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Sex ratio at birth across 100 years in Sweden and risk of cardiovascular disease and all-cause mortality - a national register study. 瑞典百年出生性别比与心血管疾病和全因死亡风险--一项全国登记研究。
IF 7.7 1区 医学 Q1 PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH Pub Date : 2024-09-01 Epub Date: 2024-07-15 DOI: 10.1007/s10654-024-01137-1
Peter M Nilsson, Kristina Sundquist, Jan Sundquist, Casey Crump, Xinjun Li

The human sex ratio at birth (SRB) undergoes temporary changes around a mean proportion of 0.51 male births. SRB has been well studied for historical, geographical, and secular trends, but until now not linked to health outcomes in the total population, e.g. for cardiovascular disease (CVD) or mortality during follow-up of birth cohorts. We used linkage analysis based on national registers in Sweden that cover all births from 1900 to 2016. SRB at birth was calculated by every 10-year birth cohort in all survivors living in 1997 for a follow-up analysis of risk of CVD and mortality with data from national registers. When the highest quartile of SRB was used as reference, a slightly increased risk of fatal CVD (HR 1.03 (95% confidence intervals, CI): 1.02-1.04), non-fatal CVD (HR 1.01; 95%CI: 1.01-1.02) and mortality (HR 1.02; 95%CI, 1.01-1.03) was found after full adjustments in men belonging to the lowest SRB quartile. A similar pattern was also found for fatal CHD in women. in the lowest SBR quartile compared to the highest, HR 1.03 (95%CI: 1.02-1.05). In conclusion, in birth cohorts with a relatively lower than expected number of males born, long-term adverse health effects were observed with slightly increased cardiovascular risk and total mortality at the population level. This could indicate that men belonging to so-called "culled cohorts" in a developed country during the 20th century are characterized by a slightly increased risk that could reflect negative early life influences and environmental exposures in pregnant women resulting in selective loss of male embryos or fetuses. In a public health perspective SRB could be of some importance to monitor as an aspect of birth statistics linked to relatively minor population health effects.

人类的出生性别比(SRB)会围绕 0.51 的平均男婴比例发生暂时性变化。人们对出生性别比的历史、地理和世俗趋势进行了深入研究,但迄今为止尚未将其与总人口的健康结果(如心血管疾病(CVD)或出生队列随访期间的死亡率)联系起来。我们采用了基于瑞典国家登记册的关联分析,该登记册涵盖了从 1900 年到 2016 年的所有出生人口。根据国家登记册的数据,对 1997 年所有幸存者的每 10 年出生队列计算出生时的 SRB,以进行心血管疾病和死亡率风险的随访分析。如果将 SRB 的最高四分位数作为参考,则在进行全面调整后发现,SRB 最低四分位数的男性发生致命心血管疾病(HR 1.03;95% 置信区间:1.02-1.04)、非致命心血管疾病(HR 1.01;95% 置信区间:1.01-1.02)和死亡(HR 1.02;95% 置信区间:1.01-1.03)的风险略有增加。SBR最低四分位数与最高四分位数相比,HR为1.03(95%CI:1.02-1.05)。总之,在男性出生人数相对低于预期的出生队列中,观察到了长期的不利健康影响,心血管风险和总死亡率在人群水平上略有增加。这可能表明,在 20 世纪的发达国家中,属于所谓 "剔除队列 "的男性的风险略有增加,这可能反映了早年生活中的负面影响和孕妇接触的环境导致男性胚胎或胎儿的选择性丧失。从公共卫生的角度来看,SRB 作为与相对较小的人口健康影响有关的出生统计的一个方面,可能具有一定的监测重要性。
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引用次数: 0
Short inter-pregnancy interval and birthweight: a reappraisal based on a follow-up study of all women in Norway with two singleton deliveries during 1970–2019 孕间隔短与出生体重:基于对1970-2019年期间挪威所有单胎分娩妇女的跟踪研究的再评估
IF 13.6 1区 医学 Q1 PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH Pub Date : 2024-08-24 DOI: 10.1007/s10654-024-01148-y
Anne Eskild, Irene Skau, Camilla Haavaldsen, Ola Didrik Saugstad, Jostein Grytten

We studied mean changes in birthweight from the first to the second delivery according to length of the inter-pregnancy interval. We also studied recurrence risk of low birthweight, preterm birth and perinatal death. We followed all women in Norway from their first to their second singleton delivery at gestational week 22 or beyond during the years 1970–2019, a total of 654 100 women. Data were obtained from the Medical Birth Registry of Norway. Mean birthweight increased from the first to the second delivery, and the increase was highest in pregnancies conceived < 6 months after the first delivery; adjusted mean birthweight increase 227 g (g) (95% CI; 219–236 g), 90 g higher than in pregnancies conceived 6–11 months after the first delivery (137 g (95% CI; 130–144 g)). After exclusion of women with a first stillbirth, the mean increase in birthweight at inter-pregnancy interval < 6 months was attenuated (152 g, 95% CI; 143–160 g), but remained higher than at longer inter-pregnancy intervals. This finding was particularly prominent in women > 35 years (218 g, 95% CI; 139 –298 g). In women with a first live born infant weighing < 2500 g, mean birthweight increased by around 1000 g to the second delivery, and the increase was most prominent at < 6 months inter-pregnancy interval. We found increased recurrence risk of preterm birth at inter-pregnancy interval < 6 months, but no increased recurrence risk of low birthweight, small for gestational age infant or perinatal death. In conclusion, we found the highest mean increase in birthweight when the inter-pregnancy interval was short. Our results do not generally discourage short pregnancy intervals.

我们根据两次妊娠间隔时间的长短,研究了从第一次分娩到第二次分娩的出生体重平均变化情况。我们还研究了低出生体重、早产和围产期死亡的复发风险。在1970-2019年期间,我们对挪威所有孕周在22周或22周以上的妇女从第一次分娩到第二次分娩的单胎分娩情况进行了跟踪调查,共计654 100名妇女。数据来自挪威出生医学登记处。从第一次分娩到第二次分娩,平均出生体重有所增加,第一次分娩后6个月受孕的孕妇出生体重增幅最大;调整后的平均出生体重增加了227克(95% CI;219-236克),比第一次分娩后6-11个月受孕的孕妇高出90克(137克(95% CI;130-144克))。在剔除第一胎死产的妇女后,怀孕间隔为 6 个月的妇女出生体重的平均增幅有所减弱(152 克,95% CI;143-160 克),但仍高于怀孕间隔更长的妇女。这一结果在 35 岁妇女中尤为突出(218 克,95% CI;139 -298 克)。在第一胎活产婴儿体重为 2500 克的妇女中,平均出生体重在第二次分娩时增加了约 1000 克,在两次妊娠间隔为 6 个月时增加最为明显。我们发现,孕间隔 6 个月时早产的复发风险增加,但低出生体重儿、小胎龄儿或围产期死亡的复发风险没有增加。总之,我们发现怀孕间隔短时,出生体重的平均增幅最大。一般来说,我们的结果并不鼓励缩短怀孕间隔。
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引用次数: 0
The HOPE cohort: cohort profile and evaluation of selection bias. HOPE 队列:队列概况和选择偏差评估。
IF 7.7 1区 医学 Q1 PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH Pub Date : 2024-08-01 Epub Date: 2024-08-19 DOI: 10.1007/s10654-024-01150-4
Mette-Marie Zacher Kjeldsen, Merete Lund Mægbæk, Xiaoqin Liu, Malene Galle Madsen, Mette Bliddal, Sofie Egsgaard, Kathrine Bang Madsen, Trine Munk-Olsen

The HOPE cohort is a Danish nationwide cohort with ongoing follow-up, holding information on postpartum depression (PPD) symptoms and diagnoses on 170,218 childbirths (142,795 unique mothers). These data have been linked with extensive register data on health and socioeconomic information on the mothers, their partners, parents, and children. This cohort profile aimed to provide an overview of the data collection and content, describe characteristics, and evaluate potential selection bias. PPD screenings, using the Edinburgh Postnatal Depression Scale, were collected from 67 of the 98 Danish municipalities, covering the period January 2015 to December 2021. This data was linked with register data on PPD diagnoses (identified through medication prescriptions and hospital contacts) as well as background information. Cohort characteristics were compared to the source population, defined as all childbirths by women residing in Denmark during the same period (452,207 childbirths). Potential selection bias was evaluated by comparing odds ratios of five well-established associations between the cohort and the source population. The HOPE cohort holds information on 170,218 childbirths (38% of the source population) involving 142,795 unique mothers. The HOPE cohort only differed slightly from the source population on most characteristics examined, but larger differences were observed on specific characteristics with an underrepresentation of the youngest and oldest age groups, women with more than three children or twins/triplets, and women born outside Denmark. Similar associations were identified across the two populations within the five well-established associations. There was no indication of selection bias on the five examined associations, and the HOPE cohort is representative of the source population on important perinatal characteristics.

HOPE 队列是一个持续跟踪的丹麦全国性队列,拥有 170,218 名产妇(142,795 名母亲)的产后抑郁症(PPD)症状和诊断信息。这些数据与有关母亲、其伴侣、父母和子女的健康和社会经济信息的大量登记数据相联系。该队列概况旨在概述数据收集和内容、描述特征并评估潜在的选择偏差。使用爱丁堡产后抑郁量表对丹麦 98 个市镇中的 67 个进行了产后抑郁筛查,时间跨度为 2015 年 1 月至 2021 年 12 月。这些数据与 PPD 诊断登记数据(通过药物处方和医院联系确认)以及背景信息相关联。群组特征与来源人群进行了比较,来源人群定义为同一时期居住在丹麦的所有分娩妇女(452207 例分娩)。通过比较队列与来源人群之间五种公认关联的几率比,对潜在的选择偏差进行了评估。HOPE 群组拥有 170,218 例分娩(占来源人群的 38%)的信息,涉及 142,795 名独特的母亲。HOPE 群组与来源人群在大多数特征上仅有细微差别,但在特定特征上观察到较大差异,其中最年轻和最年长年龄组、有三个以上孩子或双胞胎/三胞胎的妇女以及在丹麦以外出生的妇女所占比例较低。在两个人群中,发现了五种成熟关联中的类似关联。在所研究的五种关联中,没有迹象表明存在选择偏差,HOPE 队列在重要的围产期特征方面对来源人群具有代表性。
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引用次数: 0
Survival outcomes and healthcare utilization between immigrant patients and Danish-born patients with hematological cancers: a Danish population-based study. 一项基于丹麦人口的研究:血液肿瘤移民患者与丹麦出生患者的生存结果和医疗保健使用情况。
IF 7.7 1区 医学 Q1 PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH Pub Date : 2024-08-01 Epub Date: 2024-07-04 DOI: 10.1007/s10654-024-01139-z
Joachim Baech, Lasse Hjort Jakobsen, Mikkel Runason Simonsen, Marianne Tang Severinsen, Henrik Frederiksen, Carsten Utoft Niemann, Peter Brown, Judit Mészáros Jørgensen, Eldad J Dann, Søren Paaske Johnsen, Tarec Christoffer El-Galaly

Overall survival (OS) for patients with a hematological cancer may differ between immigrant and Danish-born patients due to disparities in socioeconomic status, health literacy, and language proficiency. This cohort study aimed to investigate survival and hospitalization according to immigrant status while controlling for confounders. Patients with newly diagnosed hematological cancer in 2000-2020 were identified in the Danish nationwide hematological registers and stratified into Danish-born, Western, and non-Western patients. Patients were followed from diagnosis until death, 31st December 2021, or emigration, whichever came first. Crude OS, standardized OS, and 5-years OS differences were computed using flexible parametric models and hazard ratios using Cox regression. Number of hospitalization days in the year before and after diagnosis, respectively, were calculated using Poisson regression. A total of 2,241 immigrants and 41,519 Danish-born patients with a hematological cancer were included. Standardized 5-years OS was similar between groups with 58% (95% confidence interval 57-58%) for Danish-born patients, 57% (55-60%) for Western, and 56% (53-58%) for non-Western immigrant patients. Subgroup analyses identified OS differences in selected subgroups. Non-Western immigrant patients had 1.3 (0.5-2.1) more hospitalization days in the year before diagnosis and an adjusted incidence rate ratio of hospitalization days of 1.14 (1.13-1.15) in the year after diagnosis compared with Danish-born patients. In conclusion, there were no overall differences in survival when comparing immigrant patients to Danish-born patients after controlling for relevant confounders. Healthcare utilization was slightly higher among non-Western immigrant patients before and after diagnosis, but differences were small on an individual patient level.

由于社会经济地位、健康素养和语言能力的差异,移民和丹麦出生的血液肿瘤患者的总生存率(OS)可能有所不同。这项队列研究旨在根据移民身份调查生存率和住院情况,同时控制混杂因素。研究人员从丹麦全国血液病登记册中找到了2000-2020年新确诊的血液肿瘤患者,并将其分为丹麦出生的患者、西方患者和非西方患者。患者从确诊开始接受随访,直至死亡、2021 年 12 月 31 日或移民(以先到者为准)。使用灵活的参数模型计算粗略OS、标准化OS和5年OS差异,使用Cox回归计算危险比。诊断前后一年的住院天数分别采用泊松回归法计算。共纳入了2241名移民和41519名丹麦出生的血液肿瘤患者。各组间的标准化5年OS相似,丹麦出生的患者为58%(95%置信区间为57-58%),西方移民患者为57%(55-60%),非西方移民患者为56%(53-58%)。亚组分析确定了特定亚组的 OS 差异。与丹麦出生的患者相比,非西方移民患者在确诊前一年的住院天数增加了1.3(0.5-2.1)天,确诊后一年的住院天数调整发病率比为1.14(1.13-1.15)。总之,在控制了相关的混杂因素后,移民患者与丹麦出生的患者在存活率方面没有总体差异。非西方移民患者在确诊前后的医疗保健使用率略高,但单个患者的差异很小。
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引用次数: 0
Testosterone and Alzheimer's disease: a risk assessment. 睾酮与阿尔茨海默病:风险评估。
IF 7.7 1区 医学 Q1 PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH Pub Date : 2024-08-01 Epub Date: 2024-08-10 DOI: 10.1007/s10654-024-01145-1
Tomoyuki Kawada
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引用次数: 0
Source-specific nitrate intake and all-cause mortality in the Danish Diet, Cancer, and Health Study. 丹麦饮食、癌症和健康研究》中特定来源的硝酸盐摄入量与全因死亡率。
IF 7.7 1区 医学 Q1 PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH Pub Date : 2024-08-01 Epub Date: 2024-05-28 DOI: 10.1007/s10654-024-01133-5
Nicola P Bondonno, Pratik Pokharel, Catherine P Bondonno, Dorit W Erichsen, Liezhou Zhong, Jörg Schullehner, Kirsten Frederiksen, Cecilie Kyrø, Peter Fjeldstad Hendriksen, Jonathan M Hodgson, Frederik Dalgaard, Lauren C Blekkenhorst, Ole Raaschou-Nielsen, Torben Sigsgaard, Christina C Dahm, Anne Tjønneland, Anja Olsen

Introduction: Nitrate and nitrite are naturally occurring in both plant- and animal-sourced foods, are used as additives in the processing of meat, and are found in water. There is growing evidence that they exhibit a spectrum of health effects, depending on the dietary source. The aim of the study was to examine source-dependent associations between dietary intakes of nitrate/nitrite and both all-cause and cause-specific mortality.

Methods: In 52,247 participants of the Danish Diet, Cancer and Health Study, associations between source-dependent nitrate and nitrite intakes--calculated using comprehensive food composition and national drinking water quality monitoring databases--and all-cause, cardiovascular disease (CVD)-related, and cancer-related mortality over 27 years were examined using restricted cubic splines within Cox proportional hazards models adjusting for demographic, lifestyle, and dietary confounders. Analyses were stratified by factors hypothesised to influence the formation of carcinogenic N-nitroso compounds (namely, smoking and dietary intakes of vitamin C, vitamin E, folate, and polyphenols).

Results: Plant-sourced nitrate intake was inversely associated with all-cause mortality [HRQ5vsQ1: 0.83 (0.80, 0.87)] while higher risks of all-cause mortality were seen for higher intakes of naturally occurring animal-sourced nitrate [1.09 (1.04, 1.14)], additive permitted meat-sourced nitrate [1.19 (1.14, 1.25)], and tap water-sourced nitrate [1.19 (1.14, 1.25)]. Similar source-dependent associations were seen for nitrite and for CVD-related and cancer-related mortality except that naturally occurring animal-sourced nitrate and tap water-sourced nitrate were not associated with cancer-related mortality and additive permitted meat-sourced nitrate was not associated with CVD-related mortality. No clear patterns emerged in stratified analyses.

Conclusion: Nitrate/nitrite from plant sources are inversely associated while those from naturally occurring animal-sources, additive-permitted meat sources, and tap water-sources are positively associated with mortality.

简介:硝酸盐和亚硝酸盐天然存在于植物和动物源性食物中,在肉类加工过程中被用作添加剂,也存在于水中。越来越多的证据表明,根据膳食来源的不同,硝酸盐和亚硝酸盐会对健康产生一系列影响。本研究旨在探讨膳食中硝酸盐/亚硝酸盐的摄入量与全因死亡率和特定原因死亡率之间的相关性:在丹麦饮食、癌症和健康研究的 52,247 名参与者中,使用限制性三次样条,在调整了人口、生活方式和饮食混杂因素的 Cox 比例危险模型中,检验了 27 年间与来源相关的硝酸盐和亚硝酸盐摄入量--利用全面的食物成分和国家饮用水质量监测数据库计算得出--与全因死亡率、心血管疾病(CVD)相关死亡率和癌症相关死亡率之间的关系。根据影响致癌 N-亚硝基化合物形成的假定因素(即吸烟和膳食中维生素 C、维生素 E、叶酸和多酚的摄入量)进行了分层分析:植物源硝酸盐摄入量与全因死亡率成反比[HRQ5vsQ1:0.83 (0.80, 0.87)],而动物源天然硝酸盐[1.09 (1.04, 1.14)]、添加剂允许肉类源硝酸盐[1.19 (1.14, 1.25)]和自来水源硝酸盐[1.19 (1.14, 1.25)]摄入量越高,全因死亡风险越高。亚硝酸盐与心血管疾病相关死亡率和癌症相关死亡率之间也存在类似的来源依赖关系,但动物来源的天然硝酸盐和自来水来源的硝酸盐与癌症相关死亡率无关,添加剂允许的肉类来源的硝酸盐与心血管疾病相关死亡率无关。在分层分析中没有出现明显的模式:结论:植物来源的硝酸盐/亚硝酸盐与死亡率成反比,而天然动物来源、添加剂允许的肉类来源和自来水来源的硝酸盐/亚硝酸盐与死亡率成正比。
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引用次数: 0
A phenome-wide association and factorial Mendelian randomization study on the repurposing of uric acid-lowering drugs for cardiovascular outcomes. 关于降尿酸药物重新用于心血管治疗的全表象关联和因子孟德尔随机研究。
IF 7.7 1区 医学 Q1 PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH Pub Date : 2024-08-01 Epub Date: 2024-07-11 DOI: 10.1007/s10654-024-01138-0
Lijuan Wang, Ines Mesa-Eguiagaray, Harry Campbell, James F Wilson, Veronique Vitart, Xue Li, Evropi Theodoratou

Uric acid has been linked to various disease outcomes. However, it remains unclear whether uric acid-lowering therapy could be repurposed as a treatment for conditions other than gout. We first performed both observational phenome-wide association study (Obs-PheWAS) and polygenic risk score PheWAS (PRS-PheWAS) to identify associations of uric acid levels with a wide range of disease outcomes. Then, trajectory analysis was conducted to explore temporal progression patterns of the observed disease outcomes. Finally, we investigated whether uric acid-lowering drugs could be repurposed using a factorial Mendelian randomization (MR) study design. A total of 41 overlapping phenotypes associated with uric acid levels were identified by both Obs- and PRS- PheWASs, primarily cardiometabolic diseases. The trajectory analysis illustrated how elevated uric acid levels contribute to cardiometabolic diseases, and finally death. Meanwhile, we found that uric acid-lowering drugs exerted a protective role in reducing the risk of coronary atherosclerosis (OR = 0.96, 95%CI: 0.93, 1.00, P = 0.049), congestive heart failure (OR = 0.64, 95%CI: 0.42, 0.99, P = 0.043), occlusion of cerebral arteries (OR = 0.93, 95%CI: 0.87, 1.00, P = 0.044) and peripheral vascular disease (OR = 0.60, 95%CI: 0.38, 0.94, P = 0.025). Furthermore, the combination of uric acid-lowering therapy (e.g. xanthine oxidase inhibitors) with antihypertensive treatment (e.g. calcium channel blockers) exerted additive effects and was associated with a 6%, 8%, 8%, 10% reduction in risk of coronary atherosclerosis, heart failure, occlusion of cerebral arteries and peripheral vascular disease, respectively. Our findings support a role of elevated uric acid levels in advancing cardiovascular dysfunction and identify potential repurposing opportunities for uric acid-lowering drugs in cardiovascular treatment.

尿酸与各种疾病的后果有关。然而,降尿酸疗法是否能被重新用于痛风以外的其他疾病的治疗,目前仍不清楚。我们首先进行了观察性全表型关联研究(Obs-PheWAS)和多基因风险评分PheWAS(PRS-PheWAS),以确定尿酸水平与多种疾病结局的关联。然后,我们进行了轨迹分析,以探索观察到的疾病结果的时间进展模式。最后,我们采用因子孟德尔随机化(MR)研究设计调查了降尿酸药物是否可以重新用于治疗。通过Obs-和PRS- PheWASs共发现了41种与尿酸水平相关的重叠表型,主要是心血管代谢疾病。轨迹分析表明了尿酸水平升高是如何导致心脏代谢疾病并最终导致死亡的。同时,我们发现降尿酸药物在降低冠状动脉粥样硬化(OR = 0.96,95%CI:0.93,1.00,P = 0.049)、充血性心力衰竭(OR = 0.64,95%CI:0.42,0.99,P = 0.043)、脑动脉闭塞(OR = 0.93,95%CI:0.87,1.00,P = 0.044)和外周血管疾病(OR = 0.60,95%CI:0.38,0.94,P = 0.025)。此外,降尿酸治疗(如黄嘌呤氧化酶抑制剂)与降压治疗(如钙通道阻滞剂)联合使用具有叠加效应,可使冠状动脉粥样硬化、心力衰竭、脑动脉闭塞和外周血管疾病的风险分别降低 6%、8%、8% 和 10%。我们的研究结果支持尿酸水平升高在推进心血管功能障碍中的作用,并确定了降尿酸药物在心血管治疗中的潜在再利用机会。
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引用次数: 0
Multi-biobank Mendelian randomization analyses identify opposing pathways in plasma low-density lipoprotein-cholesterol lowering and gallstone disease. 多生物库孟德尔随机分析确定了降低血浆低密度脂蛋白胆固醇与胆石症的对立途径。
IF 7.7 1区 医学 Q1 PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH Pub Date : 2024-08-01 Epub Date: 2024-07-15 DOI: 10.1007/s10654-024-01141-5
Guoyi Yang, Amy M Mason, Dipender Gill, C Mary Schooling, Stephen Burgess

Plasma low-density lipoprotein (LDL)-cholesterol is positively associated with coronary artery disease risk while biliary cholesterol promotes gallstone formation. Different plasma LDL-cholesterol lowering pathways may have distinct effects on biliary cholesterol and thereby gallstone disease risk. We conducted a Mendelian randomization (MR) study using data from the UK Biobank (30,547 gallstone disease cases/336,742 controls), FinnGen (34,461 cases/301,383 controls) and Biobank Japan (9,305 cases/168,253 controls). We first performed drug-target MR analyses substantiated by colocalization to investigate the effects of plasma LDL-cholesterol lowering therapies on gallstone disease risk. We then performed clustered MR analyses and pathway analyses to identify distinct mechanisms underlying the association of plasma LDL-cholesterol with gallstone disease risk. For a 1-standard deviation reduction in plasma LDL-cholesterol, genetic mimics of statins were associated with lower gallstone disease risk (odds ratio 0.72 [95% confidence interval 0.62, 0.83]), but genetic mimics of PCSK9 inhibitors and targeting apolipoprotein B were associated with higher risk (1.11 [1.03, 1.19] and 1.23 [1.13, 1.35]). The association for statins was supported by colocalization (posterior probability 98.7%). Clustered MR analyses identified variant clusters showing opposing associations of plasma LDL-cholesterol with gallstone disease risk, with some evidence for ancestry-and sex-specific associations. Among variants lowering plasma LDL-cholesterol, those associated with lower gallstone disease risk were mapped to glycosphingolipid biosynthesis pathway, while those associated with higher risk were mapped to pathways relating to plasma lipoprotein assembly, remodelling, and clearance and ATP-binding cassette transporters. This MR study provides genetic evidence that different plasma LDL-cholesterol lowering pathways have opposing effects on gallstone disease risk.

血浆低密度脂蛋白(LDL)胆固醇与冠状动脉疾病风险呈正相关,而胆汁胆固醇则会促进胆石的形成。不同的血浆低密度脂蛋白胆固醇降低途径可能会对胆汁胆固醇产生不同的影响,从而影响胆石症风险。我们利用英国生物库(30,547 例胆石病病例/336,742 例对照)、FinnGen(34,461 例病例/301,383 例对照)和日本生物库(9,305 例病例/168,253 例对照)的数据进行了孟德尔随机化(MR)研究。我们首先进行了通过共定位证实的药物靶向磁共振分析,以研究降低血浆低密度脂蛋白胆固醇疗法对胆石症风险的影响。然后,我们进行了聚类磁共振分析和通路分析,以确定血浆低密度脂蛋白胆固醇与胆石症风险相关的不同机制。血浆低密度脂蛋白胆固醇每降低 1 个标准差,他汀类药物的基因模拟物与较低的胆石症风险相关(几率比 0.72 [95% 置信区间 0.62, 0.83]),但 PCSK9 抑制剂和以载脂蛋白 B 为靶点的基因模拟物与较高的风险相关(1.11 [1.03, 1.19] 和 1.23 [1.13, 1.35])。他汀类药物的相关性得到了共定位的支持(后验概率为 98.7%)。聚类磁共振分析发现的变异群显示血浆低密度脂蛋白胆固醇与胆石症风险存在相反的关联,并有一些证据表明存在祖先和性别特异性关联。在降低血浆低密度脂蛋白胆固醇的变异中,与较低胆石病风险相关的变异被映射到糖磷脂生物合成途径,而与较高风险相关的变异被映射到与血浆脂蛋白组装、重塑和清除以及 ATP 结合盒转运体有关的途径。这项磁共振研究提供了遗传学证据,证明不同的血浆低密度脂蛋白胆固醇降低途径对胆石症风险具有相反的影响。
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引用次数: 0
Using the global randomization test as a Mendelian randomization falsification test for the exclusion restriction assumption. 使用全局随机化检验作为排除限制假设的孟德尔随机化证伪检验。
IF 7.7 1区 医学 Q1 PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH Pub Date : 2024-08-01 Epub Date: 2024-02-29 DOI: 10.1007/s10654-024-01097-6
Louise A C Millard, George Davey Smith, Kate Tilling

Mendelian randomization may give biased causal estimates if the instrument affects the outcome not solely via the exposure of interest (violating the exclusion restriction assumption). We demonstrate use of a global randomization test as a falsification test for the exclusion restriction assumption. Using simulations, we explored the statistical power of the randomization test to detect an association between a genetic instrument and a covariate set due to (a) selection bias or (b) horizontal pleiotropy, compared to three approaches examining associations with individual covariates: (i) Bonferroni correction for the number of covariates, (ii) correction for the effective number of independent covariates, and (iii) an r2 permutation-based approach. We conducted proof-of-principle analyses in UK Biobank, using CRP as the exposure and coronary heart disease (CHD) as the outcome. In simulations, power of the randomization test was higher than the other approaches for detecting selection bias when the correlation between the covariates was low (r2 < 0.1), and at least as powerful as the other approaches across all simulated horizontal pleiotropy scenarios. In our applied example, we found strong evidence of selection bias using all approaches (e.g., global randomization test p < 0.002). We identified 51 of the 58 CRP genetic variants as horizontally pleiotropic, and estimated effects of CRP on CHD attenuated somewhat to the null when excluding these from the genetic risk score (OR = 0.96 [95% CI: 0.92, 1.00] versus 0.97 [95% CI: 0.90, 1.05] per 1-unit higher log CRP levels). The global randomization test can be a useful addition to the MR researcher's toolkit.

如果工具并非仅通过相关暴露影响结果(违反了排除限制假设),孟德尔随机化可能会给出有偏差的因果关系估计值。我们展示了使用全局随机化检验作为排除限制假设的证伪检验。通过模拟实验,我们探讨了随机化检验在检测遗传工具与协变量集之间因(a)选择偏差或(b)水平多效性而产生的关联方面的统计能力,并与以下三种检测单个协变量关联的方法进行了比较:(i)对协变量数量进行 Bonferroni 校正,(ii)对独立协变量的有效数量进行校正,以及(iii)基于 r2 的置换方法。我们以 CRP 为暴露因子,以冠心病(CHD)为结果,在英国生物库中进行了原理验证分析。在模拟实验中,当协变量之间的相关性较低时(r2
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引用次数: 0
Cognitive ability, education, height and body mass index in relation to risk of schizophrenia and mortality following its diagnosis 认知能力、教育程度、身高和体重指数与精神分裂症风险和确诊后死亡率的关系
IF 13.6 1区 医学 Q1 PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH Pub Date : 2024-07-27 DOI: 10.1007/s10654-024-01140-6
Terese Sara Høj Jørgensen, Ida Kim Wium-Andersen, Marie Kim Wium-Andersen, Maarten Pieter Rozing, Martin Balslev Jørgensen, Thorkild IA Sørensen, Merete Osler

This study examines the hypotheses that the traits of higher IQ, longer education and taller height are associated with lower risk of death as compared to traits of low IQ, short education, and short height in men with schizophrenia compared to men without schizophrenia. In total, 937,919 men born 1939-59 and 1983–1997 with information from conscription were followed for incident schizophrenia in Danish registries. Higher levels of cognitive ability, longer education, and taller height were associated with fewer cases of schizophrenia. In a sub-sample of 652,368 men with information on body mass index, underweight was associated with more and overweight and obesity were associated with fewer cases of schizophrenia compared with normal weight. Higher cognitive ability, longer education, and taller height were associated with fewer deaths from both natural and unnatural causes in both men with and without schizophrenia. Underweight was associated with more deaths from natural and unnatural causes, whereas overweight and obesity were associated with more deaths from natural causes and fewer deaths from unnatural causes in both groups of men. Due to interaction, tall height and long educational duration were associated with fewer deaths from natural causes, and obesity was associated with fewer deaths from unnatural causes among men with schizophrenia compared to men without. In conclusion, traits in young adulthood are associated with higher mortality in men with and without schizophrenia, but traits of long educational duration and obesity seem to be especially important for lower mortality in men with schizophrenia.

与未患精神分裂症的男性相比,患精神分裂症的男性智商较高、受教育时间较长、身高较高的特征与智商较低、受教育时间较短、身高较矮的特征相比与死亡风险较低的特征相关,本研究探讨了这一假设。丹麦登记处共对 937,919 名出生于 1939-59 年和 1983-1997 年、有征兵信息的男性精神分裂症患者进行了跟踪调查。认知能力越高、受教育时间越长、身高越高的人患精神分裂症的病例越少。在有体重指数信息的 652,368 名男性子样本中,与正常体重相比,体重不足与更多精神分裂症病例有关,而超重和肥胖与更少的精神分裂症病例有关。在患有和未患有精神分裂症的男性中,较高的认知能力、较长的受教育时间和较高的身高与较少的自然和非自然死亡有关。在两组男性中,体重不足与更多的自然死亡和非自然死亡有关,而超重和肥胖与更多的自然死亡和更少的非自然死亡有关。由于相互作用,与非精神分裂症男性相比,身高和受教育时间长与较少的自然死亡有关,而肥胖与较少的非自然死亡有关。总之,在患有和未患有精神分裂症的男性中,年轻时的特征与较高的死亡率有关,但受教育时间长和肥胖的特征似乎对降低精神分裂症男性的死亡率尤为重要。
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引用次数: 0
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European Journal of Epidemiology
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