Nkx2-5 and Sarcospan genetically interact in the development of the muscular ventricular septum of the heart

The muscular ventricular septum separates the flow of oxygenated and de-oxygenated blood in air-breathing vertebrates. Defects within it, termed muscular ventricular septal defects (VSDs), are common, yet less is known about how they arise than rarer heart defects. Mutations of the cardiac transcription factor NKX2-5 cause cardiac malformations, including muscular VSDs. We describe here a genetic interaction between Nkx2-5 and Sarcospan (Sspn) that affects the risk of muscular VSD in mice. Sspn encodes a protein in the dystrophin-glycoprotein complex. Sspn knockout (Sspn(KO)) mice do not have heart defects, but Nkx2-5(+/−)/Sspn(KO) mutants have a higher incidence of muscular VSD than Nkx2-5(+/−) mice. Myofibers in the ventricular septum follow a stereotypical pattern that is disrupted around a muscular VSD. Subendocardial myofibers normally run in parallel along the left ventricular outflow tract, but in the Nkx2-5(+/−)/Sspn(KO) mutant they commonly deviate into the septum even in the absence of a muscular VSD. Thus, Nkx2-5 and Sspn act in a pathway that affects the alignment of myofibers during the development of the ventricular septum. The malalignment may be a consequence of a defect in the coalescence of trabeculae into the developing ventricular septum, which has been hypothesized to be the mechanistic basis of muscular VSDs

The genetic architecture of a congenital heart defect Is related to Its fitness cost

In newborns, severe congenital heart defects are rarer than mild ones. This epidemiological relationship between heart defect severity and incidence lacks explanation. Here, an analysis of ~10,00

Prevalence of 12 Common Health Conditions in Sexual and Gender Minority Participants in the All of Us Research Program

Importance: Limited data describe the health status of sexual or gender minority (SGM) people due to inaccurate and inconsistent ascertainment of gender identity, sex assigned at birth, and sexual orientation. Objective: To evaluate whether the prevalence of 12 health conditions is higher among SGM adults in the All of Us Research Program data compared with cisgender heterosexual (non-SGM) people. Design, setting, and participants: This cross-sectional study used data from a multidisciplinary research consortium, the All of Us Research Program, that links participant-reported survey information to electronic health records (EHR) and physical measurements. In total, 372 082 US adults recruited and enrolled at an All of Us health care provider organization or by directly visiting the enrollment website from May 31, 2017, to January 1, 2022, and were assessed for study eligibility. Exposures: Self-identified gender identity and sexual orientation group. Main outcomes and measures: Twelve health conditions were evaluated: 11 using EHR data and 1, body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), using participants' physical measurements. Logistic regression (adjusting for age, income, and employment, enrollment year, and US Census division) was used to obtain adjusted odds ratios (AORs) for the associations between each SGM group and health condition compared with a non-SGM reference group. Results: The analytic sample included 346 868 participants (median [IQR] age, 55 [39-68] years; 30 763 [8.9%] self-identified as SGM). Among participants with available BMI (80.2%) and EHR data (69.4%), SGM groups had higher odds of anxiety, depression, HIV diagnosis, and tobacco use disorder but lower odds of cardiovascular disease, kidney disease, diabetes, and hypertension. Estimated associations for asthma (AOR, 0.39 [95% CI, 0.24-0.63] for gender diverse people assigned male at birth; AOR, 0.51 [95% CI, 0.38-0.69] for transgender women), a BMI of 25 or higher (AOR, 1.65 [95% CI, 1.38-1.96] for transgender men), cancer (AOR, 1.15 [95% CI, 1.07-1.23] for cisgender sexual minority men; AOR, 0.88 [95% CI, 0.81-0.95] for cisgender sexual minority women), and substance use disorder (AOR, 0.35 [95% CI, 0.24-0.52] for gender diverse people assigned female at birth; AOR, 0.65 [95% CI, 0.49-0.87] for transgender men) varied substantially across SGM groups compared with non-SGM groups. Conclusions and relevance: In this cross-sectional analysis of data from the All of Us Research Program, SGM participants experienced health inequities that varied by group and condition. The All of Us Research Program can be a valuable resource for conducting health research focused on SGM people.</p

Design and Implementation of the All of Us Research Program COVID-19 Participant Experience (COPE) Survey

In response to the rapidly evolving COVID-19 pandemic, the All of Us Research Program longitudinal cohort study developed the COVID-19 Participant Experience (COPE) survey to better understand the pandemic experiences and health impacts of COVID-19 on diverse populations within the United States. Six survey versions were deployed between May 2020 and March 2021 covering mental health, loneliness, activity, substance use, and discrimination, as well as COVID-19 symptoms, testing, treatment, and vaccination. A total of 104,910 All of Us Research Program participants, of whom over 73% were from communities traditionally underrepresented in biomedical research, completed 275,201 surveys; 9,693 completed all six surveys. Response rates varied widely among demographic groups and were lower among participants from certain racial and ethnic minority populations, participants with low income or educational attainment, and participants with a Spanish language preference. Survey modifications improved participant response rates between the first and last surveys (13.9% to 16.1%, p \u3c 0.001). This paper describes a dataset with longitudinal COVID-19 survey data in a large, diverse population that will enable researchers to address important questions related to the pandemic, a dataset which is of additional scientific value when combined with the program\u27s other data sources