Evaluating the impact of AMPK activation, a target of metformin, on risk of cardiovascular diseases and cancer in the UK Biobank: A Mendelian randomization study

Aims/hypothesis: Whether metformin reduces cardiovascular or cancer risk is unclear owing to concerns over immortal time bias and confounding in observational studies. This study evaluated the effect of AMP-activated protein kinase (AMPK), the target of metformin, on risk of cardiovascular disease and cancer. Methods: This is a Mendelian randomisation design, using AMPK, the pharmacological target of metformin, to infer the AMPK pathway-dependent effects of metformin on risk of cardiovascular disease and cancer in participants of white British ancestry in the UK Biobank. Results: A total of 391,199 participants were included (mean age 56.9 years; 54.1% women), including 26,690 cases of type 2 diabetes, 38,098 cases of coronary artery disease and 80,941 cases of overall cancer. Genetically predicted reduction in HbA1c (%) instrumented by AMPK variants was associated with a 61% reduction in risk of type 2 diabetes (OR 0.39; 95% CI 0.20, 0.78; p = 7.69 × 10−3), a 53% decrease in the risk of coronary artery disease (OR 0.47; 95% CI 0.26, 0.84; p = 0.01) and a 44% decrease in the risk of overall cancer (OR 0.56; 95% CI 0.36, 0.85; p = 7.23 × 10−3). Results were similar using median or quartiles of AMPK score, with dose–response effects (p for trend = 4.18 × 10−3 for type 2 diabetes, 4.37 × 10−3 for coronary artery disease and 4.04 × 10−3 for overall cancer). Conclusions/interpretation: This study provides some genetic evidence that AMPK activation by metformin may protect against cardiovascular disease and cancer, which needs to be confirmed by randomised controlled trials

Comparing Risk Factor Profiles between Intracerebral Hemorrhage and Ischemic Stroke in Chinese and White Populations:Systematic Review and Meta-Analysis

<div><p>Background</p><p>Chinese populations have a higher proportion of intracerebral hemorrhage (ICH) in total strokes. However, the reasons are not fully understood.</p><p>Methods</p><p>To assess the differences in frequency of major risk factors between ICH and ischemic stroke (IS) in Chinese versus white populations of European descent, we systematically sought studies conducted since 1990 that compared frequency of risk factors between ICH and IS in Chinese or white populations. For each risk factor, in Chinese and Whites separately, we calculated study-specific and random effects pooled prevalence and odds ratios (ORs) for ICH versus IS.</p><p>Results</p><p>Six studies among 36190 Chinese, and seven among 52100 white stroke patients studied hypertension, diabetes, atrial fibrillation (AF), ischemic heart disease (IHD), hypercholesterolemia, smoking and alcohol. Pooled prevalence of AF was significantly lower in Chinese. Pooled ORs for ICH versus IS were mostly similar in Chinese and Whites. However, in Chinese–but not Whites–mean age was lower (62 versus 69 years), while hypertension and alcohol were significantly more frequent in ICH than IS (ORs 1.38, 95% CI 1.18–1.62, and 1.46, 1.12–1.91). Hypercholesterolemia and smoking were significantly less frequent in ICH in Whites, but not Chinese, while IHD, AF and diabetes were less frequent in ICH in both.</p><p>Conclusions</p><p>Different risk factor distributions in ICH and IS raise interesting possibilities about variation in mechanisms underlying the different distributions of pathological types of stroke between Chinese and Whites. Further analyses in large, prospective studies, including adjustment for potential confounders, are needed to consolidate and extend these findings.</p></div

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Life long endogenous estrogen exposure and later adulthood cognitive function in a population of naturally postmenopausal women from Southern China: The Guangzhou Biobank Cohort Study

Background: Estrogen has neurotrophic and neuroprotective properties in animal and in vitro studies. Epidemiological studies are inconclusive, but suggest a positive association between endogenous estrogen exposure (measured by reproductive period, the number of years between menarche and menopause) and later life cognitive function. Methods: Structural equation modeling was used in a cross-sectional study of 11,094 naturally postmenopausal multiparous Chinese older (≥50 years) women from the Guangzhou Biobank Cohort Study (phases 2 and 3) to assess the interrelationship of four proxies of higher endogenous estrogen exposure (longer reproductive period, older age of first pregnancy, lower parity and shorter average duration of breast feeding per child) with immediate and the delayed 10-word recall score in phases 2 and 3, and with the mini-mental state examination (MMSE) score in phase 3 (5641 women). Results: Adjusted for age, education, childhood and adulthood socio-economic position and physical activity, longer reproductive period was associated with higher scores (0.02 words per year, 95% confidence interval (CI) 0.008-0.02 for delayed recall and 0.05 MMSE score, 95%CI 0.04-0.07, respectively). Lower parity and shorter average duration of breast-feeding per child were also associated with better cognitive function. Conclusions: In a large cohort of naturally postmenopausal Chinese women proxies of greater endogenous estrogen exposure were associated with better cognitive function. These findings support biological evidence for a cognitively protective role of endogenous estrogen. © 2010 Elsevier Ltd.link_to_subscribed_fulltex

Blood Pressure and Risk of Cardiovascular Disease in UK Biobank: A Mendelian Randomization Study

This study aims to evaluate the causal association of blood pressure (BP) with cardiovascular diseases (CVDs). Two-sample Mendelian randomization was performed using a large genome-wide association study (n=299 024) and the UK Biobank cohort (n=375 256). We identified 327 and 364 single-nucleotide polymorphisms strongly and independently associated with systolic BP and diastolic BP, respectively, as genetic instruments to assess the causal association of BP with total CVD, CVD mortality, and 14 cardiovascular conditions. Nonlinearity was examined with nonlinear instrumental variable assumptions. Genetically predicted BP was significantly positively associated with total CVD (systolic BP, per 10 mm Hg: odds ratio [OR], 1.32 [95% CI, 1.25–1.40]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.15–1.26]). Similar positive causal associations were observed for 14 cardiovascular conditions including ischemic heart disease (systolic BP, per 10 mm Hg: OR, 1.33 [95% CI, 1.24–1.41]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.14–1.27]) and stroke (systolic BP, per 10 mm Hg: OR, 1.35 [95% CI, 1.24–1.48]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.12–1.28]). Nonlinearity Mendelian randomization test demonstrated linear causal association of BP with these outcomes. Consistent estimates were observed in sensitivity analyses, suggesting robustness of the associations and minimal horizontal pleiotropy. The linear positive causal association of BP and CVD was consistent with previous findings that lower BP is better, thus consolidating clinical knowledge on hypertension management in CVD risk reduction

Effect of interpregnancy interval on adverse perinatal outcomes in Southern China: a retrospective cohort study, 2000-2015

Background In January 2016, a universal two-child policy was introduced in China. The association of interpregnancy interval (IPI) with perinatal outcomes has not previously been assessed among Chinese population. We investigated the effect of IPI after live birth on the risks of preterm delivery, and small, and large for gestational age births in China. Methods We conducted a cohort study among 227 352 Chinese women with their first and second delivery during 2000 to 2015. IPI was calculated as months from first live delivery to conception of the second pregnancy. Poisson regression models with robust variance were fit to evaluate associations of IPI with risk of adverse perinatal outcomes, adjusted for potential confounders. Results Compared to IPI of 24-29 months, IPI Conclusions Women with IPI <18 months after live birth had higher risk of PTB and SGA, and IPI ≥60 months was associated with higher risk of PTB and LGA. These findings may provide information to Chinese couples about the appropriate interpregnancy interval for a second pregnancy.</p