Increased genetic risk for ß-cell failure is associated with ß-cell function decline in people with prediabetes.

Partitioned polygenic scores (pPS) have been developed to capture pathophysiologic processes underlying type 2 diabetes (T2D). We investigated the influence of T2D pPS on diabetes-related traits and T2D incidence in the Diabetes Prevention Program. We generated five T2D pPS (ß-cell, proinsulin, liver/lipid, obesity, lipodystrophy) in 2,647 participants randomized to intensive lifestyle, metformin or placebo arms. Associations were tested using general linear models and Cox regression adjusted for age, sex, and principal components. Sensitivity analyses included adjustment for BMI. Higher ß-cell pPS was associated with lower insulinogenic index and corrected insulin response at one year follow-up adjusted for baseline measures (effect per pPS standard deviation (SD) -0.04, P=9.6 x 10-7; -8.45 uU/mg, P=5.6 x 10-6, respectively) and with increased diabetes incidence adjusted for BMI at nominal significance (HR 1.10 per SD, P=0.035). The liver/lipid pPS was associated with reduced one-year baseline-adjusted triglyceride levels (effect per SD -4.37, P=0.001). There was no significant interaction between T2D pPS and randomized groups. The remaining pPS were associated with baseline measures only. We conclude that despite interventions for diabetes prevention, participants with a high genetic burden of the ß-cell cluster pPS had worsening in measures of ß-cell function.

Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People With Type 2 Diabetes.

OBJECTIVE: To identify genetic risk factors for incident cardiovascular disease (CVD) among people with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: We conducted a multiancestry time-to-event genome-wide association study for incident CVD among people with T2D. We also tested 204 known coronary artery disease (CAD) variants for association with incident CVD. RESULTS: Among 49,230 participants with T2D, 8,956 had incident CVD events (event rate 18.2%). We identified three novel genetic loci for incident CVD: rs147138607 (near CACNA1E/ZNF648, hazard ratio [HR] 1.23, P = 3.6 × 10-9), rs77142250 (near HS3ST1, HR 1.89, P = 9.9 × 10-9), and rs335407 (near TFB1M/NOX3, HR 1.25, P = 1.5 × 10-8). Among 204 known CAD loci, 5 were associated with incident CVD in T2D (multiple comparison-adjusted P < 0.00024, 0.05/204). A standardized polygenic score of these 204 variants was associated with incident CVD with HR 1.14 (P = 1.0 × 10-16). CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.

Heterogeneous effects on type 2 diabetes and cardiovascular outcomes of genetic variants and traits associated with fasting insulin.

Hyperinsulinemia is a complex and heterogeneous phenotype that characterizes molecular alterations that precede the development of type 2 diabetes (T2D). It results from a complex combination of molecular processes, including insulin secretion and insulin sensitivity, that differ between individuals. To better understand the physiology of hyperinsulinemia and ultimately T2D, we implemented a genetic approach grouping fasting insulin (FI)-associated genetic variants based on their molecular and phenotypic similarities. We identified seven distinctive genetic clusters representing different physiologic mechanisms leading to rising FI levels, ranging from clusters of variants with effects on increased FI, but without increased risk of T2D (non-diabetogenic hyperinsulinemia), to clusters of variants that increase FI and T2D risk with demonstrated strong effects on body fat distribution, liver, lipid, and inflammatory processes (diabetogenic hyperinsulinemia). We generated cluster-specific polygenic scores in 1,104,258 individuals from five multi-ancestry cohorts to show that the clusters differed in associations with cardiometabolic traits. Among clusters characterized by non-diabetogenic hyperinsulinemia, there was both increased and decreased risk of coronary artery disease despite the non-increased risk of T2D. Similarly, the clusters characterized by diabetogenic hyperinsulinemia were associated with an increased risk of T2D, yet had differing risks of cardiovascular conditions, including coronary artery disease, myocardial infarction, and stroke. The strongest cluster-T2D associations were observed with the same direction of effect in non-Hispanic Black, Hispanic, non-Hispanic White, and non-Hispanic East Asian populations. These genetic clusters provide important insights into granular metabolic processes underlying the physiology of hyperinsulinemia, notably highlighting specific processes that decouple increasing FI levels from T2D and cardiovascular risk. Our findings suggest that increasing FI levels are not invariably associated with adverse cardiometabolic outcomes.

Impact of individual and environmental factors on dietary or lifestyle interventions to prevent type 2 diabetes development: a systematic review.

BACKGROUND: The variability in the effectiveness of type 2 diabetes (T2D) preventive interventions highlights the potential to identify the factors that determine treatment responses and those that would benefit the most from a given intervention. We conducted a systematic review to synthesize the evidence to support whether sociodemographic, clinical, behavioral, and molecular factors modify the efficacy of dietary or lifestyle interventions to prevent T2D. METHODS: We searched MEDLINE, Embase, and Cochrane databases for studies reporting on the effect of a lifestyle, dietary pattern, or dietary supplement interventions on the incidence of T2D and reporting the results stratified by any effect modifier. We extracted relevant statistical findings and qualitatively synthesized the evidence for each modifier based on the direction of findings reported in available studies. We used the Diabetes Canada Clinical Practice Scale to assess the certainty of the evidence for a given effect modifier. RESULTS: The 81 publications that met our criteria for inclusion are from 33 unique trials. The evidence is low to very low to attribute variability in intervention effectiveness to individual characteristics such as age, sex, BMI, race/ethnicity, socioeconomic status, baseline behavioral factors, or genetic predisposition. CONCLUSIONS: We report evidence, albeit low certainty, that those with poorer health status, particularly those with prediabetes at baseline, tend to benefit more from T2D prevention strategies compared to healthier counterparts. Our synthesis highlights the need for purposefully designed clinical trials to inform whether individual factors influence the success of T2D prevention strategies.

Clinical trials to prevent development of type 2 diabetes (T2D) that test dietary and lifestyle interventions have resulted in different results for different study participants. We hypothesized that the differing responses could be because of different personal, social and inherited factors. We searched different databases containing details of published research studies investigating this to look at the effect of these factors on prevention of the development of T2D. We found a small amount of evidence suggesting that those with poorer health, particularly those with a higher amount of sugar in their blood, tend to benefit more from T2D prevention strategies compared to healthier counterparts. Our results suggest that further clinical trials that are designed to examine the effect of personal and social factors on interventions for T2D prevention are needed to better determine the impact of these factors on the success of diet and lifestyle interventions for T2D.

Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine.

Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.

Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2D) confers a two- to three-fold increased risk of cardiovascular disease (CVD). However, the mechanisms underlying increased CVD risk among people with T2D are only partially understood. We hypothesized that a genetic association study among people with T2D at risk for developing incident cardiovascular complications could provide insights into molecular genetic aspects underlying CVD. METHODS: From 16 studies of the Cohorts for Heart & Aging Research in Genomic Epidemiology (CHARGE) Consortium, we conducted a multi-ancestry time-to-event genome-wide association study (GWAS) for incident CVD among people with T2D using Cox proportional hazards models. Incident CVD was defined based on a composite of coronary artery disease (CAD), stroke, and cardiovascular death that occurred at least one year after the diagnosis of T2D. Cohort-level estimated effect sizes were combined using inverse variance weighted fixed effects meta-analysis. We also tested 204 known CAD variants for association with incident CVD among patients with T2D. RESULTS: A total of 49,230 participants with T2D were included in the analyses (31,118 European ancestries and 18,112 non-European ancestries) which consisted of 8,956 incident CVD cases over a range of mean follow-up duration between 3.2 and 33.7 years (event rate 18.2%). We identified three novel, distinct genetic loci for incident CVD among individuals with T2D that reached the threshold for genome-wide significance (P<5.0×10-8): rs147138607 (intergenic variant between CACNA1E and ZNF648) with a hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.15 - 1.32, P=3.6×10-9, rs11444867 (intergenic variant near HS3ST1) with HR 1.89, 95% CI 1.52 - 2.35, P=9.9×10-9, and rs335407 (intergenic variant between TFB1M and NOX3) HR 1.25, 95% CI 1.16 - 1.35, P=1.5×10-8. Among 204 known CAD loci, 32 were associated with incident CVD in people with T2D with P<0.05, and 5 were significant after Bonferroni correction (P<0.00024, 0.05/204). A polygenic score of these 204 variants was significantly associated with incident CVD with HR 1.14 (95% CI 1.12 - 1.16) per 1 standard deviation increase (P=1.0×10-16). CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.

Role of sociodemographic, clinical, behavioral, and molecular factors in precision prevention of type 2 diabetes: a systematic review.

The variability in the effectiveness of type 2 diabetes (T2D) preventive interventions highlights the potential to identify the factors that determine treatment responses and those that would benefit the most from a given intervention. We conducted a systematic review to synthesize the evidence to support whether sociodemographic, clinical, behavioral, and molecular characteristics modify the efficacy of dietary or lifestyle interventions to prevent T2D. Among the 80 publications that met our criteria for inclusion, the evidence was low to very low to attribute variability in intervention effectiveness to individual characteristics such as age, sex, BMI, race/ethnicity, socioeconomic status, baseline behavioral factors, or genetic predisposition. We found evidence, albeit low certainty, to support conclusions that those with poorer health status, particularly those with prediabetes at baseline, tend to benefit more from T2D prevention strategies compared to healthier counterparts. Our synthesis highlights the need for purposefully designed clinical trials to inform whether individual factors influence the success of T2D prevention strategies.

Genetic predisposition to macronutrient preference and workplace food choices.

Prior research identified genetic variants influencing macronutrient preference, but whether genetic differences underlying nutrient preference affect long-term food choices is unknown. Here we examined the associations of polygenic scores for carbohydrate, fat, and protein preference with 12 months' workplace food purchases among 397 hospital employees from the ChooseWell 365 study. Food purchases were obtained retrospectively from the hospital's cafeteria sales data for the 12 months before participants were enrolled in the ChooseWell 365 study. Traffic light labels, visible to employees when making purchases, measured the quality of workplace purchases. During the 12-month study period, there were 215,692 cafeteria purchases. Each SD increase in the polygenic score for carbohydrate preference was associated with 2.3 additional purchases/month (95%CI, 0.2 to 4.3; p = 0.03) and a higher number of green-labeled purchases (ß = 1.9, 95%CI, 0.5-3.3; p = 0.01). These associations were consistent in subgroup and sensitivity analyses accounting for additional sources of bias. There was no evidence of associations between fat and protein polygenic scores and cafeteria purchases. Findings from this study suggest that genetic differences in carbohydrate preference could influence long-term workplace food purchases and may inform follow-up experiments to enhance our understanding of the molecular mechanisms underlying food choice behavior.

Comparación de las variables de rendimiento en las principales ligas europeas de hockey sobre patines / Comparação das variáveis de rendimento nas principais ligas europeias de hóquei em patins / Comparison of performance variables in the main European rink hockey leagues

El presente estudio tuvo como objetivo comparar las variables de rendimiento del hockey patines en los campeonatos nacionales de la máxima categoría masculina en España (OK Liga), Portugal (Primeira Divisao) e Italia (Serie A1). Se analizaron un total de 1.665 partidos disputados entre las temporadas 2018-2019 y 2020-2021, correspondientes a la OK Liga (654), Primeira Divisao (497) y la Serie A1 (514). Se realizaron comparaciones utilizando el análisis de varianza (ANOVA) con post hoc de Bonferroni y la prueba t-Student para comparar las variables según la localización del partido. Los resultados muestran que en España se marcan menos goles por partido, que en Italia se marcan más goles por partido y que en Portugal hay más ejecuciones y goles de penalti y de falta directa, mayor cantidad de faltas y de tarjetas y un mayor porcentaje de goles de pelota parada respecto a los goles totales. En los tres campeonatos las variables de rendimiento asociadas a la victoria fueron favorables a los equipos locales. La comparación de los campeonatos puede permitir a los entrenadores tener un mejor conocimiento de las variables de rendimiento de cada competición y ayudar a las federaciones a conocer que competiciones están mejor asociadas con las variables determinantes del espectáculo deportivo, especialmente los goles, para diseñar propuestas de mejoras en los campeonatos pertinentes. (AU)

The present study aimed to compare the rink hockey performance variables in the top national championships of Spain (OK Liga), Portugal (Primeira Divisao), and Italy (Serie A1). A sample of 1,665 matches corresponding to the OK Liga (654), Primeira Divisao (497), and Serie A1 (514) played between the 2018-2019 and 2020-2021 seasons was analyzed. Comparisons were made using an analysis of the variance (ANOVA) followed by Bonferroni's post hoc multiple comparison test. Additionally, the t-Student test was used to compare each variable according to match location. The results show that in Spain, teams score fewer goals per match and inItaly more goals per match. In Portugal, we observe more set-piece shots, more goals, a higher percentage of goals coming from set-pieces compared to total goals, more fouls, and cards shown. Moreover, the performance variables associated with victory were favourable to the local teams in all three championships. Championship comparison enables coaches to understand better specific and contextual performance variables. Our research could also help governing bodies and federations know what competitions arebetter associated with several key performance indicators and design proposals to improve each championship. (AU)

O presente estudo teve como objetivo comparar as variáveis de rendimento do hóquei em patins nos campeonatos nacionais do escalão masculino mais alto em Espanha (OK Liga), Portugal (Primeira Divisão) e Itália (Série A1). Foram analisados 1.665 jogos disputados entre as épocas 2018-2019 e 2020-2021, correspondendo à OK Liga (654), Primeira Divisão (497) e Série A1 (514). As comparações foram feitas usando a análise de variância post hoc de Bonferroni (ANOVA) e o teste t de Student para comparar as variáveis de acordo com a localização do jogo. Os resultados mostram que em Espanha marcam-se menos golos por jogo e em Italia mais golos per jogo. Em Portugal há mais execuções e golos de grandes penalidades e livres diretos, mais faltas e cartões e uma maior percentagem de golos de bola parada em relação ao total de golos. Nos três campeonatos as variáveis de rendimento associadas à vitória foram favoráveis às equipas locais. A comparação dos campeonatos pode permitir que os treinadores tenham um melhor conhecimento das variáveis de rendimento de cada competição e ajudar as federações a saber quais competições estão mais associadas às variáveis determinantes do espetáculo desportivo, em especial os golos, para traçar propostas de melhora nos aspectos relevantes dos campeonatos. (AU)

Association and Interaction of Genetics and Area-Level Socioeconomic Factors on the Prevalence of Type 2 Diabetes and Obesity.

OBJECTIVE: Quantify the impact of genetic and socioeconomic factors on risk of type 2 diabetes (T2D) and obesity. RESEARCH DESIGN AND METHODS: Among participants in the Mass General Brigham Biobank (MGBB) and UK Biobank (UKB), we used logistic regression models to calculate cross-sectional odds of T2D and obesity using 1) polygenic risk scores for T2D and BMI and 2) area-level socioeconomic risk (educational attainment) measures. The primary analysis included 26,737 participants of European genetic ancestry in MGBB with replication in UKB (N = 223,843), as well as in participants of non-European ancestry (MGBB N = 3,468; UKB N = 7,459). RESULTS: The area-level socioeconomic measure most strongly associated with both T2D and obesity was percent without a college degree, and associations with disease prevalence were independent of genetic risk (P < 0.001 for each). Moving from lowest to highest quintiles of combined genetic and socioeconomic burden more than tripled T2D (3.1% to 22.2%) and obesity (20.9% to 69.0%) prevalence. Favorable socioeconomic risk was associated with lower disease prevalence, even in those with highest genetic risk (T2D 13.0% vs. 22.2%, obesity 53.6% vs. 69.0% in lowest vs. highest socioeconomic risk quintiles). Additive effects of genetic and socioeconomic factors accounted for 13.2% and 16.7% of T2D and obesity prevalence, respectively, explained by these models. Findings were replicated in independent European and non-European ancestral populations. CONCLUSIONS: Genetic and socioeconomic factors significantly interact to increase risk of T2D and obesity. Favorable area-level socioeconomic status was associated with an almost 50% lower T2D prevalence in those with high genetic risk.

Causal factors underlying diabetes risk informed by Mendelian randomisation analysis: evidence, opportunities and challenges.

Diabetes and its complications cause a heavy disease burden globally. Identifying exposures, risk factors and molecular processes causally associated with the development of diabetes can provide important evidence bases for disease prevention and spur novel therapeutic strategies. Mendelian randomisation (MR), an epidemiological approach that uses genetic instruments to infer causal associations between an exposure and an outcome, can be leveraged to complement evidence from observational and clinical studies. This narrative review aims to summarise the evidence on potential causal risk factors for diabetes by integrating published MR studies on type 1 and 2 diabetes, and to reflect on future perspectives of MR studies on diabetes. Despite the genetic influence on type 1 diabetes, few MR studies have been conducted to identify causal exposures or molecular processes leading to increased disease risk. In type 2 diabetes, MR analyses support causal associations of somatic, mental and lifestyle factors with development of the disease. These studies have also identified biomarkers, some of them derived from the gut microbiota, and molecular processes leading to increased disease risk. These studies provide valuable data to better understand disease pathophysiology and explore potential therapeutic targets. Because genetic association studies have mostly been restricted to participants of European descent, multi-ancestry cohorts are needed to examine the role of different types of physical activity, dietary components, metabolites, protein biomarkers and gut microbiome in diabetes development.

Changes in Population Health-Related Behaviors During a COVID-19 Surge: A Natural Experiment.

BACKGROUND: The study of impact of lockdowns on individual health-related behaviors has produced divergent results. PURPOSE: To identify patterns of change in multiple health-related behaviors analyzed as a whole, and their individual determinants. METHODS: Between March and August 2020, we collected data on smoking, alcohol, physical activity, weight, and sleep in a population-based cohort from Catalonia who had available pre-pandemic data. We performed multiple correspondence and cluster analyses to identify patterns of change in health-related behaviors and built multivariable multinomial logistic regressions to identify determinants of behavioral change. RESULTS: In 10,032 participants (59% female, mean (SD) age 55 (8) years), 8,606 individuals (86%) modified their behavior during the lockdown. We identified five patterns of behavioral change that were heterogeneous and directed both towards worsening and improvement in diverse combinations. Patterns ranged from "global worsening" (2,063 participants, 21%) characterized by increases in smoking, alcohol consumption, and weight, and decreases in physical activity levels and sleep time, to "improvement" (2,548 participants, 25%) characterized by increases in physical activity levels, decreases in weight and alcohol consumption, and both increases and decreases in sleep time. Being female, of older age, teleworking, having a higher education level, assuming caregiving responsibilities, and being more exposed to pandemic news were associated with changing behavior (all p < .05), but did not discriminate between favorable or unfavorable changes. CONCLUSIONS: Most of the population experienced changes in health-related behavior during lockdowns. Determinants of behavior modification were not explicitly associated with the direction of changes but allowed the identification of older, teleworking, and highly educated women who assumed caregiving responsibilities at home as susceptible population groups more vulnerable to lockdowns.

Lockdowns implemented during the first surge of the COVID-19 pandemic created highly disruptive scenarios impacting many aspects of life, including health-related behaviors. While early studies on isolated health-related behaviors partly aid in the understanding of changes in some of these behaviors, there is robust evidence supporting the idea that health-related behaviors and their changes often co-occur and should be studied and analyzed as a whole. Hence, in this study, we used hypothesis-free methods to identify inter-dependent patterns of change in health-related behaviors including tobacco smoking, alcohol consumption, physical activity, sleep, and weight in a population-based sample of 10,032 adults from Catalonia, Spain. We found that 86% of participants modified their health-related behavior during the lockdown as we identified five patterns of behavioral change, ranging from general worsening to improvement, in diverse combinations. Additionally, we found that being female, older age, teleworking, highly educated, assuming caregiving responsibilities, and having a high exposure to pandemic news were main the determinants of patterns characterized by changing behaviors (both worsening and improving). Overall, our results highlight the heterogeneity, co-occurrence, and inter-play between health-related behaviors under a natural experiment, and identify common demographic, socio-environmental and behavioral factors that might predict changes in behavior.

The mental health burden of racial and ethnic minorities during the COVID-19 pandemic.

Racial/ethnic minorities have been disproportionately impacted by COVID-19. The effects of COVID-19 on the long-term mental health of minorities remains unclear. To evaluate differences in odds of screening positive for depression and anxiety among various racial and ethnic groups during the latter phase of the COVID-19 pandemic, we performed a cross-sectional analysis of 691,473 participants nested within the prospective smartphone-based COVID Symptom Study in the United States (U.S.) and United Kingdom (U.K). from February 23, 2021 to June 9, 2021. In the U.S. (n=57,187), compared to White participants, the multivariable odds ratios (ORs) for screening positive for depression were 1·16 (95% CI: 1·02 to 1·31) for Black, 1·23 (1·11 to 1·36) for Hispanic, and 1·15 (1·02 to 1·30) for Asian participants, and 1·34 (1·13 to 1·59) for participants reporting more than one race/other even after accounting for personal factors such as prior history of a mental health disorder, COVID-19 infection status, and surrounding lockdown stringency. Rates of screening positive for anxiety were comparable. In the U.K. (n=643,286), racial/ethnic minorities had similarly elevated rates of positive screening for depression and anxiety. These disparities were not fully explained by changes in leisure time activities. Racial/ethnic minorities bore a disproportionate mental health burden during the COVID-19 pandemic. These differences will need to be considered as health care systems transition from prioritizing infection control to mitigating long-term consequences.

Using genetic variation to disentangle the complex relationship between food intake and health outcomes.

Diet is considered as one of the most important modifiable factors influencing human health, but efforts to identify foods or dietary patterns associated with health outcomes often suffer from biases, confounding, and reverse causation. Applying Mendelian randomization in this context may provide evidence to strengthen causality in nutrition research. To this end, we first identified 283 genetic markers associated with dietary intake in 445,779 UK Biobank participants. We then converted these associations into direct genetic effects on food exposures by adjusting them for effects mediated via other traits. The SNPs which did not show evidence of mediation were then used for MR, assessing the association between genetically predicted food choices and other risk factors, health outcomes. We show that using all associated SNPs without omitting those which show evidence of mediation, leads to biases in downstream analyses (genetic correlations, causal inference), similar to those present in observational studies. However, MR analyses using SNPs which have only a direct effect on the exposure on food exposures provided unequivocal evidence of causal associations between specific eating patterns and obesity, blood lipid status, and several other risk factors and health outcomes.

Genetic Architecture of Plasma Alpha-Aminoadipic Acid Reveals a Relationship With High-Density Lipoprotein Cholesterol.

Background Elevated plasma levels of alpha-aminoadipic acid (2-AAA) have been associated with the development of type 2 diabetes and atherosclerosis. However, the nature of the association remains unknown. Methods and Results We identified genetic determinants of plasma 2-AAA through meta-analysis of genome-wide association study data in 5456 individuals of European, African, and Asian ancestry from the Framingham Heart Study, Diabetes Prevention Program, Jackson Heart Study, and Shanghai Women's and Men's Health Studies. No single nucleotide polymorphisms reached genome-wide significance across all samples. However, the top associations from the meta-analysis included single-nucleotide polymorphisms in the known 2-AAA pathway gene DHTKD1, and single-nucleotide polymorphisms in genes involved in mitochondrial respiration (NDUFS4) and macrophage function (MSR1). We used a Mendelian randomization instrumental variable approach to evaluate relationships between 2-AAA and cardiometabolic phenotypes in large disease genome-wide association studies. Mendelian randomization identified a suggestive inverse association between increased 2-AAA and lower high-density lipoprotein cholesterol (P=0.005). We further characterized the genetically predicted relationship through measurement of plasma 2-AAA and high-density lipoprotein cholesterol in 2 separate samples of individuals with and without cardiometabolic disease (N=98), and confirmed a significant negative correlation between 2-AAA and high-density lipoprotein (rs=-0.53, P<0.0001). Conclusions 2-AAA levels in plasma may be regulated, in part, by common variants in genes involved in mitochondrial and macrophage function. Elevated plasma 2-AAA associates with reduced levels of high-density lipoprotein cholesterol. Further mechanistic studies are required to probe this as a possible mechanism linking 2-AAA to future cardiometabolic risk.

Precision nutrition in diabetes: when population-based dietary advice gets personal.

Diet plays a fundamental role in maintaining long-term health, with healthful diets being endorsed by current dietary guidelines for the prevention and management of type 2 diabetes. However, the response to dietary interventions varies widely, highlighting the need for refinement and personalisation beyond population-based 'one size fits all'. This article reviews the clinical evidence supporting precision nutrition as a fundamental approach for dietary advice in diabetes. Further, it proposes a framework for the eventual implementation of precision nutrition and discusses key challenges for the application of this approach in the prevention of diabetes. One implication of this approach is that precision nutrition would not exclude the parallel goal of population-based healthy dietary advice. Nevertheless, the shift in prioritising precision nutrition is needed to reflect the dynamic nature of responses to dietary interventions that vary among individuals and change over the life course.

Polygenic scores, diet quality, and type 2 diabetes risk: An observational study among 35,759 adults from 3 US cohorts.

BACKGROUND: Both genetic and lifestyle factors contribute to the risk of type 2 diabetes, but the extent to which there is a synergistic effect of the 2 factors is unclear. The aim of this study was to examine the joint associations of genetic risk and diet quality with incident type 2 diabetes. METHODS AND FINDINGS: We analyzed data from 35,759 men and women in the United States participating in the Nurses' Health Study (NHS) I (1986 to 2016) and II (1991 to 2017) and the Health Professionals Follow-up Study (HPFS; 1986 to 2016) with available genetic data and who did not have diabetes, cardiovascular disease, or cancer at baseline. Genetic risk was characterized using both a global polygenic score capturing overall genetic risk and pathway-specific polygenic scores denoting distinct pathophysiological mechanisms. Diet quality was assessed using the Alternate Healthy Eating Index (AHEI). Cox models were used to calculate hazard ratios (HRs) for type 2 diabetes after adjusting for potential confounders. With over 902,386 person-years of follow-up, 4,433 participants were diagnosed with type 2 diabetes. The relative risk of type 2 diabetes was 1.29 (95% confidence interval [CI] 1.25, 1.32; P < 0.001) per standard deviation (SD) increase in global polygenic score and 1.13 (1.09, 1.17; P < 0.001) per 10-unit decrease in AHEI. Irrespective of genetic risk, low diet quality, as compared to high diet quality, was associated with approximately 30% increased risk of type 2 diabetes (Pinteraction = 0.69). The joint association of low diet quality and increased genetic risk was similar to the sum of the risk associated with each factor alone (Pinteraction = 0.30). Limitations of this study include the self-report of diet information and possible bias resulting from inclusion of highly educated participants with available genetic data. CONCLUSIONS: These data provide evidence for the independent associations of genetic risk and diet quality with incident type 2 diabetes and suggest that a healthy diet is associated with lower diabetes risk across all levels of genetic risk.