From biobanking to personalized prevention of obesity, diabetes and metabolic syndrome

The growing prevalence of metabolic disorders creates an increasing demand for novel approaches to their prevention and therapy. Novel genetic diagnostic technologies are developed every year, which makes it possible to identify people who are at the highest genetic risk of diabetes, non-alcoholic fatty liver disease, and metabolic syndrome. Early intervention strategies can be used to prevent metabolic disorders in this group of people. Genetic risk scores (GRSs) are a powerful tool to identify people with a high genetic risk. Millions of genetic variants are analyzed in genome-wide association studies in order to combine them into GRSs. It has become possible to store and process such huge amounts of data with the help of biobanks, where biological samples are stored according to international standards. Genetic studies include more and more people every year that increases the predictive power of GRSs. It has already been demonstrated that the use of GRSs makes future preventive measures more effective. In the near future, GRSs are likely to become part of clinical guidelines so that they can be widely used to identify people at high risk for metabolic syndrome and its components.

Frailty, lifestyle, genetics and dementia risk

ObjectiveTo optimise dementia prevention strategies, we must understand the complex relationships between lifestyle behaviours, frailty and genetics.MethodsWe explored relationships between frailty index, healthy lifestyle and polygenic risk scores (all assessed at study entry) and incident all-cause dementia as recorded on hospital admission records and death register data.ResultsThe analytical sample had a mean age of 64.1 years at baseline (SD=2.9) and 53% were women. Incident dementia was detected in 1762 participants (median follow-up time=8.0 years). High frailty was associated with increased dementia risk independently of genetic risk (HR 3.68, 95% CI 3.11 to 4.35). Frailty mediated 44% of the relationship between healthy lifestyle behaviours and dementia risk (indirect effect HR 0.95, 95% CI 0.95 to 0.96). Participants at high genetic risk and with high frailty had 5.8 times greater risk of incident dementia compared with those at low genetic risk and with low frailty (HR 5.81, 95% CI 4.01 to 8.42). Higher genetic risk was most influential in those with low frailty (HR 1.31, 95% CI 1.22 to 1.40) but not influential in those with high frailty (HR 1.09, 95% CI 0.92 to 1.28).ConclusionFrailty is strongly associated with dementia risk and affects the risk attributable to genetic factors. Frailty should be considered an important modifiable risk factor for dementia and a target for dementia prevention strategies, even among people at high genetic risk.

The DAMA25 Study: Feasibility of a Lifestyle Intervention Programme for Cancer Risk Reduction in Young Italian Women with Breast Cancer Family History

Background: Diet and physical activity (PA) can modulate sporadic and possibly familial breast cancer (BC) risk. The DAMA25 study is a single-arm 12-month intervention aimed to modify dietary and PA habits in healthy young Italian women with a positive BC family history, categorized as having intermediate or high genetic risk according to NICE (National Institute for Health and Cancer Excellence) guidelines. Methods: Participants, aged 25–49 years, were asked to adopt a diet mainly based on plant-based foods and to increase moderate daily activities combined with 1 h/week of more intense activity. Cooking lessons, collective walks, educational sessions, brochures, booklets and online materials were implemented. Dietary, PA habits and anthropometry were collected at baseline and at the end of the intervention. Changes on dietary, lifestyle habits and anthropometry were evaluated by GLM adjusted for weight reduction counselling aimed to participant with a BMI ≥ 25, age and baseline values of each variable. Results: Out of 237 eligible women 107 (45.2%) agreed to participate and among them 98 (91.6%) completed the intervention. The adherence rate of the intervention was 77.8%. We observed a reduction in red and processed meat (p < 0.0001) and cakes consumption (p < 0.0001). Consumption of whole grain bread (p < 0.001), leafy vegetables (p = 0.01) and olive oil (p = 0.04) increased. We observed an increase in moderate (p < 0.0001) and more intense (p < 0.0001) recreational activities, an average 1.4 kg weight loss (p = 0.005), a reduction of waist circumference (p < 0.001) and fat mass (p = 0.015). Conclusions: The DAMA25 study shows that it is feasible an intervention to improve in the short-term dietary and PA habits and anthropometry in women with high BC familial risk.

Healthy Sleep Associated With Lower Risk of Hypertension Regardless of Genetic Risk: A Population-Based Cohort Study

Background: Hypertension is a leading contributor to the global burden of disease and to mortality. The combined effects of sleep factors on the risk of hypertension are unclear. We aimed to evaluate the effect of combined sleep factors on the risk of hypertension and to explore whether this association is independent of genetic risk.Methods: This population-based prospective cohort study included 170,378 participants from the UK Biobank study. We conducted a healthy sleep score based on a combination of major five sleep factors and a genetic risk score based on 118 risk variants. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).Results: A total of 170,378 participants were included. Compared to participants with a healthy sleep score of 0–1, those with healthy sleep scores of 2 (HR, 0.90; 95% CI, 0.83–0.98), 3 (HR, 0.81; 95% CI, 0.75–0.88), 4 (HR, 0.74; 95% CI, 0.68–0.81), or 5 (HR, 0.67; 95% CI, 0.59–0.77) had increasingly lower risks of hypertension (P for trend &lt;0.001). Participants with high genetic risk and an unfavorable sleep pattern had a 1.80-fold greater risk of hypertension than participants with low genetic risk and a favorable sleep pattern. The association between sleep patterns and hypertension persisted in subgroup analysis, stratified by the genetic risk. Nearly 18.2% of hypertension events in this cohort could be attributed to unfavorable sleep pattern.Conclusions: Favorable sleep pattern was associated with a low risk of hypertension, regardless of genetic risk. These findings highlight the potential of sleep interventions to reduce risk of hypertension across entire populations.

IGF2BP3 As an N6-Methyladenosine Reader Promotes Acute Myeloid Leukemia Progression By Regulating the Stability of Target RNA

Background: N6-methyladenosine (m6A) is the most common post-transcriptional modification of eukaryotic mRNA. Recent evidence suggests that dysregulated m6A-associated proteins and m6A modifications play a pivotal role in the initiation and progression of diseases such as cancer. Here, we identified that IGF2BP3 is specifically overexpressed in acute myeloid leukemia (AML), which constitutes a subtype of this malignancy associated with poor prognosis and high genetic risk. Methods: Bioinformatics analysis of public databases was performed to screen the differentially expressed m6A regulators in AML. Clinical samples were collected to detect the expression of IGF2BP3 in AML by RT-qPCR. The effects of IGF2BP3 on the proliferation, apoptosis and cycle of AML cells were detected by CCK-8 and flow cytometry. RNA-seq was used to identify target genes of IGF2BP3 by integrating analysis with RIP-Seq, iCLIP-Seq and MeRIP-Seq data sets. Results:High expression of IGF2BP3 is closely associated with poor prognosis of AML and is higher in patients with high genetic risk group. IGF2BP3 was the lowest expressed in AML-M3 and the highest expressed in RUNX1 mutant type. IGF2BP3 is required for maintaining AML cell survival in an m6A-dependent manner, and knockdown of IGF2BP3 suppressed dramatically induces apoptosis, reduces proliferation and impaired leukemic capacity AML cells in vitro and in vivo. Mechanistically, IGF2BP3 interacts with RCC2 mRNA and stabilizes the expression of m6A-tagged RNA. Conclusions:We provided compelling evidence to demonstrate that m6A reader IGF2BP3 contributed to tumorigenesis and poor prognosis of AML, which can serve as a target to develop therapeutics for cancer treatment. Disclosures No relevant conflicts of interest to declare. Disclosures No relevant conflicts of interest to declare.

Knowledge and Awareness about the Connection between Lifestyle and Dementia among Adolescents

Background and Aim: Dementia is a group of symptoms characterized by memory loss, judgemental loss, forgetfulness. Dementia cannot be cured; but can be prevented. There are seven stages of Dementia, no cognitive decline being the first stage to very severe cognitive decline being the seventh stage. Healthy lifestyle is important for lower risk of Dementia. Smoking, consumption of alcohol, negative thinking, depression, stress, anxiety, lack of sleep, unhealthy diet causes Dementia. Diet plays a very important role in prevention of dementia; foods such as red meat, sugar, fatty foods can increase the risk of dementia whereas foods rich in fibres, fruits can reduce the risk of Dementia. The main aim of this study is to assess the knowledge about lifestyle and dementia. Materials and Methods: This is a cross sectional survey. 121 adolescents of Saveetha Dental College, Chennai participated in the survey which was conducted through Google forms in February 2021. The questionnaire consisted of 19 questions. The data was analyzed with the help of SPSS software and chi-square test was done for the correlation between gender and awareness. Chi-square test was done for the correlation of gender with awareness among the population. ‘p-value’ was calculated and value < 0.05 was considered as significant. Results: Out of that 62 were females and 59 were males. Females were more aware about healthy lifestyles and its connection with dementia than males. 92.56% of people were aware that physical activity promotes a healthy brain. 69.2% agreed that depression can increase risk of Dementia. Majority of them agreed that physical exercise can promote a healthy brain. Conclusion: This study revealed that lifestyle is highly associated with dementia among adolescents. Healthy lifestyle leads to lower risk of dementia even if there’s high genetic risk. Females were aware about the diet which is healthy for lower risk of dementia and more smoking affects the memory. However, most of the people were neutral about the relation between BMI and Dementia.

Modification effect of ideal cardiovascular health metrics on genetic association with incident heart failure in the China Kadoorie Biobank and the UK Biobank

Background Both genetic and cardiovascular factors contribute to the risk of developing heart failure (HF), but whether idea cardiovascular health metrics (ICVHMs) offset the genetic association with incident HF remains unclear. Objectives To investigate the genetic association with incident HF as well as the modification effect of ICVHMs on such genetic association in Chinese and British populations. Methods An ICVHMs based on smoking, drinking, physical activity, diets, body mass index, waist circumference, blood pressure, blood glucose, and blood lipids, and a polygenic risk score (PRS) for HF were constructed in the China Kadoorie Biobank (CKB) of 96,014 participants and UK Biobank (UKB) of 335,782 participants which were free from HF and severe chronic diseases at baseline. Results During the median follow-up of 11.38 and 8.73 years, 1451 and 3169 incident HF events were documented in CKB and UKB, respectively. HF risk increased monotonically with the increase of PRS per standard deviation (CKB: hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.07, 1.32; UKB: 1.07; 1.03, 1.11; P for trend < 0.001). Each point increase in ICVHMs was associated with 15% and 20% lower risk of incident HF in CKB (0.85; 0.81, 0.90) and UKB (0.80; 0.77, 0.82), respectively. Compared with unfavorable ICVHMs, favorable ICVHMs was associated with a lower HF risk, with 0.71 (0.44, 1.15), 0.41 (0.22, 0.77), and 0.48 (0.30, 0.77) in the low, intermediate, and high genetic risk in CKB and 0.34 (0.26, 0.44), 0.32 (0.25, 0.41), and 0.37 (0.28, 0.47) in UKB (P for multiplicative interaction > 0.05). Participants with low genetic risk and favorable ICVHMs, as compared with high genetic risk and unfavorable ICVHMs, had 56~72% lower risk of HF (CKB 0.44; 0.28, 0.70; UKB 0.28; 0.22, 0.37). No additive interaction between PRS and ICVHMs was observed (relative excess risk due to interaction was 0.05 [−0.22, 0.33] in CKB and 0.04 [−0.14, 0.22] in UKB). Conclusions In CKB and UKB, genetic risk and ICVHMs were independently associated with the risk of incident HF, which suggested that adherence to favorable cardiovascular health status was associated with a lower HF risk among participants with all gradients of genetic risk.