Gene by environment interactions in the regulation of gene expression across primary tissues and their application to obesity and related traits

原代组织基因表达调节中基因与环境的相互作用及其在肥胖和相关性状中的应用

• 批准号: MR/L01999X/1
• 负责人: Kerrin Shannon Small
• 金额: $ 53.6万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL01999X%2F1
• 关键词: Gene; environment; interactions; regulation; gene

Gene expression is an important cellular phenotype under both genetic and environmental control. Changes in gene expression appear to underlie the majority of genetic associations identified in genome-wide association studies of common disease. Studying the genetic regulation of gene expression has thus been a fruitful strategy to unraveling the underlying mechanisms of common disease, both in identifying the genes and pathways that mediate the effects of disease and in characterizing the molecular mechanisms and tissues by which disease-associated genetic variants act. Previous research into the genetics of gene expression has focused on identifying genetic variants that regulate the total expression level of a gene. This study will expand on this approach by incorporating the effects of the environment and its interactions with the genome. In the context of a cellular trait like gene expression the environment can be interpreted as exposures that operate on the organism (eg diet, medication, physical activity, or smoking) or on the physiology of tissues and cells (including obesity, insulin and cholesterol levels). This study will investigate the joint effects of the environment (lifestyle factors and biomedical measurements) and genetics on the regulation of gene expression in a deeply phenotyped, 'omics level dataset. Importantly, this study includes multiple disease-relevant tissues as both gene regulation and disease manifestation is tissue specific. Obesity is a worldwide epidemic and is robustly associated with many co-morbidities including type 2 diabetes, cardiovascular disease, osteoarthritis, certain cancers and increased mortality. However, not all obese individuals develop the same co-morbidities and some obese individuals even appear to be metabolically healthy. Incomplete knowledge of the processes involved in the development of obesity-associated co-morbidities has limited the development of treatments or prevention strategies. While the genes driving increased body mass index (BMI) appear to act primarily in the Central Nervous System, genes underlying body fat distribution and co-morbidities such as insulin resistance and Type 2 Diabetes are active in fat tissue. Obesity has a dramatic effect on fat tissue, including cell composition, metabolism and gene expression. Obesity can thus mask, confound or modify associations between genetic variants and gene expression in fat tissue. This study will consider obesity (measured both as total adiposity and body fat distribution) as an environment in order to identify genetic variants that interact with obesity to regulate gene expression. This will allow an expanded understanding of the molecular effects of obesity on fat cells and identify genotype-dependent differences in the cellular response to obesity that could be linked to differential development of obesity co-morbidities.

基因表达是遗传和环境控制下的重要细胞表型。基因表达的变化似乎是普通疾病全基因组关联研究中大多数遗传关联的基础。因此，研究基因表达的遗传调节已经成为揭示普通疾病的潜在机制的富有成果的策略，无论是在识别介导疾病作用的基因和途径以及表征疾病相关遗传变异的分子机制和组织方面。先前对基因表达遗传学的研究重点是鉴定调节基因总表达水平的遗传变异。这项研究将通过结合环境的影响及其与基因组的相互作用来扩展这种方法。在基因表达（例如基因表达）的背景下，环境可以解释为在生物体（例如饮食，药物，体育活动或吸烟）或组织和细胞生理学（包括肥胖，胰岛素和胆固醇水平）上进行的暴露。这项研究将研究环境（生活方式因素和生物医学测量值）和遗传学对基因表达的调节，这是在深层表型中的基因表达的调节。重要的是，这项研究包括多种疾病的组织，因为基因调节和疾病表现都是组织特异性的。肥胖症是一种全球流行病，与许多合并症（包括2型糖尿病，心血管疾病，骨关节炎，某些癌症和死亡率增加）的许多合并症牢固。但是，并非所有肥胖者都会发展出相同的合并症，一些肥胖个体甚至似乎在代谢上健康。对与肥胖相关的合并症发展所涉及的过程的不完整了解限制了治疗或预防策略的发展。尽管驱动的基因增加了体重指数（BMI）似乎主要在中枢神经系统中起作用，但体内脂肪分布的基因和胰岛素抵抗和2型糖尿病等合并症在脂肪组织中活跃。肥胖对脂肪组织具有巨大的作用，包括细胞组成，代谢和基因表达。因此，肥胖可以掩盖，混淆或修改遗传变异与脂肪组织中基因表达之间的关联。这项研究将将肥胖症（既测量为总肥胖和体内脂肪分布）视为一种环境，以鉴定与肥胖相互作用以调节基因表达的遗传变异。这将使人们对肥胖对脂肪细胞的分子作用有扩展的了解，并确定基因型依赖性的细胞对肥胖反应的差异，这可能与肥胖合并症的差异发展有关。

项目成果

ACE2 expression in adipose tissue is associated with cardio-metabolic risk factors and cell type composition-implications for COVID-19.

• DOI: 10.1038/s41366-022-01136-w
• 发表时间: 2022-08
• 期刊: INTERNATIONAL JOURNAL OF OBESITY
• 影响因子: 4.9
• 作者: Moustafa, Julia S. El-Sayed;Jackson, Anne U.;Brotman, Sarah M.;Guan, Li;Villicana, Sergio;Roberts, Amy L.;Zito, Antonino;Bonnycastle, Lori;Erdos, Michael R.;Narisu, Narisu;Stringham, Heather M.;Welch, Ryan;Yan, Tingfen;Lakka, Timo;Parker, Stephen;Tuomilehto, Jaakko;Seow, Jeffrey;Graham, Carl;Huettner, Isabella;Acors, Sam;Kouphou, Neophytos;Wadge, Samuel;Duncan, Emma L.;Steves, Claire J.;Doores, Katie J.;Malim, Michael H.;Collins, Francis S.;Pajukanta, Paivi;Boehnke, Michael;Koistinen, Heikki A.;Laakso, Markku;Falchi, Mario;Bell, Jordana T.;Scott, Laura J.;Mohlke, Karen L.;Small, Kerrin S.
• 通讯作者: Small, Kerrin S.

Adiposity-Dependent Regulatory Effects on Multi-tissue Transcriptomes.

• DOI: 10.1016/j.ajhg.2016.07.001
• 发表时间: 2016-09-01
• 期刊: American journal of human genetics
• 影响因子: 9.8
• 作者: Glastonbury CA;Viñuela A;Buil A;Halldorsson GH;Thorleifsson G;Helgason H;Thorsteinsdottir U;Stefansson K;Dermitzakis ET;Spector TD;Small KS
• 通讯作者: Small KS

Identification of Rare Loss-of-Function Genetic Variation Regulating Body Fat Distribution.

• DOI: 10.1210/clinem/dgab877
• 发表时间: 2022-03-24
• 期刊: The Journal of clinical endocrinology and metabolism
• 作者: Koprulu M;Zhao Y;Wheeler E;Dong L;Rocha N;Li C;Griffin JD;Patel S;Van de Streek M;Glastonbury CA;Stewart ID;Day FR;Luan J;Bowker N;Wittemans LBL;Kerrison ND;Cai L;Lucarelli DME;Barroso I;McCarthy MI;Scott RA;Saudek V;Small KS;Wareham NJ;Semple RK;Perry JRB;O'Rahilly S;Lotta LA;Langenberg C;Savage DB
• 通讯作者: Savage DB

Fasting and time of day independently modulate circadian rhythm relevant gene expression in adipose and skin tissue.

• DOI: 10.1186/s12864-018-4997-y
• 发表时间: 2018-09-07
• 期刊: BMC genomics
• 影响因子: 4.4
• 作者: Couto Alves A;Glastonbury CA;El-Sayed Moustafa JS;Small KS
• 通讯作者: Small KS

Tensor decomposition for multiple-tissue gene expression experiments.

• DOI: 10.1038/ng.3624
• 发表时间: 2016-09
• 期刊: NATURE GENETICS
• 影响因子: 30.8
• 作者: Hore, Victoria;Vinuela, Ana;Buil, Alfonso;Knight, Julian;McCarthy, Mark I.;Small, Kerrin;Marchini, Jonathan
• 通讯作者: Marchini, Jonathan