Genetic and transcriptional characterization of a region on chromosome 7p15.2 that shows pleiotropy between endometriosis and fat distribution

染色体 7p15.2 上显示子宫内膜异位症和脂肪分布之间多效性的区域的遗传和转录特征

• 批准号: MR/K011480/1
• 负责人: Krina Zondervan
• 金额: $ 52.17万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK011480%2F1
• 关键词: Genetic; transcriptional; characterization; region; chromosome

Endometriosis is a common women's health problem characterised by the presence of deposits resembling endometrium (lining of the uterus) on ectopic sites in the pelvis, causing chronic inflammation, severe pelvic pain and reduced fertility. Family studies indicate that the disease can be inherited. In a recent study comparing genetic information from 5,675 women with endometriosis and 9,331 controls, we found a genetic variant on chromosome 7 associated with moderate-severe endometriosis. In an independent study involving 190,803 individuals, the same genetic region was found to be associated with fat distribution (waist-hip ratio). The signal is located between genes, and it is unclear how the variant - or those in its vicinity - act on transcription of DNA and ultimately on the development of endometriosis or differences in fat distribution. We are collecting endometriotic tissue, endometrium, subcutaneous abdominal fat and blood from women undergoing a laparoscopy for symptoms of endometriosis, or for tubal sterilisation. Using these samples, we will investigate whether DNA transcription in the region of interest is different between women with moderate-severe endometriosis and controls, and between tissues. We will also explore all known genetic variants in the region, and investigate how these affect transcription levels. Implicated variants will be investigated for association with endometriosis risk, and waist-hip ratio, in up to 10,936 women. The proposed work will provide crucial information on gene regulation in the implicated region and its effect on clinical phenotypes, information required for the translation of the genome-wide association findings into clinical meaningful results that can inform the development of new (non-invasive) diagnostic methods and identification of novel drug targets.

子宫内膜异位症是一种常见的女性健康问题，其特征是在盆腔异位部位存在类似子宫内膜（子宫内膜）的沉积物，导致慢性炎症，严重的盆腔疼痛和生育能力下降。家庭研究表明，这种疾病可以遗传。在最近的一项研究中，我们比较了5，675名子宫内膜异位症患者和9，331名对照者的遗传信息，发现7号染色体上的遗传变异与中重度子宫内膜异位症相关。在一项涉及190，803人的独立研究中，发现相同的遗传区域与脂肪分布（腰臀比）有关。该信号位于基因之间，目前尚不清楚该变体-或其附近的变体-如何作用于DNA的转录，并最终影响子宫内膜异位症的发展或脂肪分布的差异。我们正在收集子宫内膜异位组织，子宫内膜，皮下腹部脂肪和血液从妇女接受腹腔镜检查的子宫内膜异位症的症状，或输卵管绝育。使用这些样本，我们将调查是否DNA转录在该地区的利益是不同的妇女与中重度子宫内膜异位症和控制，以及组织之间。我们还将探索该地区所有已知的遗传变异，并研究这些变异如何影响转录水平。将在多达10，936名女性中调查相关变异与子宫内膜异位症风险和腰臀比的相关性。拟议的工作将提供有关相关区域的基因调控及其对临床表型的影响的关键信息，将全基因组关联发现转化为临床有意义的结果所需的信息，这些结果可以为新的（非侵入性）诊断方法的开发和新药物靶点的鉴定提供信息。

项目成果

World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project: IV. Tissue collection, processing, and storage in endometriosis research.

• DOI: 10.1016/j.fertnstert.2014.07.1209
• 发表时间: 2014-11
• 期刊: FERTILITY AND STERILITY
• 影响因子: 6.7
• 作者: Fassbender, Amelie;Rahmioglu, Nilufer;Vitonis, Allison F.;Vigano, Paola;Giudice, Linda C.;D'Hooghe, Thomas M.;Hummelshoj, Lone;Adamson, G. David;Becker, Christian M.;Missmer, Stacey A.;Zondervan, Krina T.
• 通讯作者: Zondervan, Krina T.

Genome-wide associations for birth weight and correlations with adult disease.

• DOI: 10.1038/nature19806
• 发表时间: 2016-10-13
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Horikoshi, Momoko;Beaumont, Robin N.;Day, Felix R.;Warrington, Nicole M.;Kooijman, Marjolein N.;Fernandez-Tajes, Juan;Feenstra, Bjarke;van Zuydam, Natalie R.;Gaulton, Kyle J.;Grarup, Niels;Bradfield, Jonathan P.;Strachan, David P.;Li-Gao, Ruifang;Ahluwalia, Tarunveer S.;Kreiner, Eskil;Rueedi, Rico;Lyytikainen, Leo-Pekka;Cousminer, Diana L.;Wu, Ying;Thiering, Elisabeth;Wang, Carol A.;Have, Christian T.;Hottenga, Jouke-Jan;Vilor-Tejedor, Natalia;Joshi, Peter K.;Boh, Eileen Tai Hui;Ntalla, Ioanna;Pitkanen, Niina;Mahajan, Anubha;van Leeuwen, Elisabeth M.;Joro, Raimo;Lagou, Vasiliki;Nodzenski, Michael;Diver, Louise A.;Zondervan, Krina T.;Bustamante, Mariona;Marques-Vidal, Pedro;Mercader, Josep M.;Bennett, Amanda J.;Rahmioglu, Nilufer;Nyholt, Dale R.;Ma, Ronald C. W.;Tam, Claudia H. T.;Tam, Wing Hung;Ganesh, Santhi K.;van Rooij, Frank J. A.;Jones, Samuel E.;Loh, Po-Ru;Ruth, Katherine S.;Tuke, Marcus A.;Tyrrell, Jessica;Wood, Andrew R.;Yaghootkar, Hanieh;Scholtens, Denise M.;Paternoster, Lavinia;Prokopenko, Inga;Kovacs, Peter;Atalay, Mustafa;Willems, Sara M.;Panoutsopoulou, Kalliope;Wang, Xu;Carstensen, Lisbeth;Geller, Frank;Schraut, Katharina E.;Murcia, Mario;van Beijsterveldt, Catharina E. M.;Willemsen, Gonneke;Appel, Emil V. R.;Fonvig, Cilius E.;Trier, Caecilie;Tiesler, Carla M. T.;Standl, Marie;Kutalik, Zoltan;Bonas-Guarch, Silvia;Hougaard, David M.;Sanchez, Friman;Torrents, David;Waage, Johannes;Hollegaard, Mads V.;de Haan, Hugoline G.;Rosendaal, Frits R.;Medina-Gomez, Carolina;Ring, Susan M.;Hemani, Gibran;McMahon, George;Robertson, Neil R.;Groves, Christopher J.;Langenberg, Claudia;Luan, Jian'an;Scott, Robert A.;Zhao, Jing Hua;Mentch, Frank D.;MacKenzie, Scott M.;Reynolds, Rebecca M.;Lowe, William L.;Toenjes, Anke;Stumvoll, Michael;Lindi, Virpi;Lakka, Timo A.;van Duijn, Cornelia M.;Kiess, Wieland;Koerner, Antje;Sorensen, Thorkild I. A.;Niinikoski, Harri;Pahkala, Katja;Raitakari, Olli T.;Zeggini, Eleftheria;Dedoussis, George V.;Teo, Yik-Ying;Saw, Seang-Mei;Melbye, Mads;Campbell, Harry;Wilson, James F.;Vrijheid, Martine;de Geus, Eco J. C. N.;Boomsma, Dorret I.;Kadarmideen, Haja N.;Holm, Jens-Christian;Hansen, Torben;Sebert, Sylvain;Hattersley, Andrew T.;Beilin, Lawrence J.;Newnham, John P.;Pennell, Craig E.;Heinrich, Joachim;Adair, Linda S.;Borja, Judith B.;Mohlke, Karen L.;Eriksson, Johan G.;Widen, Elisabeth;Kahonen, Mika;Viikari, Jorma S.;Lehtimaki, Terho;Vollenweider, Peter;Bonnelykke, Klaus;Bisgaard, Hans;Mook-Kanamori, Dennis O.;Hofman, Albert;Rivadeneira, Fernando;Uitterlinden, Andre G.;Pisinger, Charlotta;Pedersen, Oluf;Power, Christine;Hyppoenen, Elina;Wareham, Nicholas J.;Hakonarson, Hakon;Davies, Eleanor;Walker, Brian R.;Jaddoe, Vincent W. V.;Jaervelin, Marjo-Riitta;Grant, Struan F. A.;Vaag, Allan A.;Lawlor, Debbie A.;Frayling, Timothy M.;Smith, George Davey;Morris, Andrew P.;Ong, Ken K.;Felix, Janine F.;Timpson, Nicholas J.;Perry, John R. B.;Evans, David M.;McCarthy, Mark I.;Freathy, Rachel M.
• 通讯作者: Freathy, Rachel M.

World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project: I. Surgical phenotype data collection in endometriosis research.

• DOI: 10.1016/j.fertnstert.2014.07.709
• 发表时间: 2014-11
• 期刊: FERTILITY AND STERILITY
• 影响因子: 6.7
• 作者: Becker, Christian M.;Laufer, Marc R.;Stratton, Pamela;Hummelshoj, Lone;Missmer, Stacey A.;Zondervan, Krina T.;Adamson, G. David
• 通讯作者: Adamson, G. David

The future for genetic studies in reproduction.

• DOI: 10.1093/molehr/gat058
• 发表时间: 2014-01
• 期刊: Molecular human reproduction
• 影响因子: 4
• 作者: Montgomery GW;Zondervan KT;Nyholt DR
• 通讯作者: Nyholt DR

Genome-wide associations for birth weight and correlations with adult disease

出生体重的全基因组关联及其与成人疾病的相关性

• DOI: 10.17863/cam.6542
• 发表时间: 2016
• 作者: Horikoshi M