Association of varicose veins with rare protein-truncating variants in PIEZO1 identified by exome sequencing of a large clinical population.

OBJECTIVE: The present study sought to determine whether protein-truncating variants (PTVs) in PIEZO1 and CASZ1 genes, previously shown to be associated with varicose veins, were associated with an altered risk of varicose veins. METHODS: An exome sequence database of 131,918 participants from the Geisinger MyCode Community Health Initiative was used to identify individuals with genetic variants in the PIEZO1 or CASZ1 gene. Clinical phenotypes, including varicose vein diagnoses, were determined by analysis of the electronic health record data. RESULTS: We identified 12,531 individuals (9.5%) with a diagnosis of varicose veins. Exome sequence data identified 92 PIEZO1 PTVs in 305 heterozygous carriers. PIEZO1 PTVs were significantly enriched in those with varicose vein (0.37% of cases vs 0.22% of controls; odds ratio [OR], 1.7; P = .0010). Nearly all varicose vein cases were associated with frameshift or stop-gain PTVs (OR, 3.0 for stop-gain [P = .0001]; OR, 2.9 for frameshift variants [P < .0001]). In the varicose vein cases, the PTV carriers were more likely to have an encounter with a vascular surgeon (62.5% for PTV carriers; 36.9% for noncarriers; P = .0003) and more likely to have received vein ablation therapy (OR, 6.9; P < .0001). No association was found between PIEZO1 PTVs and lymphedema, and no association was found for rare missense variants in PIEZO1 with varicose veins. PTVs in CASZ1 were extremely rare (16 total carriers), with none identified in those with varicose vein. CONCLUSIONS: Rare PTVs in PIEZO1 but not CASZ1 were associated with varicose veins and the need for vein ablation therapy. These results have demonstrated that PTVs in the PIEZO1 gene are rare but represent strong genetic risk factors for varicose veins and the need for vein ablation therapy. These results have also identified a potential biologic mechanism and target for the development of novel therapies.

Systematic characterization of germline variants from the DiscovEHR study endometrial carcinoma population.

BACKGROUND: Endometrial cancer (EMCA) is the fifth most common cancer among women in the world. Identification of potentially pathogenic germline variants from individuals with EMCA will help characterize genetic features that underlie the disease and potentially predispose individuals to its pathogenesis. METHODS: The Geisinger Health System's (GHS) DiscovEHR cohort includes exome sequencing on over 50,000 consenting patients, 297 of whom have evidence of an EMCA diagnosis in their electronic health record. Here, rare variants were annotated as potentially pathogenic. RESULTS: Eight genes were identified as having increased burden in the EMCA cohort relative to the non-cancer control cohort. None of the eight genes had an increased burden in the other hormone related cancer cohort from GHS, suggesting they can help characterize the underlying genetic variation that gives rise to EMCA. Comparing GHS to the cancer genome atlas (TCGA) EMCA germline data illustrated 34 genes with potentially pathogenic variation and eight unique potentially pathogenic variants that were present in both studies. Thus, similar germline variation among genes can be observed in unique EMCA cohorts and could help prioritize genes to investigate for future work. CONCLUSION: In summary, this systematic characterization of potentially pathogenic germline variants describes the genetic underpinnings of EMCA through the use of data from a single hospital system.

Correction to: Systematic characterization of germline variants from the DiscovEHR study endometrial carcinoma population.

Following publication of the original article [1], the authors reported that Fig. 1 was not correctly processed during the production process. The correct Fig. 1 is given below.

Clinical Characteristics of Roux-en-Y Gastric Bypass Patients with Death from Accidental Overdose or Intentional Self-Harm: a Descriptive Study.

PURPOSE: The objective of this descriptive study was to identify clinical characteristics of Roux-en-Y gastric bypass (RYGB) patients who died from intentional self-harm or accidental overdose postoperatively. MATERIALS AND METHODS: This retrospective, descriptive study included RYGB patients from a large rural medical center that completed surgery between January 2004 and December 2014 and died from intentional self-harm or accidental overdose through December 2015. Specific causes of death were obtained from the National Death Index and clinical data from electronic health records. Clinical characteristics explored were age, sex, time to surgery, weight loss expectations, postoperative weight loss, medication, diagnoses, psychiatric histories (diagnoses, self-harm, suicidal ideation and behaviors, medications, substance use, preoperative Beck Depression Inventory-II scores), pain, social support, and reported life stressors. RESULTS: Overall, 22 patients of 146 total deceased patients died from intention self-harm (n = 6) or accidental overdose (n = 16) over the study period (77.3% female, mean age at time of surgery = 38.4 ± 9.1 years). Younger age (< 40 years), history of self-harm or depression, preoperative pain, and use of opioids at the time of surgery emerged as common characteristics in weight loss surgery patients who died from intentional self-harm or accidental overdose. No trends regarding social support, life stressors, or actual or expected weight loss were identified. CONCLUSION: Certain weight loss surgery patients may be at risk for death from self-harm or overdose and may benefit from greater surveillance postoperatively.

Bariatric Surgery Patients and Their Families: Health, Physical Activity, and Social Support.

BACKGROUND: This study evaluated the social environment of bariatric surgery patients in the preoperative period. METHODS: Forty bariatric surgery patients (mean = 46.2 ± 11.2 years), 35 adult cohabitating family members (mean = 45.2 ± 12.7 years), and 15 cohabitating children (mean = 11.5 ± 3.6 years) were recruited from a large rural medical center. Adult participants (patients and family members) completed height, weight, body composition, blood draws, and physical activity assessments (accelerometry), as well as eating behavior and social support inventories before the patient underwent bariatric surgery. Child participants completed demographic, height, and weight assessment only. RESULTS: Over 90 % of adult family members were overweight or obese (body mass index (BMI) ≥ 25 kg/m2, as were 50 % of children (BMI percentile ≥ 85 %). More than one third (37.1 %) of family members met the criteria for moderate to severe insulin resistance. Physical activity measured by accelerometry was moderately correlated between the patient and adult family members (r = 0.46, p = 0.023). Bariatric surgery patients reported high levels of social support from their family members on multiple social support measures. CONCLUSIONS: Many family members of bariatric surgery patients also lived with obesity and related comorbidities, and demonstrate high sedentary behavior. However, patients reported high levels of support from family members, including support in following a healthy diet and engaging in physical activity. Engaging families in behavior change may help bariatric surgery patients and their families to become healthier.

Mixed evidence for reduced local adaptation in wild salmon resulting from interbreeding with escaped farmed salmon: complexities in hybrid fitness.

Interbreeding between artificially-selected and wild organisms can have negative fitness consequences for the latter. In the Northwest Atlantic, farmed Atlantic salmon recurrently escape into the wild and enter rivers where small, declining populations of wild salmon breed. Most farmed salmon in the region derive from an ancestral source population that occupies a nonacidified river (pH 6.0-6.5). Yet many wild populations with which escaped farmed salmon might interbreed inhabit acidified rivers (pH 4.6-5.2). Using common garden experimentation, and examining two early-life history stages across two generations of interbreeding, we showed that wild salmon populations inhabiting acidified rivers had higher survival at acidified pH than farmed salmon or F1 farmed-wild hybrids. In contrast, however, there was limited evidence for reduced performance in backcrosses, and F2 farmed-wild hybrids performed better or equally well to wild salmon. Wild salmon also survived or grew better at nonacidified than acidified pH, and wild and farmed salmon survived equally well at nonacidified pH. Thus, for acid tolerance and the stages examined, we found some evidence both for and against the theory that repeated farmed-wild interbreeding may reduce adaptive genetic variation in the wild and thereby negatively affect the persistence of depleted wild populations.