Physical activity alters the effect of genetic determinants of adiposity on hypertension among individuals of European ancestry in the UKB.

Hypertension is a leading risk factor for cardiovascular disease and is modulated by genetic variants. This study aimed to assess the effect of obesity genetic liability and physical activity on hypertension among European and African ancestry individuals within the UK Biobank (UKB). Participants were 230 115 individuals of European ancestry and 3239 individuals of African ancestry from UKB. Genetic liability for obesity were estimated using previously published data including genetic variants and effect sizes for body mass index (BMI), waist-hip ratio (WHR) and waist circumference (WC) using Plink software. The outcome was defined as stage 2 hypertension (systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥90 mmHg, or the use of anti-hypertensive medications). The association between obesity genetic liability and the outcome was assessed across categories of self-reported physical activity using logistic regression. Among European ancestry participants, there was up to a 1.2 greater odds of hypertension in individuals with high genetic liability and low physical activity compared to individuals with low genetic liability and high physical activity (p < 0.001). In individuals engaging in low levels of physical activity compared with moderate/high physical activity, the effect of BMI genetic liability on hypertension was greater (p interaction = 0.04). There was no evidence of an association between obesity genetic liability and hypertension in individuals of African ancestry in the whole sample or within separate physical activity groups (p > 0.05). This study suggests that higher physical activity levels are associated with lower odds of stage 2 hypertension among European ancestry individuals who carry high genetic liability for obesity. This cannot be inferred for individuals of African ancestry, possibly due to the low African ancestry sample size within the UKB.

Oligogenic inheritance in severe adult obesity.

BACKGROUND/OBJECTIVE: The genetic architecture of extreme non-syndromic obesity in adults remains to be elucidated. A range of genes are known to cause monogenic obesity, but even when pathogenic mutations are present, there may be variable penetrance. METHODS: Whole-exome sequencing (WES) was carried out on a 15-year-old male proband of Pakistani ancestry who had severe obesity. This was followed by family segregation analysis, using Sanger sequencing. We also undertook re-analysis of WES data from 91 unrelated adults with severe obesity (86% white European ancestry) from the Personalised Medicine for Morbid Obesity (PMMO) cohort, recruited from the UK National Health Service. RESULTS: We identified an oligogenic mode of inheritance of obesity in the proband's family-this provided the impetus to reanalyze existing sequence data in a separate dataset. Analysis of PMMO participant data revealed two further patients who carried more than one rare, predicted-deleterious mutation in a known monogenic obesity gene. In all three cases, the genes involved had known autosomal dominant inheritance, with incomplete penetrance. CONCLUSION: Oligogenic inheritance may explain some of the variable penetrance in Mendelian forms of obesity. We caution clinicians and researchers to avoid confining sequence analysis to individual genes and, in particular, not to stop looking when the first potentially-causative mutation is found.

Associations of adolescents' diet and meal patterns with school performance in the Northern Finland Birth Cohort 1986: A Mendelian randomisation study.

BACKGROUND: Several observational studies indicate that dietary habits in children and adolescents are associated with school performance. These associations are heavily confounded by socio-economic characteristics, such as household income and parents' educational attainment, amongst other factors. The objective of this study was to explore the association between diet and school performance in adolescents from the Northern Finland Birth Cohort 1986 (NFBC1986). METHODS: Dietary and school performance data were collected using self-reported questionnaires from adolescents in the NFBC1986 cross-sectional, 16-year follow-up study. In this work we derived exploratory factors for the dietary variables, frequency of skipping main meals and school performance variables, performed genome-wide association studies (GWAS) against these factors to obtain genetic association data and conducted one-sample and two-sample Mendelian randomisation (MR) analyses using individual level data for up to 9220 adolescents in NFBC1986 and GWAS results from external cohorts. We report observational and MR effects of diet on school performance and cognition-related phenotypes. RESULTS: The observational study and the one-sample Mendelian randomisation analysis showed that high fat, salt and sugar (HFSS) consumption was associated with poor school performance in general/science subjects (-0.080, -0.128 to -0.033) and staple food consumption with better school performance in general/science subjects (0.071, 0.024 to 0.119) and physical education (0.065, 0.021 to 0.110). Findings from our two-sample MR analysis identified dietary principal components described best as whole brain bread, wheat, cheese, oat cereal and red wine to be associated with higher educational attainment and other cognition-related phenotypes. CONCLUSION: Using genetics, we highlighted the potential role of HFSS food consumption and consumption of the components of a staple food diet for school performance. However, further research is required to find conclusive evidence that could support a causal role of diet on school performance.

Depression mediates the relationship between alexithymia and obesity in the Northern Finland Birth Cohort 1966 (NFBC1966).

BACKGROUND: The fact that a complex relationship exists between alexithymia and body mass index (BMI) is well established, but the underlying mechanisms remain poorly understood. Here, we explore the relationship between alexithymia and depressive symptoms in relation to adiposity measures, including the direct and indirect effect of alexithymia and depressive symptoms on obesity over a 15-year time-period, in the Northern Finland Birth Cohort 1966 (NFBC1966). METHODS: The study included individuals from the Northern Finland Birth Cohort 1966 (NFBC1966) who had available data for adiposity measures (body mass index and waist-to-hip ratio), alexithymia (measured by the 20-Item Toronto Alexithymia Scale: TAS-20), depressive symptoms (measured by the 13-item depression subscale of Hopkins Symptom Checklist: HSCL-13) at age of 31 years (n = 4773) and 46 years (n = 4431). Pearson's (r) correlation, and multiple linear regression were used to investigate the relationships between alexithymia, depressive symptoms, and adiposity measures. The potential mediating role of depressive symptoms was examined via Hayes' procedure (PROCESS). RESULTS: Positive correlations were confirmed between adiposity measures (BMI and WHR) and the TAS-20 score (and its subscale), but not between obesity and HSCL-13 score. The strongest correlation was between the DIF (difficulty identifying feelings) subscale of the TAS-20 and HSCL-13 at both time points (31 y: r(3013) = 0.41, p < 0.01, 46 y: r(3013) = 0.43, p < 0.01). Depressive symptoms completely (z = 2.55 (±0.00003), p = 0.01) and partly (z = 2.16 (±0.0001), p = 0.03) mediated the alexithymia-obesity relationship over the 15-year time-period. LIMITATIONS: Other psychological and environmental factors such as interoception, dietary intake and physical activities may also play a role as a potential mediating factor in alexithymia-obesity relationship. CONCLUSIONS: Our findings provide additional insights of theoretical framework of depressive symptoms mediation effect in the relationship between alexithymia and obesity. Alexithymia and depression should, therefore, be considered in the design of future clinical obesity research.

Higher Waist Hip Ratio Genetic Risk Score Is Associated with Reduced Weight Loss in Patients with Severe Obesity Completing a Meal Replacement Programme.

Background: A better understanding of the influence of genetic factors on the response to lifestyle interventions in people with obesity may allow the development of more personalised, effective and efficient therapeutic strategies. We sought to determine the influence of six obesity-related genetic risk scores on the magnitude of weight lost by patients with severe obesity who completed a dietary intervention. Methods: In this single-centre prospective cohort study, participants with severe and complicated obesity who completed a 24-week, milk-based meal replacement programme were genotyped to detect the frequency of common risk alleles for obesity and type 2 diabetes-related traits. Genetic risk scores (GRS) for six of these traits were derived. Participants with a potentially deleterious monogenic gene variant were excluded from the analysis. Results: In 93 patients completing the programme who were not carrying a known obesity-related gene mutation, 35.5% had diabetes, 53.8% were female, mean age was 51.4 ± 11 years, mean body mass index was 51.5 ± 8.7 and mean total weight loss percent at 24 weeks was 16 ± 6.3%. The waist-hip ratio (WHR) GRS was inversely associated with percentage total weight loss at 24 weeks (adjusted ß for one standard deviation increase in WHR GRS -11.6 [-23.0, -0.3], p = 0.045), and patients in the lowest tertile of WHR GRS lost more weight. Conclusions: Patients with severe and complicated obesity with a genetic predisposition to central fat accumulation had less weight loss in a 24-week milk-based meal replacement programme, but there was no evidence for influence from the five other obesity-related genetic risk scores on the response to dietary restriction.

Urinary Sodium Excretion Enhances the Effect of Alcohol on Blood Pressure.

Alcohol consumption is linked to urinary sodium excretion and both of these traits are linked to hypertension and cardiovascular diseases (CVDs). The interplay between alcohol consumption and sodium on hypertension, and cardiovascular diseases (CVDs) is not well-described. Here, we used genetically predicted alcohol consumption and explored the relationships between alcohol consumption, urinary sodium, hypertension, and CVDs. METHODS: We performed a comparative analysis among 295,189 participants from the prospective cohort of the UK Biobank (baseline data collected between 2006 and 2010). We created a genetic risk score (GRS) using 105 published genetic variants in Europeans that were associated with alcohol consumption. We explored the relationships between GRS, alcohol consumption, urinary sodium, blood pressure traits, and incident CVD. We used linear and logistic regression and Cox proportional hazards (PH) models and Mendelian randomization in our analysis. RESULTS: The median follow-up time for composite CVD and stroke were 6.1 years and 7.1 years respectively. Our analyses showed that high alcohol consumption is linked to low urinary sodium excretion. Our results showed that high alcohol GRS was associated with high blood pressure and higher risk of stroke and supported an interaction effect between alcohol GRS and urinary sodium on stage 2 hypertension (Pinteraction = 0.03) and CVD (Pinteraction = 0.03), i.e., in the presence of high urinary sodium excretion, the effect of alcohol GRS on blood pressure may be enhanced. CONCLUSIONS: Our results show that urinary sodium excretion may offset the risk posed by genetic risk of alcohol consumption.

Mendelian randomisation analyses of UK Biobank and published data suggest that increased adiposity lowers risk of breast and prostate cancer.

Breast (BCa) and prostate (PrCa) cancer are the first and second most common types of cancer in women and men, respectively. We aimed to explore the causal effect of adiposity on BCa and PrCa risk in the UK Biobank and published data. We used Mendelian randomisation (MR) to assess the causal effect of body mass index (BMI), body fat percentage (BFP), waist circumference (WC), hip circumference (HC), and waist-to-hip ratio (WHR) on BCa and PrCa risk. We found that increased BMI, WC and HC decreased the risk of breast cancer (OR 0.70 per 5.14 kg/m2 [0.59-0.85, p = 2.1 × 10-4], 0.76 per 12.49 cm [60-0.97, p = 0.028] and 0.73 per 10.31 cm [0.59-0.90, p = 3.7 × 10-3], respectively) and increased WC and BMI decreased the risk of prostate cancer (0.68 per 11.32 cm [0.50-0.91, p = 0.01] and 0.76 per 10.23 kg/m2 [0.61-0.95, p = 0.015], respectively) in UK Biobank participants. We confirmed our results with a two-sample-MR of published data. In conclusion, our results suggest a protective effect of adiposity on the risk of BCa and PrCa highlighting the need to re-evaluate the role of adiposity as cancer risk factor.

How do lipids influence risk of violence, self-harm and suicidality in people with psychosis? A systematic review.

OBJECTIVES: Low cholesterol has been linked with violent and suicidal behaviour in people with schizophrenia. This association, if consistently present, may be a promising biological marker that could assist clinicians in decision making regarding risk and treatment. We conducted a systematic review to assess whether there is a reliable association between lipid profile (total cholesterol, high- and low-density lipoprotein cholesterol, and triglycerides) and aggression, self-harm or suicide in people with schizophrenia, and whether effects are similar in males and females. METHOD: Relevant databases were searched to identify primary research studies (up to November 2020) that (1) involved adults (some samples also included 16- to 18-year olds) with a confirmed diagnosis of schizophrenia, schizoaffective disorder or psychosis; and (2) included a standardised assessment of verbal aggression, physical aggression against objects, physical aggression against self (including suicide) or others. The search yielded 23 studies eligible for inclusion following a quality appraisal. RESULTS: Suicidality was the most commonly assessed subtype of aggression (20 studies). For suicidality, about half the studies, including the study with the largest sample size, found a link with total cholesterol. An association between low total cholesterol and violence towards others was found in six of nine studies that investigated this. The evidence for a link with violence was the strongest for total cholesterol, followed by low-density lipoprotein cholesterol and high-density lipoprotein cholesterol, and the weakest for triglycerides. Only a few studies investigated sex differences and yielded mixed evidence. Studies focussed on self-harm as well as involving females in forensic settings were lacking. CONCLUSION: There is encouraging evidence of an association between low total cholesterol and aggression towards others as well as suicidality in schizophrenia. Future studies should systematically explore this association in people with schizophrenia who have a significant history of violence, suicidality and self-harm, both inpatients and community, and also investigate underlying mechanisms.

No Evidence That Genetic Variation at the Klotho Locus Is Associated With Longevity in Caucasians from the Newcastle 85+ Study and the UK Biobank.

The demographics of Western populations are changing, with an increase in the proportion of older adults. There is evidence to suggest that genetic factors may influence the aging process: studying these may lead to interventions to help individuals live a longer and healthier life. Evidence from several groups indicates that Klotho (KL), a gene encoding a single-pass transmembrane protein that acts as an FGF23 co-receptor, may be associated with longevity and healthy aging. We aimed to explore this area further by comparing the genotype counts in 642 long-lived individuals from the Newcastle 85+ Study with 18 295 middle-aged Newcastle-based controls from the UK Biobank to test whether variants at the KL gene locus are over- or under-represented in older individuals. If KL is associated with longevity, then we would expect the genotype counts to differ between the 2 cohorts. We found that the rs2283368 CC genotype and the rs9536338 C allele, but not the KL-VS haplotype, were associated with reaching very old age. However, these associations did not replicate in the remainder of the UK Biobank cohort. Thus, our results do not reliably support the role of KL as a longevity factor.

Who will benefit from bariatric surgery for diabetes? A protocol for an observational cohort study.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) and obesity are pandemic diseases that lead to a great deal of morbidity and mortality. The most effective treatment for obesity and T2DM is bariatric or metabolic surgery; it can lead to long-term diabetes remission with 4 in 10 of those undergoing surgery having normal blood glucose on no medication 1 year postoperatively. However, surgery carries risks and, additionally, due to resource limitations, there is a restricted number of patients who can access this treatment. Moreover, not all those who undertake surgery respond equally well metabolically. The objective of the current research is to prospectively investigate predictors of T2DM response following metabolic surgery, including those directly involved in its aetiopathogenesis such as fat distribution and genetic variants. This will inform development of a clinically applicable model to help prioritise this therapy to those predicted to have remission. METHODS AND ANALYSIS: A prospective multicentre observational cohort study of adult patients with T2DM and obesity undergoing Roux-en-Y gastric bypass surgery. Patients will be comprehensively assessed before surgery to determine their clinical, metabolic, psychological, genetic and fat distribution profiles. A multivariate logistic regression model will be used to assess the value of the factors derived from the preoperative assessment in terms of prediction of diabetes remission. ETHICS AND DISSEMINATION: Formal ethics review was undertaken with a favourable opinion (UK HRA RES reference number 18/LO/0931). The dissemination plan is to present the results at conferences, in peer-reviewed journals as well as to lay media and to patient organisations. TRIAL REGISTRATION DETAILS: ClinicalTrials.gov, Identifier: NCT03842475.

Secondary analyses of global datasets: do obesity and physical activity explain variation in diabetes risk across populations?

Type 2 diabetes rates vary significantly across geographic regions. These differences are sometimes assumed to be entirely driven by differential distribution of environmental triggers, including obesity and insufficient physical activity (IPA). In this review, we discuss data which conflicts with this supposition. We carried out a secondary analysis of publicly available data to unravel the relative contribution of obesity and IPA towards diabetes risk across different populations. We used sex-specific, age-standardized estimates from Non-Communicable Disease Risk Factor Collaboration (NCD-RisC) on diabetes (1980-2014) and obesity (1975-2016) rates, in 200 countries, and from WHO on IPA rates in 168 countries in the year 2016. NCD-RisC and WHO organized countries into nine super-regions. All analyses were region- and sex-specific. Although obesity has been increasing since 1975 in every part of the world, this was not reflected in a proportional increase in diabetes rates in several regions, including Central and Eastern Europe, and High-income western countries region. Similarly, the association of physical inactivity with diabetes is not homogeneous across regions. Countries from different regions across the world could have very similar rates of diabetes, despite falling on opposite ends of IPA rate spectrum. The combined effect of obesity and IPA on diabetes risk was analyzed at the worldwide and country level. The overall findings highlighted the larger impact of obesity on disease risk; low IPA rates do not seem to be protective of diabetes, when obesity rates are high. Despite that, some countries deviate from this overall observation. Sex differences were observed across all our analyses. Overall, data presented in this review indicate that different populations, while experiencing similar environmental shifts, are apparently differentially subject to diabetes risk. Sex-related differences observed suggest that males and females are either subject to different risk factor exposures or have different responses to them.

Hemizygous mutations in L1CAM in two unrelated male probands with childhood onset psychosis.

OBJECTIVE: To identify genes underlying childhood onset psychosis. METHODS: Patients with onset of psychosis at age 13 or younger were identified from clinics across England, and they and their parents were exome sequenced and analysed for possible highly penetrant genetic contributors. RESULTS: We report two male childhood onset psychosis patients of different ancestries carrying hemizygous very rare possibly damaging missense variants (p.Arg846His and p.Pro145Ser) in the L1CAM gene. L1CAM is an X-linked Mendelian disease gene in which both missense and loss of function variants are associated with syndromic forms of intellectual disability and developmental disorder. CONCLUSIONS: This is the first study reporting a possible extension of the phenotype of L1CAM variant carriers to childhood onset psychosis. The family history and presence of other significant rare genetic variants in the patients suggest that there may be genetic interactions modulating the presentation.

Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length.

Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.

Genome-Wide and Abdominal MRI Data Provide Evidence That a Genetically Determined Favorable Adiposity Phenotype Is Characterized by Lower Ectopic Liver Fat and Lower Risk of Type 2 Diabetes, Heart Disease, and Hypertension.

Recent genetic studies have identified alleles associated with opposite effects on adiposity and risk of type 2 diabetes. We aimed to identify more of these variants and test the hypothesis that such favorable adiposity alleles are associated with higher subcutaneous fat and lower ectopic fat. We combined MRI data with genome-wide association studies of body fat percentage (%) and metabolic traits. We report 14 alleles, including 7 newly characterized alleles, associated with higher adiposity but a favorable metabolic profile. Consistent with previous studies, individuals carrying more favorable adiposity alleles had higher body fat % and higher BMI but lower risk of type 2 diabetes, heart disease, and hypertension. These individuals also had higher subcutaneous fat but lower liver fat and a lower visceral-to-subcutaneous adipose tissue ratio. Individual alleles associated with higher body fat % but lower liver fat and lower risk of type 2 diabetes included those in PPARG, GRB14, and IRS1, whereas the allele in ANKRD55 was paradoxically associated with higher visceral fat but lower risk of type 2 diabetes. Most identified favorable adiposity alleles are associated with higher subcutaneous and lower liver fat, a mechanism consistent with the beneficial effects of storing excess triglycerides in metabolically low-risk depots.

Relationship between BMI and emotion-handling capacity in an adult Finnish population: The Northern Finland Birth Cohort 1966.

BACKGROUND: Alexithymia, a difficulty in identifying and expressing emotions, has been associated with obesity and eating disorders in small-scale cross-sectional studies. Here, we assess the relationship between body mass index (BMI) and alexithymia in a large cohort of free-living Finnish adults over a 15-year period. METHODS: Participants were drawn from the Northern Finnish Birth Cohort 1966 (NFBC1966). The 20-Item Toronto Alexithymia Scale (TAS-20) was used as a measure of alexithymia and was completed at the age of 31 years (31y: n = 4841), and 46 years (46y: n = 5404). BMI was recorded at both time points. Where data at both time points were available (n = 3274), the relationship between changes in BMI and TAS-20 over this time period was also investigated. RESULTS: BMI was significantly and positively associated with TAS-20 score (p<0.0001, both at 31 years and at 46 years of ages). The association remained statistically significant after adjustment for potential confounders (sex, marital status and several socio-economic indicators). In individuals who experienced the greatest change in BMI (in either direction) over the 15-year period, there was a modest mean increase in TAS-20 score. CONCLUSIONS: Our data revealed that TAS-20 score was correlated with and co-varied with body mass status. We suggest that future clinical research should consider the role of alexithymia in obesity. Further investigation of this relationship is warranted to ensure that the needs of obese subjects with undiagnosed alexithymia are considered in the design of weight management programmes.

New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals.

BACKGROUND: Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association. METHODS AND RESULTS: Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10-8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant. CONCLUSIONS: We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.

Determinants of postprandial plasma bile acid kinetics in human volunteers.

Bile acids (BA) are signaling molecules with a wide range of biological effects, also identified among the most responsive plasma metabolites in the postprandial state. We here describe this response to different dietary challenges and report on key determinants linked to its interindividual variability. Healthy men and women (n = 72, 62 ± 8 yr, mean ± SE) were enrolled into a 12-wk weight loss intervention. All subjects underwent an oral glucose tolerance test and a mixed-meal tolerance test before and after the intervention. BA were quantified in plasma by liquid chromatography-tandem mass spectrometry combined with whole genome exome sequencing and fecal microbiota profiling. Considering the average response of all 72 subjects, no effect of the successful weight loss intervention was found on plasma BA profiles. Fasting and postprandial BA profiles revealed high interindividual variability, and three main patterns in postprandial BA response were identified using multivariate analysis. Although the women enrolled were postmenopausal, effects of sex difference in BA response were evident. Exome data revealed the contribution of preselected genes to the observed interindividual variability. In particular, a variant in the SLCO1A2 gene, encoding the small intestinal BA transporter organic anion-transporting polypeptide-1A2 (OATP1A2), was associated with delayed postprandial BA increases. Fecal microbiota analysis did not reveal evidence for a significant influence of bacterial diversity and/or composition on plasma BA profiles. The analysis of plasma BA profiles in response to two different dietary challenges revealed a high interindividual variability, which was mainly determined by genetics and sex difference of host with minimal effects of the microbiota.NEW & NOTEWORTHY Considering the average response of all 72 subjects, no effect of the successful weight loss intervention was found on plasma bile acid (BA) profiles. Despite high interindividual variability, three main patterns in postprandial BA response were identified using multivariate analysis. A variant in the SLCO1A2 gene, encoding the small intestinal BA transporter organic anion-transporting polypeptide-1A2 (OATP1A2), was associated with delayed postprandial BA increases in response to both the oral glucose tolerance test and the mixed-meal tolerance test.

Associations of Leukocyte Telomere Length With Aerobic and Muscular Fitness in Young Adults.

Decline in both telomere length and physical fitness over the life course may contribute to increased risk of several chronic diseases. The relationship between telomere length and aerobic and muscular fitness is not well characterized. We examined whether there are cross-sectional associations of mean relative leukocyte telomere length (LTL) with objective measures of aerobic fitness, muscle strength, and muscle endurance, using data on 31-year-old participants of the Northern Finland Birth Cohort 1966 (n = 4,952-5,205, varying by exposure-outcome analysis). Aerobic fitness was assessed by means of heart rate measurement following a standardized submaximal step test; muscular fitness was assessed by means of a maximal isometric handgrip strength test and a test of lower-back trunk muscle endurance. Longer LTL was associated with higher aerobic fitness and better trunk muscle endurance in models including adjustment for age, sex, body mass index, socioeconomic position, diet, smoking, alcohol consumption, physical activity level, and C-reactive protein. In a sex-stratified analysis, LTL was not associated with handgrip strength in either men or women. LTL may relate to aspects of physical fitness in young adulthood, but replication of these findings is required, along with further studies to help assess directions and causality in these associations.

Limitations of the DiaRem Score in Predicting Remission of Diabetes Following Roux-En-Y Gastric Bypass (RYGB) in an ethnically Diverse Population from a Single Institution in the UK.

PURPOSE: This study aimed to determine the predictive power of the DiaRem score following Roux-en-Y gastric bypass to identify patients who would have diabetes remission at 1 year in an ethnically diverse population. METHODS: We performed a retrospective review of 262 patients with type 2 diabetes mellitus who underwent RYGB at the Imperial Weight Centre, UK, from 2007 to 2014. Data was collected on the parameters required to calculate the DiaRem score as well as pre- and post-surgical weight and the ethnicity of the subjects. RESULTS: The studied cohort was ethnically diverse (61.3 % Caucasian, 10.3 % Asian, 5.3 % black, 2.6 % mixed and 20.6 % other). At 1-year post-surgery, there were significant reductions in mean weight (133.4 to 94.3 kg) and BMI (46.7 to 33.3 kg/m2). The mean HbA1c decreased from 8.2 to 6.1 %, and 32.5 % of the cohort underwent either partial or complete remission. 67.8 % of the patients that were classified in group 1 of the DiaRem score (most likely to have remission) had complete remission. However, 22.9 % of the patients predicted to have the least chance of remission had either partial or complete remission. CONCLUSIONS: In this ethnically diverse cohort, the DiaRem score remains a useful tool to predict diabetes remission in those that have a low DiaRem score (high chance for remission) but was more limited in its predictive power in those with a high DiaRem score (least likely to have remission). Caution must be used in the application of this model in populations other than the US white Caucasian population used to derive the score.

Analysis with the exome array identifies multiple new independent variants in lipid loci.

It has been hypothesized that low frequency (1-5% minor allele frequency (MAF)) and rare (<1% MAF) variants with large effect sizes may contribute to the missing heritability in complex traits. Here, we report an association analysis of lipid traits (total cholesterol, LDL-cholesterol, HDL-cholesterol triglycerides) in up to 27 312 individuals with a comprehensive set of low frequency coding variants (ExomeChip), combined with conditional analysis in the known lipid loci. No new locus reached genome-wide significance. However, we found a new lead variant in 26 known lipid association regions of which 16 were >1000-fold more significant than the previous sentinel variant and not in close LD (six had MAF <5%). Furthermore, conditional analysis revealed multiple independent signals (ranging from 1 to 5) in a third of the 98 lipid loci tested, including rare variants. Addition of our novel associations resulted in between 1.5- and 2.5-fold increase in the proportion of heritability explained for the different lipid traits. Our findings suggest that rare coding variants contribute to the genetic architecture of lipid traits.