Re-thinking Alzheimer\u27s disease therapeutic targets using gene-based tests

Background: Alzheimer\u27s disease (AD) is a devastating condition with no known effective drug treatments. Existing drugs only alleviate symptoms. Given repeated expensive drug failures, we assessed systematically whether approved and investigational AD drugs are targeting products of genes strongly associated with AD and whether these genes are targeted by existing drugs for other indications which could be re-purposed. Methods: We identified genes strongly associated with late-onset AD fromthe loci of genetic variants associated with AD at genome-wide-significance and from a gene-based test applied to the most extensively genotyped late-onset AD case (n=17,008)-control (n=37,154) study, the International Genomics of Alzheimer\u27s Project. We used three gene-to-drug cross-references, Kyoto Encyclopedia of Genes and Genomes, Drugbank and Drug Repurposing Hub, to identify genetically validated targets of AD drugs and any existing drugs or nutraceuticals targeting products of the genes strongly associated with late-onset AD. Findings: A total of 67 autosomal genes (forming 9 gene clusters) were identified as strongly associated with lateonset AD, 28 from the loci of single genetic variants, 51 from the gene-based test and 12 by both methods. Existing approved or investigational AD drugs did not target products of any of these 67 genes. Drugs for other indications targeted 11 of these genes, including immunosuppressive disease-modifying anti-rheumatic drugs targeting PTK2B gene products. Interpretation: Approved and investigational AD drugs are not targeting products of genes strongly associated with late-onset AD. However, other drugs targeting products of these genes exist and could perhaps be repurposing to combat late-onset AD after further scrutiny

Mode of delivery and child and adolescent psychological well-being: Evidence from Hong Kong’s “Children of 1997” birth cohort

Mode of delivery (vaginal or cesarean section) is thought to affect gut microbiota, which in turn may affect psychological well-being. As such, mode of delivery is potentially a modifiable factor for psychological well-being. Here we examined the association of mode of delivery with child and adolescent psychological well-being. We used multivariable linear regression in a populationrepresentative Hong Kong Chinese birth cohort, “Children of 1997,” to examine the adjusted associations of mode of delivery with behavioral problems assessed from parent-reported Rutter score at ~7 (n = 6294) and ~11 years (n = 5598), self-esteem assessed from self-reported Culture-Free Self- Esteem Inventory score at ~11 years (n = 6937) and depressive symptoms assessed from self-reported Patient Health Questionnaire-9 score at ~13 years (n = 5797). Cesarean Section (CS) was associated with children born in private hospitals, boys, and firstborns, higher maternal body mass index, higher maternal age, preeclampsia, higher socioeconomic position (SEP) and maternal birth in Hong Kong. CS was unrelated to behavior, self-esteem and depressive symptoms adjusted for infant characteristics (sex, gestational age, birthweight, parity and breast feeding), maternal characteristics (mother’s age and place of birth) and SEP. In a developed non-Western setting, mode of delivery was not clearly associated with childhood or early adolescent psychological well-being

Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials

Background Testosterone therapy is increasingly promoted. No randomized placebo-controlled trial has been implemented to assess the effect of testosterone therapy on cardiovascular events, although very high levels of androgens are thought to promote cardiovascular disease. Methods A systematic review and meta-analysis was conducted of placebo-controlled randomized trials of testosterone therapy among men lasting 12+ weeks reporting cardiovascular-related events. We searched PubMed through the end of 2012 using “(“testosterone” or “androgen”) and trial and (“random*”)” with the selection limited to studies of men in English, supplemented by a bibliographic search of the World Health Organization trial registry. Two reviewers independently searched, selected and assessed study quality with differences resolved by consensus. Two statisticians independently abstracted and analyzed data, using random or fixed effects models, as appropriate, with inverse variance weighting. Results Of 1,882 studies identified 27 trials were eligible including 2,994, mainly older, men who experienced 180 cardiovascular-related events. Testosterone therapy increased the risk of a cardiovascular-related event (odds ratio (OR) 1.54, 95% confidence interval (CI) 1.09 to 2.18). The effect of testosterone therapy varied with source of funding (P-value for interaction 0.03), but not with baseline testosterone level (P-value for interaction 0.70). In trials not funded by the pharmaceutical industry the risk of a cardiovascular-related event on testosterone therapy was greater (OR 2.06, 95% CI 1.34 to 3.17) than in pharmaceutical industry funded trials (OR 0.89, 95% CI 0.50 to 1.60). Conclusions The effects of testosterone on cardiovascular-related events varied with source of funding. Nevertheless, overall and particularly in trials not funded by the pharmaceutical industry, exogenous testosterone increased the risk of cardiovascular-related events, with corresponding implications for the use of testosterone therapy

Inflammation and bone mineral density: A Mendelian randomization study

Osteoporosis is a common age-related disorder leading to an increase in osteoporotic fractures and resulting in significant suffering and disability. Inflammation may contribute to osteoporosis, as it does to many other chronic diseases. We examined whether inflammation is etiologically relevant to osteoporosis, assessed from bone mineral density (BMD), as a new potential target of intervention, or whether it is a symptom/biomarker of osteoporosis. We obtained genetic predictors of inflammatory markers from genome-wide association studies and applied them to a large genome wide association study of BMD. Using two-sample Mendelian randomization, we obtained unconfounded estimates of the effect of high-sensitivity C-reactive protein (hsCRP) on BMD at the forearm, femoral neck, and lumbar spine. After removing potentially pleiotropic single nucleotide polymorphisms (SNPs) possibly acting via obesity-related traits, hsCRP, based on 16 SNPs from genes including CRP, was not associated with BMD. A causal relation of hsCRP with lower BMD was not evident in this study

Thyroid function and ischemic heart disease: a Mendelian randomization study

To clarify the role of thyroid function in ischemic heart disease (IHD) we assessed IHD risk and risk factors according to genetically predicted thyroid stimulating hormone (TSH), free thyroxine (FT4) and thyroid peroxidase antibody (TPOAb) positivity. Separate-sample instrumental variable analysis with genetic instruments (Mendelian randomization) was used in an extensively genotyped case (n = 64,374)-control (n = 130,681) study, CARDIoGRAMplusC4D. Associations with lipids, diabetes and adiposity were assessed using the Global Lipids Genetics Consortium Results (n = 196,475), the DIAbetes Genetics Replication And Meta-analysis case (n = 34,380)-control (n = 114,981) study, and the Genetic Investigation of ANthropometric Traits (body mass index in 152,893 men and 171,977 women, waist-hip ratio in 93,480 men and 116,741 women). Genetically predicted thyroid function was not associated with IHD (odds ratio (OR) per standard deviation for TSH 1.05, 95% confidence interval (CI) 0.97 to 1.12; for FT4 1.01, 95% CI 0.91 to 1.12; for TPOAb positivity 1.10, 95% CI 0.83 to 1.46) or after Bonferroni correction with risk factors, except for an inverse association of FT4 with low-density lipoprotein-cholesterol. The associations were generally robust to sensitivity analyses using a weighted median method and MR Egger. This novel study provides little indication that TSH, FT4 or TPOAb positivity affects IHD, despite potential effects on its risk factors

A Mendelian randomization study of the effect of calcium on coronary artery disease, myocardial infarction and their risk factors

Meta-analyses of randomized controlled trials (RCTs) suggest calcium could have adverse effects on cardiovascular disease, although these findings are controversial. To clarify, we assessed whether people with genetically higher calcium had a higher risk of coronary artery disease (CAD), myocardial infarction (MI) and their risk factors. We used a two-sample Mendelian randomization study. We identified genetic variants (single nucleotide polymorphisms (SNPs)) that independently contributed to serum calcium at genome-wide significance which we applied to large extensively genotyped studies of CAD, MI, diabetes, lipids, glycaemic traits and adiposity to obtain unconfounded estimates, with body mass index (BMI) as a control outcome. Based on 4 SNPs each 1 mg/dl increase in calcium was positively associated with CAD (odds ratio (OR) 1.49, 95% confidence interval (CI) 1.02–2.17), MI (OR 1.58, 95% CI 1.06–2.35), LDL-cholesterol (0.21 standard deviations, 95% CI 0.01–0.4), total cholesterol (0.21 standard deviations, 95% CI 0.03-0.38) and possibly triglycerides (0.19 standard deviations, 95% CI −0.1–0.48), but was unlikely related to BMI although the estimate lacked precision. Sensitivity analysis using 13 SNPs showed a higher risk for CAD (OR 1.87, 95% CI 1.14–3.08). Our findings, largely consistent with the experimental evidence, suggest higher serum calcium may increase the risk of CAD

Pathways between Socioeconomic Disadvantage and Childhood Growth in the Scottish Longitudinal Study, 1991–2001

Socioeconomically disadvantaged children are more likely to be of shorter stature and overweight, leading to greater risk of obesity in adulthood. Disentangling the mediatory pathways between socioeconomic disadvantage and childhood size may help in the development of appropriate policies aimed at reducing these health inequalities. We aimed to elucidate the putative mediatory role of birth weight using a representative sample of the Scottish population born 1991-2001 (n = 16,628). Estimated height and overweight/obesity at age 4.5 years were related to three measures of socioeconomic disadvantage (mother's education, Scottish Index of Multiple Deprivation, synthetic weekly income). Mediation was examined using two approaches: a 'traditional' mediation analysis and a counterfactual-based mediation analysis. Both analyses identified a negative effect of each measure of socioeconomic disadvantage on height, mediated to some extent by birth weight, and a positive 'direct effect' of mother's education and Scottish Index of Multiple Deprivation on overweight/obesity, which was partly counterbalanced by a negative 'indirect effect'. The extent of mediation estimated when adopting the traditional approach was greater than when adopting the counterfactual-based approach because of inappropriate handling of intermediate confounding in the former. Our findings suggest that higher birth weight in more disadvantaged groups is associated with reduced social inequalities in height but also with increased inequalities in overweight/obesity

Habitual coffee consumption and risk of type 2 diabetes, ischemic heart disease, depression and Alzheimer’s disease: a Mendelian randomization study

Observationally, coffee is inversely associated with type 2 diabetes mellitus (T2DM), depression and Alzheimer’s disease, but not ischemic heart disease (IHD). Coffee features as possibly protective in the 2015 Dietary Guidelines for Americans. Short-term trials suggest coffee has neutral effect on most glycemic traits, but raises lipids and adiponectin. To clarify we compared T2DM, depression, Alzheimer’s disease, and IHD and its risk factors by genetically predicted coffee consumption using two-sample Mendelian randomization applied to large extensively genotyped case-control and cross-sectional studies. Childhood cognition was used as a negative control outcome. Genetically predicted coffee consumption was not associated with T2DM (odds ratio (OR) 1.02, 95% confidence interval (CI) 0.76 to 1.36), depression (0.89, 95% CI 0.66 to 1.21), Alzheimer’s disease (1.17, 95% CI 0.96 to 1.43), IHD (0.96, 95% CI 0.80 to 1.14), lipids, glycemic traits, adiposity or adiponectin. Coffee was unrelated to childhood cognition. Consistent with observational studies, coffee was unrelated to IHD, and, as expected, childhood cognition. However, contrary to observational findings, coffee may not have beneficial effects on T2DM, depression or Alzheimer’s disease. These findings clarify the role of coffee with relevance to dietary guidelines and suggest interventions to prevent these complex chronic diseases should be sought elsewhere