Decision making and impulsiveness in abstinent alcohol-dependent people and healthy individuals: a neuropsychological examination

Background: Alcohol dependence is associated with deficits in decision making and increased impulsiveness. Therefore, we compared decision making in abstinent alcohol-dependent people ("abstainers") and matched healthy individuals ("comparison group") to determine whether impulsiveness or personality traits play a role in decision making. Methods: Abstainers (n = 40) were recruited from treatment facilities in and around Munich, Germany, and the comparison group (n = 40) through personal contacts and social media. We assessed decision making with the Iowa Gambling Task (IGT),impulsiveness with the Barratt Impulsiveness Scale (BIS-11) and personality traits with the NEO Five-Factor Inventory (NEO-FFI). Results: The comparison group performed significantly better in the IGT (mean profit (sic) 159.50, SD 977.92) than the abstainers (mean loss - (sic) 1, 400.13, SD 1, 362.10;p < .001) and showed significantly less impulsiveness in the BIS-11 (comparison group: mean 56.03, SD 7.80;abstainers: mean 63.55, SD 11.47;p < .001). None of the five personality traits assessed with the NEO-FFI differed significantly between the groups. Conclusion: The results confirm that abstinent alcohol-dependent people do not perform as well as healthy individuals in decision-making tasks and show greater impulsiveness, but in this study did not affect their decision-making ability

Genome-wide associations for birth weight and correlations with adult disease

Birth weight (BW) is influenced by both foetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease1. These lifecourse associations have often been attributed to the impact of an adverse early life environment. We performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where foetal genotype was associated with BW (P <5x10-8). Overall, ˜15% of variance in BW could be captured by assays of foetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (rg-0.22, P =5.5x10-13), T2D (rg-0.27, P =1.1x10-6) and coronary artery disease (rg-0.30, P =6.5x10-9) and, in large cohort data sets, demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P =1.9x10-4). We have demonstrated that lifecourse associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and have highlighted some of the pathways through which these causal genetic effects are mediated

Genome-wide associations for birth weight and correlations with adult disease

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW ($\textit{P}$  < 5 × 10$^{-8}$). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure ($\textit{R}$ $_{g}$ = -0.22, $\textit{P}$  = 5.5 × 10$^{-13}$), T2D ($\textit{R}$ $_{g}$ = -0.27, $\textit{P}$  = 1.1 × 10$^{-6}$) and coronary artery disease ($\textit{R}$ $_{g}$ = -0.30, $\textit{P}$  = 6.5 × 10$^{-9}$). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions ($\textit{P}$ = 1.9 × 10$^{-4}$). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.For a full list of the funders pelase visit the publisher's website and look at the supplemetary material provided. Some of the funders are: British Heart Foundation, Cancer Research UK, Medical Research Council, National Institutes of Health, Royal Society and Wellcome Trust

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.The Fenland Study is funded by the Medical Research Council (MC_U106179471) and Wellcome Trust

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Serum antibodies against CD28-- a new potential marker of dismal prognosis in melanoma patients.

BACKGROUND: Autoantibodies against CD28 have been found in patients with autoimmune and atopic diseases. These antibodies may act as superagonists and activate T cells but may also be antagonistic or induce immunosuppressive effects by activating regulatory T cells. Autoimmunity in melanoma patients has been discussed controversially. OBJECTIVE: We investigated 230 melanoma patients for the occurrence of CD28 antibodies and the effect of the latter on overall and progress-free survival. METHODS: We constructed an ELISA assay to measure CD28 serum antibodies. 230 patients with melanoma and a control-group of 625 patients consistent of 212 patients with virus hepatitis b or c, 149 patients with allergies, 78 patients with psoriasis, 46 patients with plasmocytoma and 140 healthy blood donors were investigated for the occurrence of CD28 antibodies. RESULTS: CD28 abs occur at a higher percentage in patients with melanoma and in patients with viral hepatitis than in other groups investigated (p<0.001). Occurrence of CD28 abs is significantly higher in patients receiving interferons independent from the underlying disease (p<0.001). In vitro CD28 serum antibodies have an inhibitory effect on the CD28 receptor as they lead to reduced stimulation of Jurkat cells. Presence of CD28 was correlated with a higher risk of dying from melanoma (p = 0.043), but not with a significantly shortened overall survival or progression-free survival. CONCLUSION: Interferon therapy appears to induce the production of CD28 abs. In light of reports that these CD28 abs induce immunosuppressive Tregs and - as our data show - that they are inhibitors of CD28 receptor mediated stimulation, the continuation of therapies with interferons in melanoma patients developing CD28 antibodies should be critically reconsidered, since our data indicate a worse outcome of patients with CD28 abs

Seroconversion with progress of disease.

<p>CD28 abs measured in one female patient during a period of more than 10 years in association with the course of the disease.</p

Analysis of recombinant CD28 expression in HEK cells.

<p>(A) Coimmunoprecipitation. Recombinant HEK cells were lysed with lysis buffer, and 200–500 µl of cell lysate was incubated with rabbit αFLAG antibody at 4°C for 2 hours, then 20 µl of protein A agarose slurry (GE Healthcare) was added for another 2 hours. The beads were washed three times with at least 10 volumes of lysis buffer before resolving by SDS-PAGE. Detection was done either with mouse αFLAG or mouse αCD28. As control HEK293-SLP2-FLAG was used. 1: HEK293 lysate, 2: HEK293-CD28-FLAG lysate, HEK293-SLP2-FLAG lysate. (B) Westernblot. Cells were lysed and analysed by immunoblot using αFLAG or αCD28 antibodies. 1: HEK293 lysate, 2: HEK293-CD28-FLAG lysate (C) Elisa. Recombinant CD28 is recognized by a commercial αCD28 mAb. HEK293-CD28-FLAG lysate is coated on NUNC maxisorp via FLAG-tag. Detection was done with 1: αCD30 or 2: αCD28.</p