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.

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.

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.

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.

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.

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.

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.

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.

Gut microbiome meta-analysis reveals dysbiosis is independent of body mass index in predicting risk of obesity-associated CRC.

OBJECTIVE: Obesity is a risk factor for colorectal cancer (CRC), accounting for more than 14% of CRC incidence. Microbial dysbiosis and chronic inflammation are common characteristics in both obesity and CRC. Human and murine studies, together, demonstrate the significant impact of the microbiome in governing energy metabolism and CRC development; yet, little is understood about the contribution of the microbiome to development of obesity-associated CRC as compared to individuals who are not obese. DESIGN: In this study, we conducted a meta-analysis using five publicly available stool and tissue-based 16S rRNA and whole genome sequencing (WGS) data sets of CRC microbiome studies. High-resolution analysis was employed for 16S rRNA data, which allowed us to achieve species-level information to compare with WGS. RESULTS: Characterisation of the confounders between studies, 16S rRNA variable region and sequencing method did not reveal any significant effect on alpha diversity in CRC prediction. Both 16S rRNA and WGS were equally variable in their ability to predict CRC. Results from diversity analysis confirmed lower diversity in obese individuals without CRC; however, no universal differences were found in diversity between obese and non-obese individuals with CRC. When examining taxonomic differences, the probability of being classified as CRC did not change significantly in obese individuals for all taxa tested. However, random forest classification was able to distinguish CRC and non-CRC stool when body mass index was added to the model. CONCLUSION: Overall, microbial dysbiosis was not a significant factor in explaining the higher risk of colon cancer among individuals with obesity.

Anastrozole Aromatase Inhibitor Plasma Drug Concentration Genome-Wide Association Study: Functional Epistatic Interaction Between SLC38A7 and ALPPL2.

Anastrozole is a widely prescribed aromatase inhibitor for the therapy of estrogen receptor positive (ER+) breast cancer. We performed a genome-wide association study (GWAS) for plasma anastrozole concentrations in 687 postmenopausal women with ER+ breast cancer. The top single-nucleotide polymorphism (SNP) signal mapped across SLC38A7 (rs11648166, P = 2.3E-08), which we showed to encode an anastrozole influx transporter. The second most significant signal (rs28845026, P = 5.4E-08) mapped near ALPPL2 and displayed epistasis with the SLC38A7 signal. Both of these SNPs were cis expression quantitative trait loci (eQTL)s for these genes, and patients homozygous for variant genotypes for both SNPs had the highest drug concentrations, the highest SLC38A7 expression, and the lowest ALPPL2 expression. In summary, our GWAS identified a novel gene encoding an anastrozole transporter, SLC38A7, as well as epistatic interaction between SNPs in that gene and SNPs near ALPPL2 that influenced both the expression of the transporter and anastrozole plasma concentrations.

Differential roles of ERRFI1 in EGFR and AKT pathway regulation affect cancer proliferation.

AKT signaling is modulated by a complex network of regulatory proteins and is commonly deregulated in cancer. Here, we present a dual mechanism of AKT regulation by the ERBB receptor feedback inhibitor 1 (ERRFI1). We show that in cells expressing high levels of EGFR, ERRF1 inhibits growth and enhances responses to chemotherapy. This is mediated in part through the negative regulation of AKT signaling by direct ERRFI1-dependent inhibition of EGFR In cells expressing low levels of EGFR, ERRFI1 positively modulates AKT signaling by interfering with the interaction of the inactivating phosphatase PHLPP with AKT, thereby promoting cell growth and chemotherapy desensitization. These observations broaden our understanding of chemotherapy response and have important implications for the selection of targeted therapies in a cell context-dependent manner. EGFR inhibition can only sensitize EGFR-high cells for chemotherapy, while AKT inhibition increases chemosensitivity in EGFR-low cells. By understanding these mechanisms, we can take advantage of the cellular context to individualize antineoplastic therapy. Finally, our data also suggest targeting of EFFRI1 in EGFR-low cancer as a promising therapeutic approach.

Combining a nontargeted and targeted metabolomics approach to identify metabolic pathways significantly altered in polycystic ovary syndrome.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is a condition of androgen excess and chronic anovulation frequently associated with insulin resistance. We combined a nontargeted and targeted metabolomics approach to identify pathways and metabolites that distinguished PCOS from metabolic syndrome (MetS). METHODS: Twenty obese women with PCOS were compared with 18 obese women without PCOS. Both groups met criteria for MetS but could not have diabetes mellitus or take medications that treat PCOS or affect lipids or insulin sensitivity. Insulin sensitivity was derived from the frequently sampled intravenous glucose tolerance test. A nontargeted metabolomics approach was performed on fasting plasma samples to identify differentially expressed metabolites, which were further evaluated by principal component and pathway enrichment analysis. Quantitative targeted metabolomics was then applied on candidate metabolites. Measured metabolites were tested for associations with PCOS and clinical variables by logistic and linear regression analyses. RESULTS: This multiethnic, obese sample was matched by age (PCOS, 37±6; MetS, 40±6years) and body mass index (BMI) (PCOS, 34.6±5.1; MetS, 33.7±5.2kg/m2). Principal component analysis of the nontargeted metabolomics data showed distinct group separation of PCOS from MetS controls. From the subset of 385 differentially expressed metabolites, 22% were identified by accurate mass, resulting in 19 canonical pathways significantly altered in PCOS, including amino acid, lipid, steroid, carbohydrate, and vitamin D metabolism. Targeted metabolomics identified many essential amino acids, including branched-chain amino acids (BCAA) that were elevated in PCOS compared with MetS. PCOS was most associated with BCAA (P=.02), essential amino acids (P=.03), the essential amino acid lysine (P=.02), and the lysine metabolite α-aminoadipic acid (P=.02) in models adjusted for surrogate variables representing technical variation in metabolites. No significant differences between groups were observed in concentrations of free fatty acids or vitamin D metabolites. Evaluation of the relationship of metabolites with clinical characteristics showed 1) negative associations of essential and BCAA with insulin sensitivity and sex hormone-binding globulin and 2) positive associations with homeostasis model of insulin resistance and free testosterone; metabolites were not associated with BMI or percent body fat. CONCLUSIONS: PCOS was associated with significant metabolic alterations not attributed exclusively to androgen-related pathways, obesity, or MetS. Concentrations of essential amino acids and BCAA are increased in PCOS, which might result from or contribute to their insulin resistance.

SLCO1B1 polymorphisms and plasma estrone conjugates in postmenopausal women with ER+ breast cancer: genome-wide association studies of the estrone pathway.

BACKGROUND: Estrone (E1), the major circulating estrogen in postmenopausal women, promotes estrogen-receptor positive (ER+) breast tumor growth and proliferation. Two major reactions contribute to E1 plasma concentrations, aromatase (CYP19A1) catalyzed E1 synthesis from androstenedione and steroid sulfatase (STS) catalyzed hydrolysis of estrone conjugates (E1Cs). E1Cs have been associated with breast cancer risk and may contribute to tumor progression since STS is expressed in breast cancer where its activity exceeds that of aromatase. METHODS: We performed genome-wide association studies (GWAS) to identify SNPs associated with variation in plasma concentrations of E1Cs, E1, and androstenedione in 774 postmenopausal women with resected early-stage ER+ breast cancer. Hormone concentrations were measured prior to aromatase inhibitor therapy. RESULTS: Multiple SNPs in SLCO1B1, a gene encoding a hepatic influx transporter, displayed genome-wide significant associations with E1C plasma concentrations and with the E1C/E1 ratio. The top SNP for E1C concentrations, rs4149056 (p = 3.74E-11), was a missense variant that results in reduced transporter activity. Patients homozygous for the variant allele had significantly higher average E1C plasma concentrations than did other patients. Furthermore, three other SLCO1B1 SNPs, not in LD with rs4149056, were associated with both E1C concentrations and the E1C/E1 ratio and were cis-eQTLs for SLCO1B3. GWAS signals of suggestive significance were also observed for E1, androstenedione, and the E1/androstenedione ratio. CONCLUSION: These results suggest a mechanism for genetic variation in E1C plasma concentrations as well as possible SNP biomarkers to identify ER+ breast cancer patients for whom STS inhibitors might be of clinical value.

Accumulating evidence for a role of TCF7L2 variants in bipolar disorder with elevated body mass index.

OBJECTIVES: Bipolar disorder (BD) is a complex disease associated with various hereditary traits, including a higher body mass index (BMI). In a prior genome-wide association study, we found that BMI modified the association of rs12772424 - a common variant in the gene encoding transcription factor 7-like 2 (TCF7L2) - with risk for BD. TCF7L2 is a transcription factor in the canonical Wnt pathway, involved in multiple disorders, including diabetes, cancer and psychiatric conditions. Here, using an independent sample, we evaluated 26 TCF7L2 single nucleotide polymorphisms (SNPs) to explore further the association of BD with the TCF7L2-BMI interaction. METHODS: Using a sample of 662 BD cases and 616 controls, we conducted SNP-level and gene-level tests to assess the evidence for an association between BD and the interaction of BMI and genetic variation in TCF7L2. We also explored the potential mechanism behind the detected associations using human brain expression quantitative trait loci (eQTL) analysis. RESULTS: The analysis provided independent evidence of an rs12772424-BMI interaction (p = 0.011). Furthermore, while overall there was no evidence for SNP marginal effects on BD, the TCF7L2-BMI interaction was significant at the gene level (p = 0.042), with seven of the 26 SNPs showing SNP-BMI interaction effects with p < 0.05. The strongest evidence of interaction was observed for rs7895307 (p = 0.006). TCF7L2 expression showed a significant enrichment of association with the expression of other genes in the Wnt canonical pathway. CONCLUSIONS: The current study provides further evidence suggesting that TCF7L2 involvement in BD risk may be regulated by BMI. Detailed, prospective assessment of BMI, comorbidity, and other possible contributing factors is necessary to explain fully the mechanisms underlying this association.

Pharmacogenomics of estrogens on changes in carotid artery intima-medial thickness and coronary arterial calcification: Kronos Early Estrogen Prevention Study.

Prior to the initiation of menopausal hormone treatment (MHT), genetic variations in the innate immunity pathway were found to be associated with carotid artery intima-medial thickness (CIMT) and coronary arterial calcification (CAC) in women (n = 606) enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). Whether MHT might affect these associations is unknown. The association of treatment outcomes with variation in the same 764 candidate genes was evaluated in the same KEEPS participants 4 yr after randomization to either oral conjugated equine estrogens (0.45 mg/day), transdermal 17ß-estradiol (50 µg/day), each with progesterone (200 mg/day) for 12 days each month, or placebo pills and patch. Twenty SNPs within the innate immunity pathway most related with CIMT after 4 yr were not among those associated with CIMT prior to MHT. In 403 women who completed the study in their assigned treatment group, single nucleotide polymorphisms (SNPs) within the innate immunity pathway were found to alter the treatment effect on 4 yr change in CIMT (i.e., significant interaction between treatment and genetic variation in the innate immunity pathway; P < 0.001). No SNPs by treatment effects were observed with changes of CAC >5 Agatston units after 4 yr. Results of this study suggest that hormonal status may interact with genetic variants to influence cardiovascular phenotypes, specifically, the pharmacogenomic effects within the innate immunity pathway for CIMT.

Genome-wide association analysis identified splicing single nucleotide polymorphism in CFLAR predictive of triptolide chemo-sensitivity.

BACKGROUND: Triptolide is a therapeutic diterpenoid derived from the Chinese herb Tripterygium wilfordii Hook f. Triptolide has been shown to induce apoptosis by activation of pro-apoptotic proteins, inhibiting NFkB and c-KIT pathways, suppressing the Jak2 transcription, activating MAPK8/JNK signaling and modulating the heat shock responses. RESULTS: In the present study, we used lymphoblast cell lines (LCLs) derived from 55 unrelated Caucasian subjects to identify genetic markers predictive of cellular sensitivity to triptolide using genome wide association study. Our results identified SNPs on chromosome 2 associated with triptolide IC50 (p < 0.0001). This region included biologically interesting genes as CFLAR, PPIl3, Caspase 8/10, NFkB and STAT6. Identification of a splicing-SNP rs10190751, which regulates CFLAR alternatively spliced isoforms predictive of the triptolide cytotoxicity suggests its role in triptolides action. Our results from functional studies in Panc-1 cell lines further demonstrate potential role of CFLAR in triptolide toxicity. Analysis of gene-expression with cytotoxicity identified JAK1 expression to be a significant predictor of triptolide sensitivity. CONCLUSIONS: Overall out results identified genetic factors associated with triptolide chemo-sensitivity thereby opening up opportunities to better understand its mechanism of action as well as utilize these biomarkers to predict therapeutic response in patients.

Aromatase inhibitor-associated bone fractures: a case-cohort GWAS and functional genomics.

Bone fractures are a major consequence of osteoporosis. There is a direct relationship between serum estrogen concentrations and osteoporosis risk. Aromatase inhibitors (AIs) greatly decrease serum estrogen levels in postmenopausal women, and increased incidence of fractures is a side effect of AI therapy. We performed a discovery case-cohort genome-wide association study (GWAS) using samples from 1071 patients, 231 cases and 840 controls, enrolled in the MA.27 breast cancer AI trial to identify genetic factors involved in AI-related fractures, followed by functional genomic validation. Association analyses identified 20 GWAS single nucleotide polymorphism (SNP) signals with P < 5E-06. After removal of signals in gene deserts and those composed entirely of imputed SNPs, we applied a functional validation "decision cascade" that resulted in validation of the CTSZ-SLMO2-ATP5E, TRAM2-TMEM14A, and MAP4K4 genes. These genes all displayed estradiol (E2)-dependent induction in human fetal osteoblasts transfected with estrogen receptor-α, and their knockdown altered the expression of known osteoporosis-related genes. These same genes also displayed SNP-dependent variation in E2 induction that paralleled the SNP-dependent induction of known osteoporosis genes, such as osteoprotegerin. In summary, our case-cohort GWAS identified SNPs in or near CTSZ-SLMO2-ATP5E, TRAM2-TMEM14A, and MAP4K4 that were associated with risk for bone fracture in estrogen receptor-positive breast cancer patients treated with AIs. These genes displayed E2-dependent induction, their knockdown altered the expression of genes related to osteoporosis, and they displayed SNP genotype-dependent variation in E2 induction. These observations may lead to the identification of novel mechanisms associated with fracture risk in postmenopausal women treated with AIs.