348-OR：通过多家畜全基因组测序（WGS）元分析确定与成像测量的肝脏脂肪变性相关的基因位点

IF 6.2 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetes Pub Date : 2024-07-19 DOI:10.2337/db24-348-or

NICHOLETTE ALLRED, CHINMAY RAUT, YANHUA CHEN, ANTONINO OLIVERI, JEFFREY O'CONNELL, KATHLEEN RYAN, JEROME I. ROTTER, STEPHEN S. RICH, AARON HAKIM, PATRICIA PEYSER, LAWRENCE F. BIELAK, CHING-TI LIU, JAMES G. TERRY, MYRIAM FORNAGE, LYNNE E. WAGENKNECHT, ELIZABETH K. SPELIOTES, NHLBI TRANS-OMICS FOR PRECISION MEDICINE (TOPMED)PROGRAM, GOLD CONSORTIUM

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引用次数: 0

摘要

导言和目标：脂肪肝，以前称为非酒精性脂肪肝（NAFLD），是全球最常见的慢性肝病；然而，几乎没有有效的预防/治疗方法，使其成为当代最大的未满足公共卫生需求之一。迄今为止，遗传学研究仅限于在以欧洲血统为主的人群中确定常见变体，或侧重于替代表型（如肝酶），以确定与合并症的关联。在此，我们介绍一项多安塞斯特全基因组测序（WGS）关联研究，以发现与成像测量的肝脂肪变性相关的罕见变异。研究方法使用 SAIGEgds 对九项影像测量肝脂肪变性的研究进行了研究、祖先和性别分层关联分析，并对年龄、性别、每周酒精饮品量和主成分混杂估计值进行了调整。采用固定效应模型对分层结果进行了元分析。Cochran's Q 检验和 I2 指标用于估计异质性。结果元分析纳入了 23156 名欧洲、非洲、西班牙和中国血统的个体，并确定了五个重要的基因位点（P<5x10-08）：PNPLA3、PPP1R3B、HAPLN4、chr14上的基因间区域和F11-AS1。另有 9 个变异具有关联趋势（P<5x10-07）。性别分层荟萃分析表明，在 chr10 上的基因间区域、RP11-115J16.1 和 UBE3B 中存在其他关联。在欧洲血统样本中，RP11-115J16.1 的变异仍然显著。在非裔美国人中，SLC2A1-AS1 和 LINC01684 的显著相关变异是新的位点。结论总之，利用 WGS 对成像测量的肝脂肪变性进行的多种姓分析复制了以前的相关位点，并发现了新的性别和祖先特异性位点。目前正在进行功能研究，以确定这些发现的生物学影响。披露 N. Allred：无。C. Raut：无。Y. Chen: None.A. Oliveri: None.J. O'Connell: None.K. Ryan: None.J.I. Rotter：J.I. Rotter: None.S.S. Rich: None.A. Hakim：无。P. Peyser：无。L.F. Bielak：无。C. Liu: None.J.G. Terry：无：无。M. Fornage：无。L.E. Wagenknecht：无：无。E.K. Speliotes：其他关系；密歇根大学。资助国家糖尿病和消化性肾病研究所 (R01 DK128871)

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348-OR: Multiancestry Whole Genome Sequencing (WGS) Meta-analysis to Identify Loci Associated with Imaging-Measured Hepatic Steatosis

Introduction and Objective: Steatotic liver disease, formerly called non-alcoholic fatty liver disease (NAFLD), is the most common cause of chronic liver disease worldwide; yet, few effective methods for prevention/treatment exist making it one of the biggest unmet public health needs of our time. To date, genetic studies have been limited to identifying common variants in predominantly European-ancestry populations or focused on surrogate phenotypes, e.g. liver enzymes, identifying association with comorbidities. Here we present a multi-ancestry whole genome sequencing (WGS) association study to discover rare variants associated with imaging-measured hepatic steatosis. Methods: Study-, ancestry- and sex-stratified association analyses were conducted using SAIGEgds in nine studies with imaging-measured hepatic steatosis adjusted for age, sex, alcoholic drinks per week and principal component estimates of admixture. Stratified results were meta-analyzed using a fixed-effects model. Cochran’s Q-test and the I2 metric were used to estimate heterogeneity. Results: Meta-analyses included 23,156 European, African, Hispanic and Chinese ancestry individuals and identified five significant loci (P<5x10-08): PNPLA3, PPP1R3B, HAPLN4, intergenic region on chr14 and F11-AS1. Nine additional variants trended toward association (P<5x10-07). Sex-stratified meta-analyses revealed additional associations in an intergenic region on chr10, RP11-115J16.1 and UBE3B. Variants in RP11-115J16.1 remained significant in European ancestry samples. Significantly associated variants in SLC2A1-AS1 and LINC01684 were novel loci in African Americans. Conclusion: Taken together, multi-ancestry analysis of imaging-measured hepatic steatosis using WGS replicated previously associated loci and identified novel sex- and ancestry-specific loci. Functional studies are underway to determine the biological impact of these findings. Disclosure N. Allred: None. C. Raut: None. Y. Chen: None. A. Oliveri: None. J. O'Connell: None. K. Ryan: None. J.I. Rotter: None. S.S. Rich: None. A. Hakim: None. P. Peyser: None. L.F. Bielak: None. C. Liu: None. J.G. Terry: None. M. Fornage: None. L.E. Wagenknecht: None. E.K. Speliotes: Other Relationship; University of Michigan. Funding National Institute of Diabetes and Digestive Kidney Disease (R01 DK128871)

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来源期刊

Diabetes 医学-内分泌学与代谢

CiteScore

12.50

自引率

2.60%

发文量

1968

审稿时长

1 months

期刊介绍： Diabetes is a scientific journal that publishes original research exploring the physiological and pathophysiological aspects of diabetes mellitus. We encourage submissions of manuscripts pertaining to laboratory, animal, or human research, covering a wide range of topics. Our primary focus is on investigative reports investigating various aspects such as the development and progression of diabetes, along with its associated complications. We also welcome studies delving into normal and pathological pancreatic islet function and intermediary metabolism, as well as exploring the mechanisms of drug and hormone action from a pharmacological perspective. Additionally, we encourage submissions that delve into the biochemical and molecular aspects of both normal and abnormal biological processes. However, it is important to note that we do not publish studies relating to diabetes education or the application of accepted therapeutic and diagnostic approaches to patients with diabetes mellitus. Our aim is to provide a platform for research that contributes to advancing our understanding of the underlying mechanisms and processes of diabetes.

348-OR： 通过多家畜全基因组测序（WGS）元分析确定与成像测量的肝脏脂肪变性相关的基因位点

摘要

348-OR：通过多家畜全基因组测序（WGS）元分析确定与成像测量的肝脏脂肪变性相关的基因位点