The circulating proteome and brain health:Mendelian randomisation and cross-sectional analyses

Decline in cognitive function is the most feared aspect of ageing. Poorer midlife cognitive function is associated with increased dementia and stroke risk. The mechanisms underlying variation in cognitive function are uncertain. Here, we assessed associations between 1160 proteins' plasma levels and two measures of cognitive function, the digit symbol substitution test (DSST) and the Montreal Cognitive Assessment in 1198 PURE-MIND participants. We identified five DSST performance-associated proteins (NCAN, BCAN, CA14, MOG, CDCP1), with NCAN and CDCP1 showing replicated association in an independent cohort, GS (N = 1053). MRI-assessed structural brain phenotypes partially mediated (8-19%) associations between NCAN, BCAN, and MOG, and DSST performance. Mendelian randomisation analyses suggested higher CA14 levels might cause larger hippocampal volume and increased stroke risk, whilst higher CDCP1 levels might increase intracranial aneurysm risk. Our findings highlight candidates for further study and the potential for drug repurposing to reduce the risk of stroke and cognitive decline.</p

Genetic tools for coronary risk assessment in type 2 diabetes: A cohort study from the ACCORD clinical trial

OBJECTIVE We evaluated whether the increasing number of genetic loci for coronary artery disease (CAD) identified in the general population could be used to predict the risk of major CAD events (MCE) among participants with type 2 diabetes at high cardiovascular risk. RESEARCH DESIGN AND METHODS A weighted genetic risk score (GRS) derived from 204 variants representative of all the 160 CAD loci identified in the general population as of December 2017 was calculated in 5,360 and 1,931 white participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Outcome Reduction With Initial Glargine Intervention (ORIGIN) studies, respectively. The association between GRS and MCE (combining fatal CAD events, nonfatal myocardial infarction, and unstable angina) was assessed by Cox proportional hazards regression. RESULTS The GRS was associated with MCE risk in both ACCORD and ORIGIN (hazard ratio [HR] per SD 1.27, 95% CI 1.18–1.37, P = 4 3 10210, and HR per SD 1.35, 95% CI 1.16–1.58, P = 2 3 1024, respectively). This association was independent from interventions tested in the trials and persisted, though attenuated, after adjustment for classic cardiovascular risk predictors. Adding the GRS to clinical predictors improved incident MCE risk classification (relative integrated discrimination improvement +8%, P = 7 3 1024). The performance of this GRS was superior to that of GRS based on the smaller number of CAD loci available in previous years. CONCLUSIONS When combined into a GRS, CAD loci identified in the general population are associated with CAD also in type 2 diabetes. This GRS provides a significant improvement in the ability to correctly predict future MCE, which may increase further with the discovery of new CAD loci

Genetic Polymorphisms in the Hypothalamic Pathway in Relation to Subsequent Weight Change – The DiOGenes Study

BACKGROUND: Single nucleotide polymorphisms (SNPs) in genes encoding the components involved in the hypothalamic pathway may influence weight gain and dietary factors may modify their effects. AIM: We conducted a case-cohort study to investigate the associations of SNPs in candidate genes with weight change during an average of 6.8 years of follow-up and to examine the potential effect modification by glycemic index (GI) and protein intake. METHODS AND FINDINGS: Participants, aged 20-60 years at baseline, came from five European countries. Cases ('weight gainers') were selected from the total eligible cohort (n = 50,293) as those with the greatest unexplained annual weight gain (n = 5,584). A random subcohort (n = 6,566) was drawn with the intention to obtain an equal number of cases and noncases (n = 5,507). We genotyped 134 SNPs that captured all common genetic variation across the 15 candidate genes; 123 met the quality control criteria. Each SNP was tested for association with the risk of being a 'weight gainer' (logistic regression models) in the case-noncase data and with weight gain (linear regression models) in the random subcohort data. After accounting for multiple testing, none of the SNPs was significantly associated with weight change. Furthermore, we observed no significant effect modification by dietary factors, except for SNP rs7180849 in the neuromedin β gene (NMB). Carriers of the minor allele had a more pronounced weight gain at a higher GI (P = 2 x 10⁻⁷). CONCLUSIONS: We found no evidence of association between SNPs in the studied hypothalamic genes with weight change. The interaction between GI and NMB SNP rs7180849 needs further confirmation

Whole genome sequence analysis of the TALLYHO/Jng mouse

Background: The TALLYHO/Jng (TH) mouse is a polygenic model for obesity and type 2 diabetes first described in the literature in 2001. The origin of the TH strain is an outbred colony of the Theiler Original strain and mice derived from this source were selectively bred for male hyperglycemia establishing an inbred strain at The Jackson Laboratory. TH mice manifest many of the disease phenotypes observed in human obesity and type 2 diabetes. Results: We sequenced the whole genome of TH mice maintained at Marshall University to a depth of approximately 64.8X coverage using data from three next generation sequencing runs. Genome-wide, we found approximately 4.31 million homozygous single nucleotide polymorphisms (SNPs) and 1.10 million homozygous small insertions and deletions (indels) of which 98,899 SNPs and 163,720 indels were unique to the TH strain compared to 28 previously sequenced inbred mouse strains. In order to identify potentially clinically-relevant genes, we intersected our list of SNP and indel variants with human orthologous genes in which variants were associated in GWAS studies with obesity, diabetes, and metabolic syndrome, and with genes previously shown to confer a monogenic obesity phenotype in humans, and found several candidate variants that could be functionally tested using TH mice. Further, we filtered our list of variants to those occurring in an obesity quantitative trait locus, tabw2, identified in TH mice and found a missense polymorphism in the Cidec gene and characterized this variant’s effect on protein function. Conclusions: We generated a complete catalog of variants in TH mice using the data from whole genome sequencing. Our findings will facilitate the identification of causal variants that underlie metabolic diseases in TH mice and will enable identification of candidate susceptibility genes for complex human obesity and type 2 diabetes

FTO gene-lifestyle interactions on serum adiponectin concentrations and central obesity in a Turkish population

The aim of the study was to investigate whether lifestyle factors modify the association fat mass and obesity-associated (FTO) gene single nucleotide polymorphisms (SNPs) and obesity in a Turkish population. The study included 400 unrelated individuals, aged 24-50 years recruited in a hospital setting. Dietary intake and physical activity were assessed using 24-hour dietary recall and self-report questionnaire, respectively. A genetic risk score (GRS) was developed using FTO SNPs, rs9939609 and rs10163409. Body mass index and fat mass index were significantly associated with FTO SNP rs9939609 (P=0.001 and P=0.002, respectively) and GRS (P=0.002 and P=0.003, respectively). The interactions between SNP rs9939609 and physical activity on adiponectin concentrations, and SNP rs10163409 and dietary protein intake on increased waist circumference were statistically significant (Pinteraction=0.027 and Pinteraction=0.044, respectively). This study demonstrated that the association between FTO SNPs and central obesity might be modified by lifestyle factors in this Turkish population

Diagnosis and management of patients with significantly abnormal glycaemic profiles during pregnancy after bariatric surgery: PRESAGE (Pregnancy with significantly abnormal glycaemic exposure - bariatric patients)

International audienc

Contraception et obésité

International audienceThe prevalence of obesity is increasing massively over several decades in industrialized countries. Obese women are sexually active but they use fewer contraceptive methods and are at high risk of unintended pregnancy. In addition, obesity is an important risk factor for venous thromboembolism events and arterial thrombosis (myocardial infarction and ischemic stroke). All of these data are to be considered in choosing a contraceptive method for obese women. Except depot medroxyprogesterone acetate injection, the progestin-only contraceptives (progestin only pills and etonogestrel subdermal implant) and the intra-uterine devices are the preferred contraceptive methods in obese women. The combined estrogen-progestin contraceptives (pill, patch and vaginal ring) may be proposed in very strict conditions (no other associated vascular risk factor). Obesity does not increase the risk of failure of most contraceptive methods. Bariatric surgery is a complex situation. It requires to program a possible pregnancy and contraception is needed for several months. Some bariatric surgical techniques such as by-pass can induce gastrointestinal malabsorption. In this situation, all oral contraceptives are not recommended because of a higher risk of failure