Leptin-Melanocortin pathway variants and gastric emptying in patients with obesity.

BACKGROUND: Accelerated gastric emptying (GE) is a trait seen in obesity. Mutations in the hypothalamic leptin-melanocortin 4 receptor (Leptin-MC4R) pathway have been associated with obesity. We sought to investigate the association of leptin-MC4R pathway variants and GE in patients with obesity. METHODS: This is a cross-sectional study of patients with a history of severe obesity that were genotyped and completed a GE test by scintigraphy. We evaluated the percentage of GE (GE %) at 2 and 4 h between both groups using ANCOVA with weight and sex as covariates. We subdivide patients into carriers based on the location of the identified variants (i.e., upstream or downstream of the Leptin-MC4R pathway) and compared them with noncarriers using ANOVA. Results are presented as mean and standard deviation (± SD). KEY RESULTS: A total of 95 patients; nine carriers (67% females; 39.78 ± 12.33 years; BMI: 49.14 ± 12.96 kg/m2) and 86 noncarriers (87% female; 49.98 ± 13.74 years; BMI: 40.75 ± 6.29 kg/m2) were included. At 2 and 4 h, carriers had a delayed GE when compared noncarriers (p = 0.03 and p = 0.005, respectively). In carriers, when compared upstream carriers vs. downstream carriers vs. noncarriers by location there was a significant difference in GE among groups at 2 h and at 4 h (p = 0.02 and p = 0.01, respectively). CONCLUSIONS & INFERENCES: Carriers of heterozygous variants in the Leptin-MC4R pathway had a delayed GE compared to noncarriers. These findings point the important relationship between the Leptin-MC4R pathway and gastric motility.

Type 2 Diabetes Remission in Patients with Heterozygous Variants in the Leptin-Melanocortin Pathway after Roux-en-Y Gastric Bypass: A Matched Case-Control Study.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) is associated with a high rate of type 2 diabetes (T2D) remission. Carriers of heterozygous variants in the leptin-melanocortin pathway (LMP) are more likely to experience weight recurrence after RYGB. Our aim was to investigate if carrier status and associated weight regain affects the rate of T2D remission after RYGB. METHODS: Carriers of LMP variants with a diagnosis of T2D prior to RYGB (N = 16) were matched to non-carriers (N = 32) based on sex, age, and BMI. We assessed for post-operative T2D remission status post-surgery on a yearly basis, for up to 15 years. Our primary endpoint was the proportion of patients achieving T2D remission at 1 year. We conducted a survival analysis for all patients that achieved remission at least at one time-point to evaluate for maintenance of T2D remission by using a log-rank test. RESULTS: Both carriers and non-carriers had similar baseline and procedural characteristics. The proopiomelanocortin gene in the LMP pathway had the most variants (n = 5, 31%). Carriers had a lower total body weight loss percentage at nadir (28.7% ± 6.9) than non-carriers (33.7% ± 8.8, p = 0.04). The proportion of patients achieving T2D remission at 1 year was 68.8% for carriers and 71.9% for non-carriers (p = 1.0). Survival curves for maintenance of first remission were similar for both groups (p = 0.73), with a median survival of 8 years for both carriers and non-carriers. CONCLUSIONS: Despite inferior weight loss outcomes at nadir, carriers had similar T2D remission rates when compared to non-carriers. Weight-independent metabolic benefits of RYGB might contribute to this observation.

Paired Indoor and Outdoor Nitrogen Dioxide Associated With Childhood Asthma Outcomes in a Mixed Rural-Urban Setting: A Feasibility Study.

INTRODUCTION: Nitrogen dioxide (NO2) is known to be a trigger for asthma exacerbation. However, little is known about the role of seasonal variation in indoor and outdoor NO2 levels in childhood asthma in a mixed rural-urban setting of North America. METHODS: This prospective cohort study, as a feasibility study, included 62 families with children (5-17 years) that had diagnosed persistent asthma residing in Olmsted County, Minnesota. Indoor and outdoor NO2 concentrations were measured using passive air samples over 2 weeks in winter and 2 weeks in summer. We assessed seasonal variation in NO2 levels in urban and rural residential areas and the association with asthma control status collected from participants' asthma diaries during the study period. RESULTS: Outdoor NO2 levels were lower (median: 2.4 parts per billion (ppb) in summer, 3.9 ppb in winter) than the Environmental Protection Agency (EPA) annual standard (53 ppb). In winter, a higher level of outdoor NO2 was significantly associated with urban residential living area (P = .014) and lower socioeconomic status (SES) (P = .027). For both seasons, indoor NO2 was significantly higher (P < .05) in rural versus urban areas and in homes with gas versus electric stoves (P < .05). Asthma control status was not associated with level of indoor or outdoor NO2 in this cohort. CONCLUSIONS: NO2 levels were low in this mixed rural-urban community and not associated with asthma control status in this small feasibility study. Further research with a larger sample size is warranted for defining a lower threshold of NO2 concentration with health effect on asthma in mixed rural-urban settings.

Cardiovascular Risk and Diseases in Patients With and Without Leptin-Melanocortin Pathway Variants.

OBJECTIVE: To study differences in cardiovascular risk factors and diseases between patients with and without genetic variants in the leptin-melanocortin pathway. METHODS: A cross-sectional study of patients with a history of severe obesity genotyped in June 2019 as participants of the Mayo Clinic Biobank was conducted in March 2022 to assess differences in cardiovascular risk and diseases between carriers of a heterozygous variant in the leptin-melanocortin pathway and noncarriers. Cardiovascular risk factors included hypertension, diabetes, dyslipidemia, and smoking. Cardiovascular disease includes coronary artery disease, peripheral artery disease, and cerebrovascular accidents. Patients with a history of bariatric surgery were excluded. We used logistic regression models to estimate the odds ratio and 95% CI, adjusting for age, body mass index (BMI), and sex. RESULTS: Among a total of 168 carriers (8%; 121 [72%] female; mean [SD] age, 65.1 [14.9] years; BMI, 44.0 [7.4] kg/m2) and 2039 noncarriers (92%; 1446 [71%] female; mean [SD] age, 64.9 [14.4] years; BMI, 42.9 [6.6] kg/m2), carriers had higher prevalence odds of hypertension (odds ratio, 3.26; 95% CI, 2.31 to 4.61; P<.001) and reported higher number of cardiovascular risk factors compared with noncarriers (2.4 [1.1] vs 2.0 [1.1]; P<.001). There were no significant differences in the adjusted odds associated with diabetes, dyslipidemia, smoking, or cardiovascular disease. CONCLUSION: Despite having similar body weight and BMI, carriers of heterozygous variants in the leptin-melanocortin pathway had higher rates of hypertension than noncarriers. These findings point to an association between hypertension and leptin-melanocortin pathway variants.

Effects of Heterozygous Variants in the Leptin-Melanocortin Pathway on Roux-en-Y Gastric Bypass Outcomes: a 15-Year Case-Control Study.

INTRODUCTION: Heterozygous variants in the leptin-melanocortin pathway are associated with obesity. However, their effect on the long-term outcomes after Roux-en-Y gastric bypass (RYGB) is still unknown. METHODS: In this matched case-control study, 701 participants from the Mayo Clinic Biobank with a history of RYGB were genotyped. Sixty-three patients had a heterozygous variant in the leptin-melanocortin pathway. After excluding patients with potential confounders, carriers were randomly matched (on sex, age, body mass index [BMI], and years since surgery) with two non-carrier controls. The electronic medical record of carriers and matched non-carriers was reviewed for up to 15 years after RYGB. RESULTS: A total of 50 carriers and 100 matched non-carriers with a history of RYGB were included in the study. Seven different genes (LEPR, PCSK1, POMC, SH2B1, SRC1, MC4R, and SIM1) in the leptin-melanocortin pathway were identified. At the time of surgery, the mean age was 50.8 ± 10.6 years, BMI 45.6 ± 7.3 kg/m2, and 79% women. There were no differences in postoperative years of follow-up, Roux limb length, or gastric pouch size between groups. Fifteen years after RYGB, the percentage of total body weight loss (%TBWL) in carriers was - 16.6 ± 10.7 compared with - 28.7 ± 12.9 in non-carriers (diff = 12.1%; 95% CI, 4.8 to 19.3) and the percentage of weight regain after maximum weight loss was 52.7 ± 29.7 in carriers compared with 29.8 ± 20.7 in non-carriers (diff = 22.9%; 95% CI, 5.3 to 40.5). The nadir %TBWL was lower - 32.1 ± 8.1 in carriers compared with - 36.8 ± 10.4 in non-carriers (diff = 4.8%; 95% CI 1.8 to 7.8). CONCLUSIONS: Carriers of a heterozygous variant in the leptin-melanocortin pathway have a progressive and significant weight regain in the mid- and long-term after RYGB. Genotyping patients experiencing significant weight regain after RYGB could help implement multidisciplinary and individualized weight loss interventions to improve weight maintenance after surgery.

Role of geographic risk factors and social determinants of health in COVID-19 epidemiology: Longitudinal geospatial analysis in a midwest rural region.

Background: Studies examining the role of geographic factors in coronavirus disease-2019 (COVID-19) epidemiology among rural populations are lacking. Methods: Our study is a population-based longitudinal study based on rural residents in four southeast Minnesota counties from March through October 2020. We used a kernel density estimation approach to identify hotspots for COVID-19 cases. Temporal trends of cases and testing were examined by generating a series of hotspot maps during the study period. Household/individual-level socioeconomic status (SES) was measured using the HOUSES index and examined for association between identified hotspots and SES. Results: During the study period, 24,243 of 90,975 residents (26.6%) were tested for COVID-19 at least once; 1498 (6.2%) of these tested positive. Compared to other rural residents, hotspot residents were overall younger (median age: 40.5 vs 43.2), more likely to be minorities (10.7% vs 9.7%), and of higher SES (lowest HOUSES [SES] quadrant: 14.6% vs 18.7%). Hotspots accounted for 30.1% of cases (14.5% of population) for rural cities and 60.8% of cases (27.1% of population) for townships. Lower SES and minority households were primarily affected early in the pandemic and higher SES and non-minority households affected later. Conclusion: In rural areas of these four counties in Minnesota, geographic factors (hotspots) play a significant role in the overall burden of COVID-19 with associated racial/ethnic and SES disparities, of which pattern differed by the timing of the pandemic (earlier in pandemic vs later). The study results could more precisely guide community outreach efforts (e.g., public health education, testing/tracing, and vaccine roll out) to those residing in hotspots.

Body mass index and blood pressure in bipolar patients: Target cardiometabolic markers for clinical practice.

OBJECTIVE: To evaluate the association between cardiometabolic markers and bipolar disorder (BD), examining the impact of sex and cardiometabolic medication use, from a large case-control biorepository of more than 1300 participants. PATIENTS AND METHODS: Recruited from July 2009 through September 2017, cardiometabolic markers were harvested from electronic health records (EHR) of participants (n=661) from the Mayo Clinic Individualized Medicine Biobank for Bipolar Disorder and Mayo Clinic Biobank age-sex-matched controls (n=706). Markers were compared between cases and controls using logistic regression, stratified by sex, adjusting for cardiometabolic medications and current smoking status. We studied the effect of psychotropics in case-only analyses. RESULTS: The mean age of the sample was 52.5 ± 11.6 years and 55% were female. BD patients had higher rates of smoking, but lower utilization of lipid-lowering medication compared with controls. After adjustment, BD was associated with obesity [Odds ratio (CI) 1.62 (1.22-2.15)], elevated systolic blood pressure (SBP) [2.18 (1.55-3.06)] and elevated triglycerides [1.58 (1.13-2.2)]. When stratified by sex, obesity [1.8 (1.23-2.66)] and systolic blood pressure [2.32 (1.46-3.7)] were associated with BD females compared to female controls; however, only systolic blood pressure [2.04 (1.23-3.42)] was associated with male bipolars compared to male controls. Psychotropics were marginally associated with mean BMI, abnormal triglycerides, and HbA1c. LIMITATIONS: EHR cross-sectional data CONCLUSION: To our knowledge, this is the largest case controlled study to date to explore the association between cardiometabolic markers and bipolar disorder adjusting for utilization of cardiometabolic medication. Identification of significant, non-laboratory based cardiometabolic markers that are associated with increased risk of major cardiovascular adverse events in patients with bipolar disorder, underscores, both the utility and importance of risk monitoring that can be easily done in community mental health centers.

Characteristics and utilisation of the Mayo Clinic Biobank, a clinic-based prospective collection in the USA: cohort profile.

PURPOSE: The Mayo Clinic Biobank was established to provide a large group of patients from which comparison groups (ie, controls) could be selected for case-control studies, to create a prospective cohort with sufficient power for common outcomes and to support electronic health record (EHR) studies. PARTICIPANTS: A total of 56 862 participants enrolled (21% response rate) into the Mayo Clinic Biobank from Rochester, Minnesota (77%, n=43 836), Jacksonville, Florida (18%, n=10 368) and La Crosse, Wisconsin (5%, n=2658). Participants were all Mayo Clinic patients, 18 years of age or older and US residents. FINDINGS TO DATE: Overall, 43% of participants were 65 years of age or older and female participants were more frequent (59%) than males at all sites. Most participants resided in the Upper Midwest regions of the USA (Minnesota, Iowa, Illinois or Wisconsin), Florida or Georgia. Self-reported race among Biobank participants was 90% white. Here we provide examples of the types of studies that have successfully utilised the resource, including (1) investigations of the population itself, (2) provision of controls for case-control studies, (3) genotype-driven research, (4) EHR-based research and (5) prospective recruitment to other studies. Over 270 projects have been approved to date to access Biobank data and/or samples; over 200 000 sample aliquots have been approved for distribution. FUTURE PLANS: The data and samples in the Mayo Clinic Biobank can be used for various types of epidemiological and clinical studies, especially in the setting of case-control studies for which the Biobank samples serve as control samples. We are planning cohort studies with additional follow-up and acquisition of genetic information on a large scale.

Acceptability of Electronic Visits for Return of Research Results in the Mayo Clinic Biobank.

OBJECTIVE: To understand patient characteristics related to acceptability of returning individual research results via various modalities, focusing on electronic visits (e-visits). PATIENTS AND METHODS: Twelve hundred participants from the Mayo Clinic Biobank were selected using a stratified random sampling approach based on sex, age, and education level. Mailed surveys ascertained return of results preferences for 2 disease vignettes (cystic fibrosis and hereditary breast cancer) and a pharmacogenomics vignette. The study was conducted from October 1, 2013, through March 31, 2014. RESULTS: In all, 685 patients (57%) responded, and 60% reported liking e-visits, although the option of receiving results in an office visit was liked most frequently. Multivariable logistic models showed that the odds of liking the use of e-visits for returning results for cystic fibrosis and hereditary breast cancer were higher among those with higher education and better genetic knowledge and among those not living in proximity to the Mayo Clinic (Rochester, Minnesota). Level of genetic knowledge was not considerably associated with accepting e-visits, whereas education level remained important. For all vignettes, those who are divorced were less likely to accept e-visits. CONCLUSION: Researchers are faced with a difficult challenge of returning results with a method that is both acceptable to recipients and logistically feasible. This study implies that the use of e-visits may be a viable option for return of results to stratify the chasm between in-person genetic counseling and online portal receipt of results.