Does ACE2 mediate the detrimental effect of exposures related to COVID-19 risk: A Mendelian randomization investigation.

OBJECTIVES: Adiposity, smoking, and lower socioeconomic position (SEP) increase COVID-19 risk while the association of vitamin D, blood pressure, and glycemic traits in COVID-19 risk were less clear. Whether angiotensin-converting enzyme 2 (ACE2), the key receptor for SARS-CoV-2, mediates these associations has not been investigated. We conducted a Mendelian randomization study to assess the role of these exposures in COVID-19 and mediation by ACE2. METHODS: We extracted genetic variants strongly related to various exposures (vitamin D, blood pressure, glycemic traits, smoking, adiposity, and educational attainment [SEP proxy]), and ACE2 cis-variants from genome-wide association studies (GWAS, n ranged from 28 204 to 3 037 499) and applied them to GWAS summary statistics of ACE2 (n = 28 204) and COVID-19 (severe, hospitalized, and susceptibility, n ≤ 2 942 817). We used inverse variance weighted as the main analyses, with MR-Egger and weighted median as sensitivity analyses. Mediation analyses were performed based on product of coefficient method. RESULTS: Higher adiposity, lifetime smoking index, and lower educational attainment were consistently associated with higher risk of COVID-19 phenotypes while there was no strong evidence for an association of other exposures in COVID-19 risk. ACE2 partially mediates the detrimental effects of body mass index (ranged from 4.3% to 8.2%), waist-to-hip ratio (ranged from 11.2% to 16.8%), and lower educational attainment (ranged from 4.0% to 7.5%) in COVID-19 phenotypes while ACE2 did not mediate the detrimental effect of smoking. CONCLUSIONS: We provided genetic evidence that reducing ACE2 could partly lower COVID-19 risk amongst people who were overweight/obese or of lower SEP.

The effect of a low glycaemic index diet on reducing day-long glycaemia in healthy young adults: A randomized crossover trial.

AIM: To compare the effect of a low glycaemic index (LGI) diet on reducing day-long glycaemia with a macronutrient-matched high glycaemic index (HGI) diet, using customized meal delivery to ensure compliance. MATERIALS AND METHODS: We conducted a single-blinded, randomized crossover trial in 14 healthy adults (57% female) with a mean ± SD age of 21.6 ± 1.7 years. A flash glucose monitoring sensor was installed on the subjects on day 1 to capture the interstitial glucose level every 15 minutes for 14 days. Subjects were randomized to receive an LGI (dietary GI = 40) or HGI (dietary GI = 60) diet (three meals and two snacks) from day 2 for 5 consecutive days, followed by a 2-day washout, then switched to the alternative diet for another 5 days. A paired t-test was used to test the differences in the incremental area under the curve (iAUC) of glucose, postprandial glucose (PPG) concentration and maximum postprandial glucose rise (MPGR) between the LGI and HGI periods. RESULTS: Subjects had lower iAUC for average day-long glycaemia during the LGI intervention period compared with the HGI period (mean ± SD, 865 ± 297 vs. 1024 ± 267 mmol x min/L; P = .047). PPG for breakfast and snack 2, and MPGR for breakfast, snack 2 and dinner, were lower in the LGI period. CONCLUSIONS: In young healthy adults, following an LGI diet resulted in lower average day-long glycaemia compared with a macronutrient-matched HGI diet. Our results support the use of LGI diets to reduce the risk of developing glucose intolerance.

Intake of free sugar and micronutrient dilution in Australian children and adolescents.

PURPOSES: This cross-sectional analysis aimed to investigate the association between free sugar intake and micronutrient intake in Australian children and adolescents and to assess the effectiveness of the cut-off of < 10% energy intake from free sugar (%EFS) as recommended by the World Health Organization (WHO). METHODS: Dietary data of children and adolescents from the Australian Health Survey 2011-12 were analyzed (n = 1466). Free sugar intake was estimated using a published methodology with modification to suit the definition of free sugar. Six cut-offs for %EFS were created in 5% increments. Participants' mean intakes of 18 micronutrients, as well as their intakes of core (healthy) and discretionary (unhealthy) foods, at different cut-offs were compared using ANCOVA, with age, sex, and socioeconomic status measures as covariates. The odds ratios of not meeting the nutrient reference values (NRVs) for Australia and New Zealand of each micronutrient were calculated using logistic regression. RESULTS: Micronutrient intake decreased with increasing %EFS and the peak intakes of most micronutrients appeared between 0-15%EFS. The absolute intakes of most micronutrients were not significantly different between participants who consumed < 10%EFS and ≥ 10%EFS. Those with > 20%EFS were less likely to meet the NRVs of more than half of the micronutrients. Additionally, as %EFS increased, intakes of core food groups decreased, while intakes of discretionary food groups increased. CONCLUSIONS: The dilution effect in micronutrient intake with increasing free sugar intake was evident in Australian children and adolescents. However, meeting the WHO cut-off was associated with limited improvement in micronutrient adequacy.

Discrepancy in socioeconomic status does not fully explain the variation in diet quality between consumers of different coffee types.

PURPOSE: Habitual consumers of different coffee types may vary in socioeconomic status (SES), which is an important determinant of diet quality. Nonetheless, research on diet quality among coffee consumers was scarce. We aimed to compare the diet quality of coffee consumers with different preferences towards coffee type and additive usage. METHODS: In this cross-sectional analysis, intake data of food, coffee, and additive usage from the adult respondents of the 2011-2012 Australian Health Survey were used. Participants were grouped according to the type of coffee (espresso and ground coffee, E&G; coffee made from coffee mixes and instant coffee, M&I; non-consumers, NC) and additives (milk, sugar, and intense sweetener) consumed. Adjusted food group intake was compared between consumption groups using general linear model. RESULTS: E&G drinkers had better SES than M&I and NC. After adjusting for covariates, the mean dairy intake of E&G drinkers was 22.2% higher than M&I drinkers (p < 0.001) and 33.1% higher than NC (p < 0.001). Mean discretionary food intake of E&G drinkers was 12.1% lower than M&I (p = 0.003) and 12.3% lower than NC (p = 0.001). In terms of additive usage, non-users of coffee additive had the lowest dairy food intake and the highest discretionary food intake. CONCLUSIONS: Coffee consumers' different preferences towards coffee type and additive usages reflected significant variations in their diet quality, even after adjustment of SES. Therefore, future epidemiological studies should consider separating coffee drinkers according to their habitual consumption of different types of coffee.

Association of iron homeostasis biomarkers in type 2 diabetes and glycaemic traits: a bidirectional two-sample Mendelian randomization study.

BACKGROUND: Mendelian randomization (MR) studies show iron positively associated with type 2 diabetes (T2D) but included potentially biasing hereditary haemochromatosis variants and did not assess reverse causality. METHODS: We assessed the relation of iron homeostasis with T2D and glycaemic traits bidirectionally, using genome-wide association studies (GWAS) of iron homeostasis biomarkers [ferritin, serum iron, total iron-binding capacity (TIBC), transferrin saturation (TSAT) (n ≤ 246 139)], T2D (DIAMANTE n = 933 970 and FinnGen n = 300 483), and glycaemic traits [fasting glucose (FG), 2-h glucose, glycated haemoglobin (HbA1c) and fasting insulin (FI) (n ≤ 209 605)]. Inverse variance weighting (IVW) was the main analysis, supplemented with sensitivity analyses and assessment of mediation by hepcidin. RESULTS: Iron homeostasis biomarkers were largely unrelated to T2D, although serum iron was potentially associated with higher T2D [odds ratio: 1.07 per standard deviation; 95% confidence interval (CI): 0.99 to 1.16; P-value: 0.078) in DIAMANTE only. Higher ferritin, serum iron, TSAT and lower TIBC likely decreased HbA1c, but were not associated with other glycaemic traits. Liability to T2D likely increased TIBC (0.03 per log odds; 95% CI: 0.01 to 0.05; P-value: 0.005), FI likely increased ferritin (0.29 per log pmol/L; 95% CI: 0.12 to 0.47; P-value: 8.72 x 10-4). FG likely increased serum iron (0.06 per mmol/L; 95% CI: 0.001 to 0.12; P-value: 0.046). Hepcidin did not mediate these associations. CONCLUSION: It is unlikely that ferritin, TSAT and TIBC cause T2D although an association for serum iron could not be excluded. Glycaemic traits and liability to T2D may affect iron homeostasis, but mediation by hepcidin is unlikely. Corresponding mechanistic studies are warranted.

Evaluating the role of non-alcoholic fatty liver disease in cardiovascular diseases and type 2 diabetes: a Mendelian randomization study in Europeans and East Asians.

BACKGROUND: Whether non-alcoholic fatty liver disease (NAFLD) causes cardiovascular disease (CVD) and type 2 diabetes (T2D) is unclear and possible differences between ethnicities have not been thoroughly explored. We used Mendelian randomization (MR) to assess the role of NAFLD in CVD and T2D risk in Europeans and East Asians. METHODS: We conducted a MR study using genetic predictors of alanine aminotransferase (ALT), liability to NAFLD, aspartate transaminase (AST), liver magnetic resonance imaging corrected T1 and proton density fat fraction and combined them with genome-wide association studies (GWAS) summary statistics of CVD, T2D and glycaemic traits (sample size ranging from 14 400 to 977 320). Inverse-variance weighted analysis was used to assess the effect of NAFLD in these outcomes, with sensitivity analyses and replication in FinnGen. We conducted analyses in East Asians using ethnicity-specific genetic predictors of ALT and AST, and the respective outcome GWAS summary statistics. RESULTS: In Europeans, higher ALT was associated with higher T2D risk (odds ratio: 1.77 per standard deviation, 95% CI 1.5 to 2.08), with similar results for other exposures, across sensitivity analyses and in FinnGen. Although NAFLD proxies were related to higher coronary artery disease (CAD) and stroke risk, sensitivity analyses suggested possible bias by horizontal pleiotropy. In East Asians, higher ALT was possibly associated with higher T2D risk, and ALT and AST were inversely associated with CAD. CONCLUSIONS: NAFLD likely increases the risk of T2D in Europeans and East Asians. Potential differential effects on CAD between Europeans and East Asians require further investigation.

Identifying factors contributing to increased susceptibility to COVID-19 risk: a systematic review of Mendelian randomization studies.

BACKGROUND: To summarize modifiable factors for coronavirus disease 2019 (COVID-19) suggested by Mendelian randomization studies. METHODS: In this systematic review, we searched PubMed, EMBASE and MEDLINE, from inception to 15 November 2021, for Mendelian randomization studies in English. We selected studies that assessed associations of genetically predicted exposures with COVID-19-related outcomes (severity, hospitalization and susceptibility). Risk of bias of the included studies was evaluated based on the consideration of the three main assumptions for instrumental variable analyses. RESULTS: We identified 700 studies through systematic search, of which 50 Mendelian randomization studies were included. Included studies have explored a wide range of socio-demographic factors, lifestyle attributes, anthropometrics and biomarkers, predisposition to diseases and druggable targets in COVID-19 risk. Mendelian randomization studies suggested that increases in smoking, obesity and inflammatory factors were associated with higher risk of COVID-19. Predisposition to ischaemic stroke, combined bipolar disorder and schizophrenia, attention-deficit and hyperactivity disorder, chronic kidney disease and idiopathic pulmonary fibrosis was potentially associated with higher COVID-19 risk. Druggable targets, such as higher protein expression of histo-blood group ABO system transferase (ABO), interleukin (IL)-6 and lower protein expression of 2'-5' oligoadenylate synthetase 1 (OAS1) were associated with higher risk of COVID-19. There was no strong genetic evidence supporting the role of vitamin D, glycaemic traits and predisposition to cardiometabolic diseases in COVID-19 risk. CONCLUSION: This review summarizes modifiable factors for intervention (e.g. smoking, obesity and inflammatory factors) and proteomic signatures (e.g. OAS1 and IL-6) that could help identify drugs for treating COVID-19.

Perspective: Is it Time to Expand Research on "Nuts" to Include "Seeds"? Justifications and Key Considerations.

The health benefits of nuts reported throughout the literature are extensive and well established for reducing the risk of, and managing several chronic conditions such as cardiovascular disease, type 2 diabetes, nonalcoholic fatty liver disease, and cognition. Despite their comparable nutrient profile to nuts, seeds are often not assessed in clinical and epidemiological studies. Interestingly, dietary guidelines and recommendations often refer to "nuts and seeds" collectively, even though they are not consistently examined together in nutrition research when determining associated health benefits. The purpose of this review is to call for future nutrition research to consider combining nuts and seeds. This review provides justification for this proposal by summarizing current definitions for nuts and seeds and highlighting the similarities or dissimilarities in their nutrient compositions. Following this, we summarize current evidence on the health benefits of nuts and seeds, research gaps that should be addressed, and considerations for future research using both epidemiological and interventional study designs.

The longitudinal association between coffee and tea consumption and the risk of metabolic syndrome and its component conditions in an older adult population.

The present study aimed to assess the longitudinal associations of coffee and tea consumption with metabolic syndrome and its component conditions in a group of Australian older adults who participated in the Blue Mountains Eye Study (n 2554, mean age: 64 years, 43 % female). Participants' coffee and tea intake were measured using a validated food frequency questionnaire. Hazard ratios (HRs) over a 10-year period were estimated using Cox hazard regression models adjusting for lifestyle factors. Results showed that coffee consumption was not associated with the incidence of metabolic syndrome, high fasting glucose, high triglycerides, central obesity, high blood pressure and low HDL-cholesterol (HDL-C). Tea consumption was not associated with incidence of metabolic syndrome and the component conditions except for the risk of having low HDL-C, in which a nominally inverse association was observed (multivariate-adjusted HR at 2-3 cups/d: 0⋅48, 95 % CI 0⋅26, 0⋅87, P = 0⋅016; 4 cups/d or more: 0⋅50, 95 % CI 0⋅27, 0⋅93, P = 0⋅029). After stratifying for fruit consumption (P interaction between tea and fruit = 0⋅007), consuming four cups of tea per day was nominally associated with lower incidence of metabolic syndrome among those with high fruit consumption (multivariable-adjusted HR: 0⋅44, 95 % CI 0⋅20, 0⋅93, P = 0⋅033). Our results did not support a significant association between tea and coffee consumption and metabolic syndrome. Tea consumption may be associated with a lower risk of having low HDL-C, while high tea and fruit consumption together may be associated with a lower risk of developing metabolic syndrome.

The direct and indirect associations of usual free sugar intake on BMI z-scores of Australian children and adolescents.

This cross-sectional analysis aimed to assess the association between free sugar consumption and the BMI z-score of Australian children and adolescents. Data from the 2007 Australian National Children's Nutrition and Physical Activity Survey were analyzed. Structural equation modeling was used to assess the direct association between usual free sugar intake and age-and-sex-specific BMI z-score, and the indirect association mediated via energy overconsumption. Weak and statistically non-significant associations were found for the direct (BMI z-score ß = -0.02 per 10% change in energy intake from free sugar, p = 0.705) and indirect pathways (BMI z-score ß = -0.04 per 10% change in energy intake from free sugar, p = 0.705). We concluded that free sugar intake was not associated with BMI z-score in this cohort. Instead of focusing on a single energy source in the diet, improving the quality of the whole diet may be a better approach in tackling childhood obesity.