Analyses of potential causal contributors to increased waist/hip ratio-associated cardiometabolic disease: A combined and sex-stratified Mendelian randomization study.

BACKGROUND: Increased waist/hip ratio (WHR) contributes to type 2 diabetes, fatty liver, dyslipidaemia, hypertension and coronary artery disease, with potential sex-differential effects. Postulated mediators include increased lipid flux, branched-chain amino acids, glycine and glycoprotein acetyl, but their relative contributions and sex-specific impact on WHR-associated cardiometabolic disease (CMD) are not established. METHODS: We therefore undertook combined and sex-stratified Mendelian randomization (MR) to assess the relative causal contributions of these mediators to WHR-associated CMD using summary statistics from the largest genome-wide association studies in European ancestries. RESULTS: In sex-combined MR analyses, increased WHR significantly reduces high-density lipoprotein (beta = -0.416, SE = 0.029, p = 2.87E-47), increases triglyceride (beta = 0.431, SE = 0.029, p = 1.87E-50), type 2 diabetes (odds ratio = 2.747, SE = 0.09, p = 26E-23), coronary artery disease (odds ratio = 1.478, SE = 0.045, p = 6.96E-18), alanine transaminase (beta = 0.062, SE = 0.004, p = 6.88E-67), and systolic (beta = 0.134, SE = 0.022, p = 7.81E-10) and diastolic blood pressure (beta = 0.162, SE = 0.026, p = 5.38E-10). Adjustment for the mediators attenuated WHR's effects, but the associations remained significant with concordant results in females. In males, a similar pattern was seen, except after adjusting for the effect of the ratio of monounsaturated fatty acid to total free fatty acid, the potential causal effect of WHR was no longer significant: high-density lipoprotein (beta = -0.117, SE = 0.069, p = .09) and triglyceride (beta = 0.051, SE = 0.068, p = .459). CONCLUSIONS: MR suggests WHR increases the risk of CMD independent of these mediators, with the exception of dyslipidaemia in males, which is largely driven by the monounsaturated fatty acid to total free fatty acid ratio.

Erythritol as a Potential Causal Contributor to Cardiometabolic Disease: A Mendelian Randomization Study.

People with type 2 diabetes frequently use low-calorie sweeteners to manage glycemia and reduce caloric intake. Use of erythritol, a low-calorie sweetener, has increased recently. Higher circulating concentration associates with major cardiac events and metabolic disease in observational data, prompting some concern. As observational data may be prone to confounding and reverse causality, we undertook bidirectional Mendelian randomization (MR) to investigate potential causal associations between erythritol and coronary artery disease (CAD), BMI, waist-hip-ratio (WHR), and glycemic and renal traits in cohorts of European ancestry. Analyses were undertaken using instruments comprising genome-wide significant variants from three cohorts with erythritol measurement. Across instruments, we did not find supportive evidence that increased erythritol increases CAD (b = -0.033 ± 0.02, P = 0.14; b = 0.46 ± 0.37, P = 0.23). MR indicates erythritol may decrease BMI (b = -0.04 ± 0.018, P = 0.03; b = -0.04 ± 0.0085, P = 1.23 × 10-5; b = -0.083 ± 0.092, P = 0.036), with potential evidence from one instrument of increased BMI adjusted for WHR (b = 0.046 ± 0.022, P = 0.035). No evidence of causal association was found with other traits. In conclusion, we did not find supportive evidence from MR that erythritol increases cardiometabolic disease. These findings await confirmation in well-designed prospective studies.

Investigating the association between fasting insulin, erythrocytosis and HbA1c through Mendelian randomization and observational analyses.

Background: Insulin resistance (IR) with associated compensatory hyperinsulinemia (HI) are early abnormalities in the etiology of prediabetes (preT2D) and type 2 diabetes (T2D). IR and HI also associate with increased erythrocytosis. Hemoglobin A1c (HbA1c) is commonly used to diagnose and monitor preT2D and T2D, but can be influenced by erythrocytosis independent of glycemia. Methods: We undertook bidirectional Mendelian randomization (MR) in individuals of European ancestry to investigate potential causal associations between increased fasting insulin adjusted for BMI (FI), erythrocytosis and its non-glycemic impact on HbA1c. We investigated the association between the triglyceride-glucose index (TGI), a surrogate measure of IR and HI, and glycation gap (difference between measured HbA1c and predicted HbA1c derived from linear regression of fasting glucose) in people with normoglycemia and preT2D. Results: Inverse variance weighted MR (IVWMR) suggested that increased FI increases hemoglobin (Hb, b=0.54 ± 0.09, p=2.7 x 10-10), red cell count (RCC, b=0.54 ± 0.12, p=5.38x10-6) and reticulocyte (RETIC, b=0.70 ± 0.15, p=2.18x10-6). Multivariable MR indicated that increased FI did not impact HbA1c (b=0.23 ± 0.16, p=0.162) but reduced HbA1c after adjustment for T2D (b=0.31 ± 0.13, p=0.016). Increased Hb (b=0.03 ± 0.01, p=0.02), RCC (b=0.02 ± 0.01, p=0.04) and RETIC (b=0.03 ± 0.01, p=0.002) might modestly increase FI. In the observational cohort, increased TGI associated with decreased glycation gap, (i.e., measured HbA1c was lower than expected based on fasting glucose, (b=-0.09 ± 0.009, p<0.0001)) in people with preT2D but not in those with normoglycemia (b=0.02 ± 0.007, p<0.0001). Conclusions: MR suggests increased FI increases erythrocytosis and might potentially decrease HbA1c by non-glycemic effects. Increased TGI, a surrogate measure of increased FI, associates with lower-than-expected HbA1c in people with preT2D. These findings merit confirmatory studies to evaluate their clinical significance.

Association Between Obesity and Chronic Kidney Disease: Multivariable Mendelian Randomization Analysis and Observational Data From a Bariatric Surgery Cohort.

Obesity is postulated to independently increase chronic kidney disease (CKD), even after adjusting for type 2 diabetes (T2D) and hypertension. Dysglycemia below T2D thresholds, frequently seen with obesity, also increases CKD risk. Whether obesity increases CKD independent of dysglycemia and hypertension is unknown and likely influences the optimal weight loss (WL) needed to reduce CKD. T2D remission rates plateau with 20-25% WL after bariatric surgery (BS), but further WL increases normoglycemia and normotension. We undertook bidirectional inverse variance weighted Mendelian randomization (IVWMR) to investigate potential independent causal associations between increased BMI and estimated glomerular filtration rate (eGFR) in CKD (CKDeGFR) (<60 mL/min/1.73 m2) and microalbuminuria (MA). In 5,337 BS patients, we assessed whether WL influences >50% decline in eGFR (primary outcome) or CKD hospitalization (secondary outcome), using <20% WL as a comparator. IVWMR results suggest that increased BMI increases CKDeGFR (b = 0.13, P = 1.64 × 10-4; odds ratio [OR] 1.14 [95% CI 1.07, 1.23]) and MA (b = 0.25; P = 2.14 × 10-4; OR 1.29 [1.13, 1.48]). After adjusting for hypertension and fasting glucose, increased BMI did not significantly increase CKDeGFR (b = -0.02; P = 0.72; OR 0.98 [0.87, 1.1]) or MA (b = 0.19; P = 0.08; OR 1.21 [0.98, 1.51]). Post-BS WL significantly reduced the primary outcome with 30 to <40% WL (hazard ratio [HR] 0.53 [95% CI 0.32, 0.87]) but not 20 to <30% WL (HR 0.72 [0.44, 1.2]) and ≥40% WL (HR 0.73 [0.41, 1.30]). For CKD hospitalization, progressive reduction was seen with increased WL, which was significant for 30 to <40% WL (HR 0.37 [0.17, 0.82]) and ≥40% WL (HR 0.24 [0.07, 0.89]) but not 20 to <30% WL (HR 0.60 [0.29, 1.23]). The data suggest that obesity is likely not an independent cause of CKD. WL thresholds previously associated with normotension and normoglycemia, likely causal mediators, may reduce CKD after BS.

Insulin Response to Oral Glucose and Cardiometabolic Disease: A Mendelian Randomization Study to Assess Potential Causality.

Mendelian randomization (MR) suggests that postprandial hyperinsulinemia (unadjusted for plasma glucose) increases BMI, but its impact on cardiometabolic disease, a leading cause for mortality and morbidity in people with obesity, is not established. Fat distribution i.e., increased centripetal and/or reduced femoro-gluteal adiposity, is causally associated with and better predicts cardiometabolic disease than BMI. We therefore undertook bidirectional MR to assess the effect of corrected insulin response (CIR) (insulin 30 min after a glucose challenge adjusted for plasma glucose) on BMI, waist-to-hip ratio (WHR), leg fat, type 2 diabetes (T2D), triglyceride (TG), HDL, liver fat, hypertension (HTN), and coronary artery disease (CAD) in people of European descent. Inverse variance-weighted MR suggests a potential causal association between increased CIR and increased BMI (b = 0.048 ± 0.02, P = 0.03), increased leg fat (b = 0.029 ± 0.012, P = 0.01), reduced T2D (b = -0.73 ± 0.15, P = 6 × 10-7, odds ratio [OR] 0.48 [95% CI 0.36-0.64]), reduced TG (b = -0.07 ± 0.02, P = 0.003), and increased HDL (b = 0.04 ± 0.01, P = 0.006) with some evidence of horizontal pleiotropy. CIR had neutral effects on WHR (b = 0.009 ± 0.02, P = 0.69), liver fat (b = -0.08 ± 0.04, P = 0.06), HTN (b = -0.001 ± 0.004, P = 0.7, OR 1.00 [95% CI 0.99-1.01]), and CAD (b = -0.002 ± 0.002, P = 0.48, OR 0.99 [95% CI 0.81-1.21]). T2D decreased CIR (b -0.22 ± 0.04, P = 1.3 × 10-7), with no evidence that BMI, TG, HDL, liver fat, HTN, and CAD modulate CIR. In conclusion, we did not find evidence that increased CIR increases cardiometabolic disease. It might increase BMI with favorable fat distribution, reduce T2D, and improve lipids.

Obesity and Cardiovascular Disease: The Emerging Role of Inflammation.

Obesity is a growing public health challenge across the globe. It is associated with increased morbidity and mortality. Cardiovascular disease (CVD) is the leading cause of mortality for people with obesity. Current strategies to reduce CVD are largely focused on addressing traditional risk factors such as dyslipidemia, type 2 diabetes (T2D) and hypertension. Although this approach is proven to reduce CVD, substantial residual risk remains for people with obesity. This necessitates a better understanding of the etiology of CVD in people with obesity and alternate therapeutic approaches. Reducing inflammation may be one such strategy. A wealth of animal and human data indicates that obesity is associated with adipose tissue and systemic inflammation. Inflammation is a known contributor to CVD in humans and can be successfully targeted to reduce CVD. Here we will review the etiology and pathogenesis of inflammation in obesity associated metabolic disease as well as CVD. We will review to what extent these associations are causal based on human genetic studies and pharmacological studies. The available data suggests that anti-inflammatory treatments can be used to reduce CVD, but off-target effects such as increased infection have precluded its broad therapeutic application to date. The role of anti-inflammatory therapies in improving glycaemia and metabolic parameters is less established. A number of clinical trials are currently ongoing which are evaluating anti-inflammatory agents to lower CVD. These studies will further clarify whether anti-inflammatory agents can safely reduce CVD.

Experience of Women in IR in the Arab World: Survey by the Pan Arab Interventional Radiology Society.

We report our assessment of the experience of female interventional radiologists in different Arab countries based on an online questionnaire that was sent to 57 female interventional radiologists in 5 Arab countries. These interventional radiologists were identified from the Pan Arab Interventional Radiology Society database and through personal communications. The survey included items related to demographics, social status, and the professional challenges of interventional radiologists, with a response rate of 93%. Forty-five percent of respondents were between 31 and 45 years of age. Interventional radiology practice represented 25%-50% of work time for 51% of respondents, and the main challenges reported were related to radiation exposure, balancing family/work life, and the male-dominated interventional radiology community.

Assessing Parents' Needs in Using Phone Applications to Improve Medication Adherence in an Outpatient Pediatric Oncology Clinic.

BACKGROUND: Poor adherence in pediatric oncology leads to significant morbidity and mortality. Currently used medication reminder aids have shown little to no benefit in improving adherence. Phone applications (apps) have demonstrated improved adherence in recent studies involving the adult and pediatric patients. At this time, no pediatric oncology center is recommending a particular phone app. OBJECTIVE: The objective of this study was to determine the proportion of parents of pediatric oncology patients interested in using a phone app for medication reminders and desired features. METHODS: In this single-center observational trial, 45 questionnaires were completed by parents accompanying their child at a pediatric oncology center. See Supplemental Digital Content 1 (http://links.lww.com/JPHO/A327) for a copy of the questionnaire. Participants had a child on active cancer treatment and were able to read and write English. Primary outcomes included a number of parents currently using a phone app, the number of parents interested in using a phone app, main reasons for not using a phone app and desired phone app features. RESULTS: Overall, 95.6% of parents had never used a phone app to aid in medication adherence. Over 85% of these parents were highly interested in using a phone app, but most were not aware of available phone apps to use (57.1%). Desired features included: refill notifications, tracking doses administered, personalizable medication schedule, free of charge, no advertisements, ability to input special instructions, use on multiple devices, unique alarms, tracking child's results, and privacy protection. CONCLUSIONS: A majority of parents at an outpatient pediatric oncology clinic were interested in using a phone app to assist in medication adherence but were unaware of an available phone app. An ideal criteria list was created with 10 desired features to evaluate available phone apps that may be recommended for this population. Further studies are needed to evaluate if phone apps recommended by this tool improve adherence.