Maternal Glucose and LDL-Cholesterol Levels Are Related to Placental Leptin Gene Methylation, and, Together With Nutritional Factors, Largely Explain a Higher Methylation Level Among Ethnic South Asians

BackgroundLeptin, mainly secreted by fat cells, plays a core role in the regulation of appetite and body weight, and has been proposed as a mediator of metabolic programming. During pregnancy leptin is also secreted by the placenta, as well as being a key regulatory cytokine for the development, homeostatic regulation and nutrient transport within the placenta. South Asians have a high burden of type 2 diabetes, partly attributed to a “thin-fat-phenotype”.ObjectiveOur aim was to investigate how maternal ethnicity, adiposity and glucose- and lipid/cholesterol levels in pregnancy are related to placental leptin gene (LEP) DNA methylation.MethodsWe performed DNA methylation analyses of 13 placental LEP CpG sites in 40 ethnic Europeans and 40 ethnic South Asians participating in the STORK-Groruddalen cohort.ResultsSouth Asian ethnicity and gestational diabetes (GDM) were associated with higher placental LEP methylation. The largest ethnic difference was found for CpG11 [5.8% (95% CI: 2.4, 9.2), p<0.001], and the strongest associations with GDM was seen for CpG5 [5.2% (1.4, 9.0), p=0.008]. Higher maternal LDL-cholesterol was associated with lower placental LEP methylation, in particular for CpG11 [-3.6% (-5.5, -1.4) per one mmol/L increase in LDL, p<0.001]. After adjustments, including for nutritional factors involved in the one-carbon-metabolism cycle (vitamin D, B12 and folate levels), ethnic differences in placental LEP methylation were strongly attenuated, while associations with glucose and LDL-cholesterol persisted.ConclusionsMaternal glucose and lipid metabolism is related to placental LEP methylation, whilst metabolic and nutritional factors largely explain a higher methylation level among ethnic South Asians.

Emotional distress, anxiety and depression in South Asians with long-term conditions: a qualitative systematic review

People with physical-mental comorbidity have a poorer quality of life, worse clinical outcomes and increased mortality compared to people with physical conditions alone. South Asians (SAs) are the largest minority group in the UK and are more likely to have long-term conditions (LTCs) such as diabetes and heart disease. SAs are less likely to recognise symptoms which may represent mental health problems. To explore how people of SA origin with LTCs understand, experience and seek help for emotional distress, depression and anxiety. Systematic review of qualitative studies exploring emotional distress in SAs with diabetes or coronary heart disease, within primary and community care settings worldwide. Comprehensive searches of eight electronic databases from inception to 1st September 2021. Data extracted included study characteristics, and understanding, experience and help-seeking behaviour for emotional distress. Thematic synthesis was undertaken. The CASP checklist for qualitative studies was used to assess quality of papers, and GRADE-CERQual used to determine the overall strength of evidence. Twenty one studies from 3,165 unique citations were included. Three main themes were identified. Understanding of emotional distress: non-medical terminology used, such as ‘tension,’ and a complex relationship between emotional and physical illness. Experiences of emotional distress: multiple forms of inequality, distress at diagnosis of their LTC, cultural factors, and gender differences. Help-seeking behaviour: self-management, seeking help from family, friends, and faith, and inadequate clinical support. This review provides a greater understanding of SAs’ conceptualisation of emotional distress in the context of LTCs, to support improvement in its recognition and management.

South Asian-Specific MYBPC3Δ25bp Deletion Carriers Display Hypercontraction and Impaired Diastolic Function Under Exercise Stress

Background: A 25-base pair (25bp) intronic deletion in the MYBPC3 gene enriched in South Asians (SAs) is a risk allele for late-onset left ventricular (LV) dysfunction, hypertrophy, and heart failure (HF) with several forms of cardiomyopathy. However, the effect of this variant on exercise parameters has not been evaluated.Methods: As a pilot study, 10 asymptomatic SA carriers of the MYBPC3Δ25bp variant (52.9 ± 2.14 years) and 10 age- and gender-matched non-carriers (NCs) (50.1 ± 2.7 years) were evaluated at baseline and under exercise stress conditions using bicycle exercise echocardiography and continuous cardiac monitoring.Results: Baseline echocardiography parameters were not different between the two groups. However, in response to exercise stress, the carriers of Δ25bp had significantly higher LV ejection fraction (%) (CI: 4.57 ± 1.93; p < 0.0001), LV outflow tract peak velocity (m/s) (CI: 0.19 ± 0.07; p < 0.0001), and higher aortic valve (AV) peak velocity (m/s) (CI: 0.103 ± 0.08; p = 0.01) in comparison to NCs, and E/A ratio, a marker of diastolic compliance, was significantly lower in Δ25bp carriers (CI: 0.107 ± 0.102; p = 0.038). Interestingly, LV end-diastolic diameter (LVIDdia) was augmented in NCs in response to stress, while it did not increase in Δ25bp carriers (CI: 0.239 ± 0.125; p = 0.0002). Further, stress-induced right ventricular systolic excursion velocity s' (m/s), as a marker of right ventricle function, increased similarly in both groups, but tricuspid annular plane systolic excursion increased more in carriers (slope: 0.008; p = 0.0001), suggesting right ventricle functional differences between the two groups.Conclusions: These data support that MYBPC3Δ25bp is associated with LV hypercontraction under stress conditions with evidence of diastolic impairment.

Culturally tailored DSMES: A new key for South Asian patients with Type 2 Diabetes Mellitus

South Asians have an exceptionally high risk for developing Type 2 diabetes mellitus. It is very challenging for healthcare providers to successfully manage diabetes and control glucose levels at target due to the unique lifestyle of the South Asian population. Culturally tailored diabetes self-management education and support (DSMES) can be more effective in guiding South Asian patients with Type 2 diabetes. Unique considerations to address lifestyle modification for South Asians include a diet that typically consists of a high carbohydrate to lipids/proteins ratio, preference for high glucose index fruits, regular intake of traditional sweets or desserts, late afternoon tea break followed by late dinner, lack of vigorous exercise (yoga or walking being the preferred activity), lack of DSMES knowledge and skills, and poor access to culturally appropriate resources for diabetes care. We present a 38-year-old male diagnosed with diabetes four years ago who showed poor glucose control before our intervention. Our interventions included education on the importance of blood glucose monitoring, exercise, and diet. Based on our experience with this case, we propose the following recommendations for a tailored approach to DSMES for South Asian patients with Type 2 diabetes: make appropriate dietary changes (decrease total daily caloric intake, decrease the percentage of carbohydrates, addlow glucose index fruits and vegetables, avoid late afternoon tea breaks, eat dinner before 8 PM); incorporate appropriate daily physical activity; and monitor blood glucose daily for prompt feedback.

The iHealth-T2D study, prevention of type 2 diabetes amongst South Asians with central obesity and prediabetes: study protocol for a randomised controlled trial

Background People from South Asia are at increased risk of type 2 diabetes (T2D). There is an urgent need to develop approaches for the prevention of T2D in South Asians that are cost-effective, generalisable and scalable across settings. Hypothesis Compared to usual care, the risk of T2D can be reduced amongst South Asians with central obesity or raised HbA1c, through a 12-month lifestyle modification programme delivered by community health workers. Design Cluster randomised clinical trial (1:1 allocation to intervention or usual care), carried out in India, Pakistan, Sri Lanka and the UK, with 30 sites per country (120 sites total). Target recruitment 3600 (30 participants per site) with annual follow-up for 3 years. Entry criteria South Asian, men or women, age 40–70 years with (i) central obesity (waist circumference ≥ 100 cm in India and Pakistan; ≥90 cm in Sri Lanka) and/or (ii) prediabetes (HbA1c 6.0–6.4% inclusive). Exclusion criteria: known type 1 or 2 diabetes, normal or underweight (body mass index < 22 kg/m2); pregnant or planning pregnancy; unstable residence or planning to leave the area; and serious illness. Endpoints The primary endpoint is new-onset T2D at 3 years, defined as (i) HbA1c ≥ 6.5% or (ii) physician diagnosis and on treatment for T2D. Secondary endpoints at 1 and 3 years are the following: (i) physical measures: waist circumference, weight and blood pressure; (ii) lifestyle measures: smoking status, alcohol intake, physical activity and dietary intake; (iii) biochemical measures: fasting glucose, insulin and lipids (total and HDL cholesterol, triglycerides); and (iv) treatment compliance. Intervention Lifestyle intervention (60 sites) or usual care (60 sites). Lifestyle intervention was delivered by a trained community health worker over 12 months (5 one-one sessions, 4 group sessions, 13 telephone sessions) with the goal of the participants achieving a 7% reduction in body mass index and a 10-cm reduction in waist circumference through (i) improved diet and (ii) increased physical activity. Usual care comprised a single 30-min session of lifestyle modification advice from the community health worker. Results We screened 33,212 people for inclusion into the study. We identified 10,930 people who met study entry criteria, amongst whom 3682 agreed to take part in the intervention. Study participants are 49.2% female and aged 52.8 (SD 8.2) years. Clinical characteristics are well balanced between intervention and usual care sites. More than 90% of follow-up visits are scheduled to be complete in December 2020. Based on the follow-up to end 2019, the observed incidence of T2D in the study population is in line with expectations (6.1% per annum). Conclusion The iHealth-T2D study will advance understanding of strategies for the prevention of diabetes amongst South Asians, use approaches for screening and intervention that are adapted for low-resource settings. Our study will thus inform the implementation of strategies for improving the health and well-being of this major global ethnic group. IRB approval 16/WM/0171 Trial registration EudraCT 2016-001350-18. Registered on 14 April 2016. ClinicalTrials.govNCT02949739. Registered on 31 October 2016, First posted on 31/10/2016.

Diabetes and hypertension among South Asians in New York and Atlanta leveraging hospital electronic health records

Background Diabetes and hypertension disparities are pronounced among South Asians. There is regional variation in the prevalence of diabetes and hypertension in the US, but it is unknown whether there is variation among South Asians living in the US. The objective of this study was to compare the burden of diabetes and hypertension between South Asian patients receiving care in the health systems of two US cities. Methods Cross-sectional analyses were performed using electronic health records (EHR) for 90,137 South Asians receiving care at New York University Langone in New York City (NYC) and 28,868 South Asians receiving care at Emory University (Atlanta). Diabetes was defined as having 2 + encounters with a diagnosis of diabetes, having a diabetes medication prescribed (excluding Acarbose/Metformin), or having 2 + abnormal A1C levels (≥ 6.5%) and 1 + encounter with a diagnosis of diabetes. Hypertension was defined as having 3 + BP readings of systolic BP ≥ 130 mmHg or diastolic BP ≥ 80 mmHg, 2 + encounters with a diagnosis of hypertension, or having an anti-hypertensive medication prescribed. Results Among South Asian patients at these two large, private health systems, age-adjusted diabetes burden was 10.7% in NYC compared to 6.7% in Atlanta. Age-adjusted hypertension burden was 20.9% in NYC compared to 24.7% in Atlanta. In Atlanta, 75.6% of those with diabetes had comorbid hypertension compared to 46.2% in NYC. Conclusions These findings suggest differences by region and sex in diabetes and hypertension risk. Additionally, these results call for better characterization of race/ethnicity in EHRs to identify ethnic subgroup variation, as well as intervention studies to reduce lifestyle exposures that underlie the elevated risk for type 2 diabetes and hypertension development in South Asians.

Genetic alteration of human MYH6 is mimicked by SARS-CoV-2 polyprotein: mapping viral variants of cardiac interest

Acute cardiac injury has been observed in a subset of COVID-19 patients, but the molecular basis for this clinical phenotype is unknown. It has been hypothesized that molecular mimicry may play a role in triggering an autoimmune inflammatory reaction in some individuals after SARS-CoV-2 infection. Here we investigate if linear peptides contained in proteins that are primarily expressed in the heart also occur in the SARS-CoV-2 proteome. Specifically, we compared the library of 136,704 8-mer peptides from 144 human proteins (including splicing variants) to 9,926 8-mers from all 17 viral proteins in the reference SARS-CoV-2 proteome. No 8-mers were exactly identical between the reference human proteome and the reference SARS-CoV-2 proteome. However, there were 45 8-mers that differed by only one amino acid when compared to the reference SARS-CoV-2 proteome. Interestingly, analysis of protein-coding mutations from 141,456 individuals showed that one of these 8-mers from the SARS-CoV-2 Replicase polyprotein 1a/1ab (KIALKGGK) is identical to a MYH6 peptide encoded by the c.5410C>A (Q1804K) genetic variation, which has been observed at low prevalence in Africans/African Americans (0.08%), East Asians (0.3%), South Asians (0.06%) and Latino/Admixed Americans (0.003%). Furthermore, analysis of 4.85 million SARS-CoV-2 genomes from over 200 countries shows that viral evolution has already resulted in 20 additional 8-mer peptides that are identical to human heart-enriched proteins encoded by reference sequences or genetic variants. Whether such mimicry contributes to cardiac inflammation during or after COVID-19 illness warrants further experimental evaluation. We suggest that SARS-CoV-2 variants harboring peptides identical to human cardiac proteins should be investigated as ‘viral variants of cardiac interest’.