Lei Peng, Jiajia Shen, Lurong Li, Jiahao Liu, Xingzhou Jiang, Guoxin Zhang, Yuanyuan Li
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In the present study, MR was used to assess whether direct foetal effects on birthweight were causally associated with liver structure, function and disease risk independent of intrauterine effects.</p><p><strong>Materials and methods: </strong>We extracted single nucleotide polymorphisms (SNPs) from genome-wide association studies (GWAS) about direct foetal-affected birthweight (321 223 cases) to conduct univariable and multivariable MR analyses to explore the relationships between birthweight and 4 liver structure measures, 9 liver function measures and 18 liver diseases. A two-step MR analysis was used to further assess and quantify the mediating effects of the mediators.</p><p><strong>Results: </strong>When isolating direct foetal effects, genetically predicted lower birthweight was associated with a higher risk of non-alcoholic fatty liver disease (NAFLD) (odds ratios [OR], 95% confidence interval [CI]: 1.61, 1.29-2.02, p < 0.001), higher magnetic resonance imaging [MRI] proton density fat fraction (PDFF) and higher serum gamma glutamyltransferase (GGT). Two-step MR identified two candidate mediators that partially mediate the direct foetal effect of lower birthweight on NAFLD, including fasting insulin (proportion mediated: 22.29%) and triglycerides (6.50%).</p><p><strong>Conclusions: </strong>Our MR analysis reveals a direct causal association between lower birthweight and liver MRI PDFF, as well as the development of NAFLD, which persisted even after accounting for the potential influence of maternal factors. In addition, we identified fasting insulin and triglycerides as mediators linking birthweight and hepatic outcomes, providing insights for early clinical interventions.</p>","PeriodicalId":158,"journal":{"name":"Diabetes, Obesity & Metabolism","volume":null,"pages":null},"PeriodicalIF":5.4000,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Birthweight influences liver structure, function and disease risk: Evidence of a causal association.\",\"authors\":\"Lei Peng, Jiajia Shen, Lurong Li, Jiahao Liu, Xingzhou Jiang, Guoxin Zhang, Yuanyuan Li\",\"doi\":\"10.1111/dom.15910\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Aim: </strong>Low birthweight is an issue during pregnancy associated with an increased risk of developing liver disease later in life. 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引用次数: 0
摘要
目的:出生时体重过轻是一个与日后罹患肝病的风险增加有关的孕期问题。以往探讨这一问题的孟德尔随机化(MR)研究并未分离出胎儿对出生体重的直接影响。在本研究中,MR 被用来评估胎儿对出生体重的直接影响是否与肝脏结构、功能和疾病风险存在因果关系,而与宫内影响无关:我们从有关胎儿直接影响出生体重的全基因组关联研究(GWAS)中提取了单核苷酸多态性(SNPs),对出生体重与4种肝脏结构指标、9种肝功能指标和18种肝脏疾病之间的关系进行了单变量和多变量MR分析。采用两步磁共振分析法进一步评估和量化中介效应:结果:在分离胎儿的直接影响时,遗传预测的较低出生体重与较高的非酒精性脂肪肝(NAFLD)风险相关(几率比[OR],95%置信区间[CI]:1.61,1.29-2):1.61, 1.29-2.02, p 结论:我们的磁共振分析揭示了较低出生体重与肝脏磁共振成像 PDFF 以及非酒精性脂肪肝之间的直接因果关系,即使考虑了母体因素的潜在影响,这种因果关系依然存在。此外,我们还发现空腹胰岛素和甘油三酯是连接出生体重和肝脏结果的介质,这为早期临床干预提供了启示。
Birthweight influences liver structure, function and disease risk: Evidence of a causal association.
Aim: Low birthweight is an issue during pregnancy associated with an increased risk of developing liver disease later in life. Previous Mendelian randomisation (MR) studies which explored this issue have not isolated the direct impact of the foetus on birthweight. In the present study, MR was used to assess whether direct foetal effects on birthweight were causally associated with liver structure, function and disease risk independent of intrauterine effects.
Materials and methods: We extracted single nucleotide polymorphisms (SNPs) from genome-wide association studies (GWAS) about direct foetal-affected birthweight (321 223 cases) to conduct univariable and multivariable MR analyses to explore the relationships between birthweight and 4 liver structure measures, 9 liver function measures and 18 liver diseases. A two-step MR analysis was used to further assess and quantify the mediating effects of the mediators.
Results: When isolating direct foetal effects, genetically predicted lower birthweight was associated with a higher risk of non-alcoholic fatty liver disease (NAFLD) (odds ratios [OR], 95% confidence interval [CI]: 1.61, 1.29-2.02, p < 0.001), higher magnetic resonance imaging [MRI] proton density fat fraction (PDFF) and higher serum gamma glutamyltransferase (GGT). Two-step MR identified two candidate mediators that partially mediate the direct foetal effect of lower birthweight on NAFLD, including fasting insulin (proportion mediated: 22.29%) and triglycerides (6.50%).
Conclusions: Our MR analysis reveals a direct causal association between lower birthweight and liver MRI PDFF, as well as the development of NAFLD, which persisted even after accounting for the potential influence of maternal factors. In addition, we identified fasting insulin and triglycerides as mediators linking birthweight and hepatic outcomes, providing insights for early clinical interventions.
期刊介绍:
Diabetes, Obesity and Metabolism is primarily a journal of clinical and experimental pharmacology and therapeutics covering the interrelated areas of diabetes, obesity and metabolism. The journal prioritises high-quality original research that reports on the effects of new or existing therapies, including dietary, exercise and lifestyle (non-pharmacological) interventions, in any aspect of metabolic and endocrine disease, either in humans or animal and cellular systems. ‘Metabolism’ may relate to lipids, bone and drug metabolism, or broader aspects of endocrine dysfunction. Preclinical pharmacology, pharmacokinetic studies, meta-analyses and those addressing drug safety and tolerability are also highly suitable for publication in this journal. Original research may be published as a main paper or as a research letter.