<div>Abstract<p>Lynch syndrome is the most common inherited cancer syndrome that increases the risk of developing colorectal and endometrial cancer. Universal screening guidelines were first recommended by the Centers for Disease Control and Prevention (CDC) in 2009 and are updated annually by multiple societies. Therefore, one would expect genetic testing rates to increase over time. But testing remains underutilized among those with colorectal or endometrial cancer, even though early detection can improve prognosis and survival rates. In this study, we aimed to understand differences in genetic testing uptake among those with colorectal cancer or endometrial cancer from 2005, 2010, 2015, using data from the National Health Interview Survey (NHIS). We examined genetic testing uptake across cancer-type, age (≤50 or ≥51), sex, race, insurance, and education using a χ<sup>2</sup> statistical analysis. Despite an upward genetic testing trend in 2010, we found no significant differences in genetic testing uptake over time. In 2010, non-White individuals experienced the highest increase from 2005 in comparison with White individuals. However, genetic testing rates declined for both groups by 2015. Our findings show that genetic testing for colorectal cancer and endometrial cancer did not increase over a 10-year period in spite of guidelines that recommend testing.</p><p><b>Prevention Relevance:</b> Genetic testing uptake for colorectal cancer and endometrial cancer has not increased over a 10-year period in spite of universal screening guidelines. More genetic testing education is needed at the provider and patient level to improve screening strategies for cancer patients who are most at risk for Lynch syndrome.</p></div>
Abstract Background Abdominal and thoracic aortic aneurysms (AAA; TAA) remain a large cause of deaths worldwide. This is in part a result of the lack of prognostic markers or early warning signs, leading to undiagnosed aortic aneurysms. Sox6 has been found to function as a regulator of renin expression controlling the rate limiting step in the renin angiotensin aldosterone system. We hypothesized that the transcription factor Sox6 may serve as an important regulator of mechanisms contributing to hypertension induced aortic aneurysms. Methods Our approach includes mRNA analysis, immunohistology staining, and protein expression studies in human samples from patients affected with AAA and TAA. In vivo, we use Angiotensin (II) to induce AAA in mice with a tamoxifen inducible Cre to specifically knock out Sox6 in smooth muscle cells. Additionally, we utilize large-scale biobank data linking de-identified medical records with genotype information to perform phenotype and laboratory-wide association scans to assess the effects of SOX6 expression in a clinical cohort. Results In a large biobank population, SOX6 gene expression is associated with aortic aneurysm in humans of European ancestry. Protein expression of Sox6 and TNFα was upregulated in tissue from patients affected by AAA and TAA. Moreover, we found that knocking out Sox6 in smooth muscle cells protected mice from hypertension-induced AAA, suggesting that Sox6 may be a molecular target in aortic aneurysms. Conclusions The data presented here suggest that the transcription factor Sox6 functions in the development of abdominal aortic aneurysms, and hypertension-induced rupture. Clinical Perspective Using electronic health records and biobank samples, we found that the transcription factor SOX6 is associated with abdominal and thoracic aortic aneurysm and its expression is upregulated in tissue from patients affected by those diseases. Laboratory-wide association study (LabWAS) provides several clinical laboratory measurements associated with aortic aneurysm diagnosis that may be potential biomarkers for the disease. Mice with smooth muscle-specific Sox6 knock out attenuated hypertension-induced abdominal aortic aneurysm. These novel mice may be useful tools to elucidate the mechanisms associated with abdominal aortic aneurysm.
Polycystic ovary syndrome (PCOS) is a complex multifactorial disorder with a substantial genetic component. However, the clinical manifestations of PCOS are heterogeneous with notable differences between lean and obese women, implying a different pathophysiology manifesting in differential body mass index (BMI). We performed a meta-analysis of genome-wide association study (GWAS) data from six well-characterised cohorts, using a case-control study design stratified by BMI, aiming to identify genetic variants associated with lean and overweight/obese PCOS subtypes.
Abstract Disclosure: A.G. Marshall: None. Z. Vue, PhD: None. E. Garza-Lopez: None. H. Beasley, PhD: None. V. Exil: None. K. Actkins: None. T. Miller-Fleming: None. A.O. Hinton: None. Heart failure (HF) is accompanied by symptoms and signs caused by cardiac dysfunction, resulting in reduced longevity. Critically, HF has been associated with mitochondria dysfunction, causing pathophysiology that might contribute to age-dependent decrease in cardiac function. Thus, we hypothesize that reduced cardiac function in response to HF, affects mitochondrial function and morphology. To test this, we investigated mitochondrial morphological changes using 3D reconstruction from 4 control human hearts and 4 human heart failure patients. Mitochondrial samples were 3D rendered and quantified using serial block facing-scanning electron microscopy and the Amira software. From our HF reconstructions, there are many phenotypes, including fragmentation, nanotunnels, and mitochondrial clustering, compared to controls, which may be associated to mitochondrial dysfunction. Surprisingly, we saw altered expression of CHCHD6 and CHCHD3 in human heart failure samples, based on immunofluorescence. Thus, we knocked out CHCHD6 and CHCHD3 in mouse fibroblasts, myotubes and human-induced pluripotent stem cell-derived cardiomyocytes and saw fragmentation in all three models. Presently, HF represents an unmet need with no approved clinical therapies for damaged myocardium replacement. Here, we suggest that CHCHD3 and CHCHD6 may be a molecular target that functions in the development of HF and possibly develop novel therapeutics for the treatment of HF. Presentation: Friday, June 16, 2023
Importance Leveraging real-world clinical biobanks to investigate the associations between genetic and environmental risk factors for mental illness may help direct clinical screening efforts and evaluate the portability of polygenic scores across environmental contexts. Objective To examine the associations between sexual trauma, polygenic liability to mental health outcomes, and clinical diagnoses of schizophrenia, bipolar disorder, and major depressive disorder in a clinical biobank setting. Design, Setting, and Participants This genetic association study was conducted using clinical and genotyping data from 96 002 participants across hospital-linked biobanks located at Vanderbilt University Medical Center (VUMC), Nashville, Tennessee (including 58 262 individuals with high genetic similarity to the 1000 Genomes Project [1KG] Northern European from Utah reference population [1KG-EU-clustered] and 11 047 with high genetic similarity to the 1KG African-ancestry reference population of Yoruba in Ibadan, Nigeria [1KG-YRI-clustered]), and Mass General Brigham (MGB), Boston, Massachusetts (26 693 individuals with high genetic similarity to the combined European-ancestry superpopulation [1KG-EU-clustered]). Clinical data analyzed included diagnostic billing codes and clinical notes spanning from 1976 to 2023. Data analysis was performed from 2022 to 2024. Exposures Clinically documented sexual trauma disclosures and polygenic scores for schizophrenia, bipolar disorder, and major depressive disorder. Main Outcomes and Measures Diagnoses of schizophrenia, bipolar disorder, and major depressive disorder, determined by aggregating related diagnostic billing codes, were the dependent variables in logistic regression models including sexual trauma disclosure status, polygenic scores, and their interactions as the independent variables. Results Across the VUMC and MGB biobanks, 96 002 individuals were included in analyses (VUMC 1KG-EU-clustered: 33 011 [56.7%] female; median [range] age, 56.8 [10.0 to &gt;89] years; MGB 1KG-EU-clustered: 14 647 [54.9%] female; median [range] age, 58.0 [10.0 to &gt;89] years; VUMC 1KG-YRI-clustered: 6961 [63.0%] female; median [range] age, 44.6 [10.1 to &gt;89] years). Sexual trauma history was associated with all mental health conditions across institutions (ORs ranged from 8.83 [95% CI, 5.50-14.18] for schizophrenia in the VUMC 1KG-YRI-clustered cohort to 17.65 [95% CI, 12.77-24.40] for schizophrenia in the VUMC 1KG-EU-clustered cohort). Sexual trauma history and polygenic scores jointly explained 3.8% to 8.8% of mental health phenotypic variance. Schizophrenia and bipolar disorder polygenic scores had greater associations with mental health outcomes in individuals with no documented disclosures of sexual trauma (schizophrenia interaction: OR, 0.70 [95% CI, 0.56-0.88]; bipolar disorder interaction: OR, 0.83 [95% CI, 0.74-0.94]). Conclusions and Relevance Sexual trauma and mental health polygenic scores, while correlated with one another, were independent and joint risk factors for severe mental illness in a large, diverse hospital biobank population. Furthermore, associations of schizophrenia and bipolar disorder polygenic scores with respective diagnoses were greater in those without disclosures, suggesting that genetic predisposition to mental illness as measured by polygenic scores may be less impactful in the presence of this severe environmental risk factor.
Abstract Polycystic ovary syndrome (PCOS) is a highly heterogenous reproductive endocrine disorder that affects up to 15% of women and is one of the leading causes of infertility. However, its genetic etiology remains poorly understood. Additionally, PCOS patients have a greater risk of having metabolic disorders, such as insulin resistance and cardiovascular diseases, but it is estimated that up to 75% of women remain undiagnosed. Delayed treatment and care can exacerbate comorbid conditions and be detrimental to high risk populations like African American and Hispanic women. We aim to characterize genetic and environmental variables contributing to PCOS and understand its shared etiological features with metabolic disorders. To do this, we developed two algorithms to identify diverse PCOS patients using medical records. The broad algorithm used a combination of PCOS-related billing codes (Code Based) and identified a large dataset (N = 8,340) who exhibited diverse PCOS symptoms, while the strict algorithm required PCOS keywords in addition to billing codes (Regex Based). The strict algorithm identified a smaller cohort of patients (N = 4,593) who exhibited more classically diagnoseable PCOS characteristics according to Rotterdam and NIH criteria. Using both datasets, we tested PCOS case status against 1,853 phenotypes in the medical database using a logistic regression model and identified comorbidity patterns for women of European and African descent. We observed that European descent women consistently had more distinct phenotypes associated with PCOS case status than African American women. Next, we examined the interacting effects of self-reported race on PCOS case status and found four significant phenotypes (p < 6.25e-4) in our Regex Based algorithm. African American women with PCOS had greater odds of being diagnosed with “Early onset of delivery” (p = 1.3e-4, OR = 1.86), “Hereditary hemolytic anemias” (p =1.8e-4, OR = 0.65), and “Other hereditary hemolytic anemias” (p = 3.7e-04, OR = 0.90). Meanwhile, European descent women had greater odds of being diagnosed with “Hypertensive chronic kidney disease” (p = 1.7e-04, OR = 0.68). Results show that European and African American women have unique metabolic comorbidity patterns and it may also indicate that clinical PCOS diagnostic standards vary between these groups with possible disparity-causing effects.
Cancer-induced hypercalcemia (CIH) is common in cancer patients with metastatic disease and in up to 30% of cases without metastasis. During malignancy, tumor cells secrete factors such as parathyroid hormone related protein (PTHrP) that causes the destruction of bone tissue, or osteolysis. The resulting persistent osteolysis leads to a progressive increase in systemic calcium or CIH. High circulating Ca2+ is sensed by the calcium-sensing receptor (CaSR), which plays a significant role in maintaining Ca2+ homeostasis, and also stimulates the secretion of PTHrP which promotes tumor cell proliferation and motility. Moreover, more than 200 mutations including single nucleotide polymorphisms (SNPs) in the CaSR gene have been described, including the inactivating A986S CaSR at rs1801725 and Q1011E CaSR at rs1801726 SNPs with reduced sensitivity to Ca2+ . Although the CaSR is the major cell surface Ca2+ sensor in most cell types, its function in the Ca2+ rich bone microenvironment remains unclear. We show that high Ca2+ adaptation of MDA-MB-231 cells, did not lead to altered expression of the receptor in the surviving cells. However, the receptor was desensitized to high Ca2+ and the cells were more motile and formed larger colonies in 3D cultures. Meanwhile, gene expression profiling of triple negative breast cancer cells (TNBC) cells transiently exposed to high Ca2+ reveals the expression of early response genes and Ca2+ -inducible genes with known functions in tumor growth and/or motility. Since breast cancer (BC) frequently metastasizes to skeletal tissues, these data suggest that BC cells that successfully colonize the bone microenvironment undergo high Ca2+ adaptation or priming via the expression of high Ca2+ inducible genes that facilitate cell growth and/or motility.Citation Format: Heather K. Beasley, Ky'Era V. Actkins, Sarrah E. Widatalla, Diva S. Whalen, Stephen D. Williams, Olga Y. Korolkova, Amos M. Sakwe. The role of the calcium-sensing receptor (CaSR) in the adaptation of breast cancer cells in high Ca2+ microenvironments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 133.
Abstract Clinical laboratory (lab) tests are used in clinical practice to diagnose, treat, and monitor disease conditions. Test results are typically stored in electronic health records (EHRs), and a growing number of EHRs are linked to patient DNA, offering unprecedented opportunities to query relationships between clinical lab tests and genetics. Clinical lab data, however, are of uneven quality, and previous studies have focused on a small number of lab traits. We present two methods, QualityLab and LabWAS, to clean and analyze EHR labs at scale in a Lab-Wide Association Scan. In a proof of concept analysis focused on blood lipids and coronary artery disease, we found that heritability estimates of QualityLab lipid values were comparable to previous reports; polygenic scores for lipids were strongly associated with the referent lipid in a LabWAS; and a LabWAS of a polygenic score for coronary artery disease recapitulated known heart disease biomarker profiles and identified novel associations. Our methods extend previous EHR-based analysis tools and increase the amount of EHR data usable for discovery.
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