Two Genetic Loci Associated with Leukopenia after Chemotherapy in Patients with Breast Cancer.

PURPOSE: To identify molecular predictors of grade 3/4 neutropenic or leukopenic events (NLE) after chemotherapy using a genome-wide association study (GWAS). EXPERIMENTAL DESIGN: A GWAS was performed on patients in the phase III chemotherapy study SUCCESS-A (n = 3,322). Genotyping was done using the Illumina HumanOmniExpress-12v1 array. Findings were functionally validated with cell culture models and the genotypes and gene expression of possible causative genes were correlated with clinical treatment response and prognostic outcomes. RESULTS: One locus on chromosome 16 (rs4784750; NLRC5; P = 1.56E-8) and another locus on chromosome 13 (rs16972207; TNFSF13B; P = 3.42E-8) were identified at a genome-wide significance level. Functional validation revealed that expression of these two genes is altered by genotype-dependent and chemotherapy-dependent activity of two transcription factors. Genotypes also showed an association with disease-free survival in patients with an NLE. CONCLUSIONS: Two loci in NLRC5 and TNFSF13B are associated with NLEs. The involvement of the MHC I regulator NLRC5 implies the possible involvement of immuno-oncological pathways.

Awareness and Support of Clinician- and Patient-Collected Human Papillomavirus Testing for Cervical Cancer Screening Among Primary Care Clinicians.

Background: Cervical cancer screening has shifted toward human papillomavirus (HPV)-based testing, but uptake of primary HPV screening in the United States is unknown and previous studies highlight delays in clinician adoption of guideline updates. Methods: We conducted a cross-sectional electronic survey of primary care clinicians (n = 252; response rate = 30.9%) assessing awareness and support of primary HPV screening. We assessed factors for association with past use of HPV testing and support of clinician- and patient-collected HPV testing individually using Fisher's exact test and jointly using Firth's logistic regression. Results: Most clinicians (79%) were familiar with one or more primary HPV screening guidelines. Support for clinician-collected (89%) and patient-collected (82%) HPV testing was high, but only 34.5% reported prior use. Guideline familiarity was positively associated with HPV testing in practice (p = 0.0001). Support of clinician-collected testing was positively associated with more years in practice (p = 0.03), internal (vs. family) medicine specialty (p = 0.03), and guideline familiarity (p ≤ 0.0001). Male clinicians more frequently supported patient collection for patients overdue for screening (p = 0.013). Physicians more frequently than advanced practice providers (APPs) supported patient collection for screening-adherent women (p = 0.021). Multivariable analysis showed those unfamiliar with guidelines were less likely to have used HPV testing [odds ratio, OR: 0.10 (0.03-0.32)] or to support clinician-collected HPV testing [OR: 0.16 (0.07-0.37)]. APPs were less likely than physicians to support patient-collected HPV testing among screening-adherent women [OR: 0.42 (0.20-0.87)]. Conclusions: We observed high levels of guideline awareness and clinician support for primary HPV testing, despite relatively low use. This merits further exploration to inform future interventions to increase uptake.

Socioeconomic disadvantage and human papillomavirus (HPV) vaccination uptake.

IMPORTANCE: Despite availability of safe and effective human papillomavirus (HPV) vaccines, vaccination uptake remains low in the U.S. Research examining the impact of neighborhood socioeconomic status on HPV vaccination may help target interventions. OBJECTIVE: To examine the association between area deprivation and HPV vaccine initiation and completion. DESIGN, SETTING, PARTICIPANTS: Retrospective cohort study of individuals aged 11-18 years residing in the upper Midwest region. Receipt of HPV vaccination was examined over a three-year follow-up period (01/01/2016-12/31/2018). MAIN OUTCOMES AND MEASURES: Outcomes of interest were initiation and completion of HPV vaccination. Demographic data were collected from the Rochester Epidemiology Project (REP). Area-level socioeconomic disadvantage was measured by calculating an Area Deprivation Index (ADI) score for each person, a measure of socioeconomic disadvantage derived from American Community Survey data. Multivariable mixed effect Cox proportional hazards models were used to examine the association of ADI quartiles (Q1-Q4) with HPV vaccine series initiation and completion, given initiation. RESULTS: Individuals residing in census block groups with higher deprivation had significantly lower likelihood of HPV vaccine initiation (Q2: HR = 0.91, 0.84-0.99 Q3: HR = 0.83, 0.76-0.90; Q4: HR = 0.84, 0.74-0.96) relative to those in the least-deprived block groups (Q1). Similarly, those living in block groups with higher deprivation had significantly lower likelihood of completion (Q2: HR = 0.91, 0.86-0.97; Q3: HR = 0.87, 0.81-0.94; Q4: HR = 0.82, 0.74-0.92) compared to individuals in the least-deprived block groups (Q1). CONCLUSIONS AND RELEVANCE: Lower probability of both HPV vaccine-series initiation and completion were observed in areas with greater deprivation. Our results can inform allocation of resources to increase HPV vaccination rates in our primary care practice and provide an example of leveraging public data to inform similar efforts across diverse health systems.

Disparities Among Limited English Proficient Patients in Colon Cancer Screening with Multi-target DNA Stool Test.

Racial and language minority groups in the U.S. are at a higher risk for morbidity and mortality from colorectal cancer (CRC), partially due to lower screening rates. This is a retrospective cohort study comparing successful multi-target stool DNA test (mt-sDNA) test completion among patients with limited English proficiency (LEP) and English proficient (EP) patients, from 2015 to 2018. Patients with LEP were frequency matched to EP patients by age at a 3:1 ratio. The percentage of mt-sDNA tests without useful results was 53% among patients with LEP compared to 29% among EP patients (p < 0.0001). The median number of days from order placement to test completion was 62.5 among patients with LEP compared to 33 for EP patients (p = 0.003). This study demonstrates a significant disparity in CRC screening completion using the mt-sDNA test among populations with LEP, which may widen existing disparities in CRC mortality.

Health Care Provider Characteristics Associated With Colorectal Cancer Screening Preferences and Use.

OBJECTIVE: To assess health care provider (HCP) preferences related to colorectal cancer (CRC) screening overall, and by HCP and patient characteristics. PARTICIPANTS AND METHODS: We developed a survey based on the Theoretical Domains Framework to assess factors associated with CRC screening preferences in clinical practice. The survey was administered online November 6 through December 6, 2019, to a validated panel of HCPs drawn from US national databases and professional organizations. The final analysis sample included 779 primary care clinicians (PCCs) and 159 gastroenterologists (GIs). RESULTS: HCPs chose colonoscopy as their preferred screening method for average-risk patients (96.9% (154/159) for GIs, 75.7% (590/779) for PCCs). Among PCCs, 12.2% (95/779) preferred multi-target stool DNA (mt-sDNA), followed by fecal immunochemical test (FIT), (7.3%; 57/779) and guaiac-based fecal occult blood test (gFOBT) (4.8%; 37/779). Preference among PCCs and GIs generally shifted toward noninvasive screening options for patients who were unable to undergo invasive procedures; concerned about taking time from work; unconvinced about need for screening; and refusing other screening recommendations. Among PCCs, preference for mt-sDNA over FIT and gFOBT was less frequent in larger compared with smaller clinical practices. Additionally, preference for mt-sDNA over FIT was more likely among PCCs with more years of clinical experience, higher patient volumes (> 25/day), and practice locations in suburban and rural settings (compared to urban). CONCLUSION: Both PCCs and GIs preferred colonoscopy for CRC screening of average-risk patients, although PCCs did so less frequently and with approximately a quarter preferring stool-based tests (particularly mt-sDNA). PCCs' preference varied by provider and patient characteristics. Our findings underscore the importance of informed choice and shared decision-making about CRC screening options.

No Association Between Pharmacogenomics Variants and Hospital and Emergency Department Utilization: A Mayo Clinic Biobank Retrospective Study.

BACKGROUND: The use of pharmacogenomics data is increasing in clinical practice. However, it is unknown if pharmacogenomics data can be used more broadly to predict outcomes like hospitalization or emergency department (ED) visit. We aim to determine the association between selected pharmacogenomics phenotypes and hospital utilization outcomes (hospitalization and ED visits). METHODS: This cohort study utilized 10,078 patients from the Mayo Clinic Biobank in the RIGHT protocol with sequence and interpreted phenotypes for 10 selected pharmacogenes including CYP2D6, CYP2C9, CYP2C19, CYP3A5, HLA B 5701, HLA B 5702, HLA B 5801, TPMT, SLCO1B1, and DPYD. The primary outcome was hospitalization with ED visits as a secondary outcome. We used Cox proportional hazards model to test the association between each pharmacogenomics phenotype and the risk of the outcomes. RESULTS: During the follow-up period (median [in years] = 7.3), 13% (n=1354) and 8% (n=813) of the subjects experienced hospitalization and ED visits, respectively. Compared to subjects who did not experience hospitalization, hospitalized patients were older (median age [in years]: 67 vs 65), poorer self-rated health (15% vs 4.7% for fair/poor), and higher disease burden (median number of chronic conditions: 7 vs 4) at baseline. There was no association of hospitalization with any of the pharmacogenomics phenotypes. The pharmacogenomics phenotypes were not associated with disease burden, a well-established risk factor for hospital utilization outcomes. Similar findings were observed for patients with ED visits during the follow-up period. CONCLUSION: We found no association of 10 well-established pharmacogenomics phenotypes with either hospitalization or ED visits in this relatively large biobank population and outside the context of specific drug use related to these genes. Traditional risk factors for hospitalization like age and self-rated health were much more likely to predict hospitalization and/or ED visits than this pharmacogenomics information.

Long-term lithium therapy and risk of chronic kidney disease in bipolar disorder: A historical cohort study.

AIMS: Long-term lithium therapy (LTLT) has been associated with kidney insufficiency in bipolar disorder (BD). We aimed to investigate the risk factors of chronic kidney disease (CKD) development and progression among BD patients receiving LTLT. METHODS: We included adult patients with BD on LTLT (≥1 year) who were enrolled in the Mayo Clinic Bipolar Biobank, Rochester, Minnesota. We reviewed electronic medical records to extract information related to lithium therapy and kidney-related data to assess changes in the estimated glomerular filtration rate (eGFR). CKD severity was assessed based on eGFR. RESULTS: Among 154 patients who received LTLT, 41 patients (27%) developed CKD, of whom 20 (49%) patients continued lithium (continuers) and 19 (46%) discontinued it (discontinuers). The median time to stage 3 CKD development was 21.7 years from the start of Li treatment. Type-2 diabetes mellitus and benzodiazepine use were independent predictors for CKD development in the survival analysis, after controlling for age. The subsequent CKD progression rate did not differ between continuers and discontinuers (mean GFR 48.6 vs. 44.1, p = 0.13) at the end of follow-up duration (mean duration: 3.5 ± 4.4 years for continuers and 4.9 ± 5.3 years for discontinuers). CONCLUSION: CKD was observed in one fourth of patients with BD receiving LTLT. There was no significant difference in the progression of CKD among Li continuers versus discontinuers, at the mean follow-up duration of 4.2 years, after the CKD diagnosis. Progression of CKD could be influenced by existing comorbidities and may not necessarily be due to lithium alone.

Next-Generation Sequencing of CYP2C19 in Stent Thrombosis: Implications for Clopidogrel Pharmacogenomics.

PURPOSE: Describe CYP2C19 sequencing results in the largest series of clopidogrel-treated cases with stent thrombosis (ST), the closest clinical phenotype to clopidogrel resistance. Evaluate the impact of CYP2C19 genetic variation detected by next-generation sequencing (NGS) with comprehensive annotation and functional studies. METHODS: Seventy ST cases on clopidogrel identified from the PLATO trial (n = 58) and Mayo Clinic biorepository (n = 12) were matched 1:1 with controls for age, race, sex, diabetes mellitus, presentation, and stent type. NGS was performed to cover the entire CYP2C19 gene. Assessment of exonic variants involved measuring in vitro protein expression levels. Intronic variants were evaluated for potential splicing motif variations. RESULTS: Poor metabolizers (n = 4) and rare CYP2C19*8, CYP2C19*15, and CYP2C19*11 alleles were identified only in ST cases. CYP2C19*17 heterozygote carriers were observed more frequently in cases (n = 29) than controls (n = 18). Functional studies of CYP2C19 exonic variants (n = 11) revealed 3 cases and only 1 control carrying a deleterious variant as determined by in vitro protein expression studies. Greater intronic variation unique to ST cases (n = 169) compared with controls (n = 84) was observed with predictions revealing 13 allele candidates that may lead to a potential disruption of splicing and a loss-of-function effect of CYP2C19 in ST cases. CONCLUSION: NGS detected CYP2C19 poor metabolizers and paradoxically greater number of so-called rapid metabolizers in ST cases. Rare deleterious exonic variation occurs in 4%, and potentially disruptive intronic alleles occur in 16% of ST cases. Additional studies are required to evaluate the role of these variants in platelet aggregation and clopidogrel metabolism.

Colorectal cancer screening completion: An examination of differences by screening modality.

Average-risk colorectal cancer (CRC) screening is broadly recommended, using one of several endorsed test options. However, CRC screening participation rates remain below national goals. To gain further insights regarding recent, population-based patterns in overall and test-specific CRC screening participation, we conducted a retrospective study of adults, ages 50-75 years, utilizing comprehensive data resources from the Rochester Epidemiology Project (REP). Among residents of Olmsted County, MN eligible and due for CRC screening, we identified 5818 residents across three annual cohorts who completed screening between 1/1/2016 and 12/31/2018. We summarized CRC screening rates as incidence per 1000 population and used Poisson regression to test for overall and mode-specific CRC trends. We also analyzed rates of follow-up colonoscopy within 6-months after a positive stool-based screening result. While no significant differences over time were observed in overall CRC screening incidence rates among those due for screening, we observed a statistically significant increase in mt-sDNA test and statistically significant decreases in screening colonoscopy and FIT/FOBT test completion rates; differences in screening overall and by modality were observed by age, sex, and race/ethnicity. The diagnostic colonoscopy follow-up rate within six months after a positive stool-based test was significantly higher following mt-sDNA (84.9%) compared to FIT/FOBT (42.6%). In this retrospective, population-based study, overall CRC screening incidence rates remained stable from 2016 to 2018, while test-specific rates for mt-sDNA significantly increased and decreased for colonoscopy and FIT/FOBT. Adherence with follow-up colonoscopy after a positive stool-based test was significantly higher among patients who underwent mt-sDNA screening compared to FIT/FOBT.

MAPT haplotype-stratified GWAS reveals differential association for AD risk variants.

INTRODUCTION: MAPT H1 haplotype is implicated as a risk factor for neurodegenerative diseases including Alzheimer's disease (AD). METHODS: Using Alzheimer's Disease Genetics Consortium (ADGC) genome-wide association study (GWAS) data (n = 18,841), we conducted a MAPT H1/H2 haplotype-stratified association to discover MAPT haplotype-specific AD risk loci. RESULTS: We identified 11 loci-5 in H2-non-carriers and 6 in H2-carriers-although none of the MAPT haplotype-specific associations achieved genome-wide significance. The most significant H2 non-carrier-specific association was with a NECTIN2 intronic (P = 1.33E-07) variant, and that for H2 carriers was near NKX6-1 (P = 1.99E-06). The GABRG2 locus had the strongest epistasis with MAPT H1/H2 variant rs8070723 (P = 3.91E-06). Eight of the 12 genes at these loci had transcriptome-wide significant differential expression in AD versus control temporal cortex (q < 0.05). Six genes were members of the brain transcriptional co-expression network implicated in "synaptic transmission" (P = 9.85E-59), which is also enriched for neuronal genes (P = 1.0E-164), including MAPT. DISCUSSION: This stratified GWAS identified loci that may confer AD risk in a MAPT haplotype-specific manner. This approach may preferentially enrich for neuronal genes implicated in synaptic transmission.

Postmenopause as a key factor in the composition of the Endometrial Cancer Microbiome (ECbiome).

Incidence rates for endometrial cancer (EC) are rising, particularly in postmenopausal and obese women. Previously, we showed that the uterine and vaginal microbiome distinguishes patients with EC from those without. Here, we sought to examine the impact of patient factors (such as menopause status, body mass index, and vaginal pH) in the microbiome in the absence of EC and how these might contribute to the microbiome signature in EC. We find that each factor independently alters the microbiome and identified postmenopausal status as the main driver of a polymicrobial network associated with EC (ECbiome). We identified Porphyromas somerae presence as the most predictive microbial marker of EC and we confirm this using targeted qPCR, which could be of use in detecting EC in high-risk, asymptomatic women. Given the established pathogenic behavior of P. somerae and accompanying network in tissue infections and ulcers, future investigation into their role in EC is warranted.