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

Socio-economic disparities of childhood body mass index in a newly developed population: Evidence from Hong Kong's 'Children of 1997' birth cohort

Background: Childhood adiposity in developed countries is often associated with lower socio-economic position (SEP) of the family and neighbourhood. However, the association of adiposity with SEP varies with national income. The authors examined whether childhood BMI was associated with family or neighbourhood socio-economic characteristics in a recently and rapidly developed Chinese population. Methods: The authors used multilevel modelling in Hong Kong's population-representative 'Children of 1997' birth cohort (n=8327) to examine the association of BMI z-score and overweight (including obesity) at ages 6-11 years with parental education, mother's birthplace, sex and neighbourhood median income. Results: In 7108 (85 % successful follow-up) children, boys were more adipose than girls. The association of parental education with BMI z-score varied with mother's birthplace (p value for interaction 0.001). In children of Hong Kong-born mothers, parental education was negatively associated with BMI z-score (mean difference -0.15, 95% CI -0.25 to -0.05 for highest compared with lowest). However, in children of mainland China-born mothers, parental education was positively associated with BMI z-score (0.18, 95% CI 0.02 to 0.34 in the same comparison). Neighbourhood had no association with BMI z-score. Conclusions: In this recently developed Chinese population, there was no consistent association between socio-economic characteristics and childhood BMI. Other factors, such as experience of economic transition, as proxied by mother's place of birth, exerted a modifying impact. The cultural and biological mechanisms underlying these socio-historical intergenerational influences need to be determined, so that effective interventions can be implemented in China and elsewhere.published_or_final_versio

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

Parental death during childhood and adult cardiovascular risk in a developing country: The Guangzhou Biobank Cohort study

Background: In observational studies from western countries childhood emotional adversity is usually associated with adult cardiovascular disease. These findings are open to contextual biases making evidence from other settings valuable. We examined the association of a potential marker of childhood emotional adversity with cardiovascular disease risk factors in a developing country. Methods: We used multivariable regression in cross-sectional analysis of older (≥50 years) men (n = 7,885) and women (n = 20,886) from the Guangzhou Biobank Cohort Study (2003-8) to examine the adjusted association of early life (<18 years) parental death (none, one or two deaths) with blood pressure, fasting glucose, LDL-cholesterol, HDL-cholesterol, triglycerides, body mass index (BMI), waist-hip ratio (WHR) and white blood cell count (WBC). We used seated height and delayed 10-word recall to assess content validity of parental death as a measure of childhood emotional adversity. We also examined whether associations varied by sex. Results: Early life parental death was associated with shorter age- and sex-adjusted seated height. It was also associated with lower 10-word recall score adjusted for age, sex, socio-economic position, leg length and lifestyle. Similarly, adjusted early life parental death was not associated with blood pressure, fasting glucose, LDL-cholesterol or HDL-cholesterol but was associated with lower BMI (-0.40, 95% confidence interval (CI) -0.62 to -0.19 for 2 compared with no early life parental deaths) and triglycerides. Associations varied by sex for WHR and WBC. Among men only, early life parental death was associated with lower WHR (-0.008, 95% CI -0.015 to -0.001) and WBC (-0.35 10 9/L, 95% CI -0.56 to -0.13). Conclusions: In a non-western population from a developing country, childhood emotional adversity was negatively associated with some cardiovascular risk factors, particularly among men. Our study suggests that some of the observed associations in western populations may be socially rather than biologically based or may be population specific. © 2011 Schooling et al.published_or_final_versio

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

Fruit and vegetable consumption and cardiovascular risk factors in older Chinese: The Guangzhou Biobank Cohort Study

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Systematic differences among never, occasional and moderate alcohol users in southern China, and its use in alcohol research: a cross-sectional study

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