英國(guó)維康信托桑格研究所（Wellcome Trust Sanger Institute）的研究人員借助基因組相關(guān)性掃描（genome-wide association scan）技術(shù),，發(fā)現(xiàn)了一個(gè)骨關(guān)節(jié)炎發(fā)病密切相關(guān)的突變基因—MCF2L。相關(guān)研究結(jié)果于9月9日刊登在American Journal of Human Genetics期刊上,。
骨關(guān)節(jié)炎是一種有著多個(gè)遺傳學(xué)病因的復(fù)雜疾病,，臨床表現(xiàn)為因關(guān)節(jié)軟骨退行性病變引起的關(guān)節(jié)疼痛和關(guān)節(jié)畸形,。該病的發(fā)病率隨年齡的增長(zhǎng)而增高，尤其在70歲以上的人群中,，骨關(guān)節(jié)炎的發(fā)病率高達(dá)40%,。由于其病因十分復(fù)雜,，之前僅有兩個(gè)與疾病發(fā)生相關(guān)的基因被證實(shí)，分別是GDF5基因和位于7號(hào)染色體上的一個(gè)信號(hào)區(qū)域基因,。
此次,，研究人員通過(guò)與包括冰島、愛(ài)沙尼亞,、荷蘭在內(nèi)的多中心國(guó)際合作,，總共調(diào)查了19 041份臨床資料。借助基因組相關(guān)性掃描技術(shù),，研究人員首先將3 177份骨關(guān)節(jié)炎患者與4 894份健康人群的基因組數(shù)據(jù)對(duì)比,，初篩到600 000個(gè)突變基因，再經(jīng)過(guò)一系列的信息核對(duì),，確定了1 000份資料詳盡的基因組項(xiàng)目數(shù)據(jù),，并從中篩選到了迄今為止第三個(gè)與骨關(guān)節(jié)炎發(fā)病相關(guān)的遺傳學(xué)基因突變。新發(fā)現(xiàn)的突變基因名為MCF2L,，位于第13號(hào)染色體,，本身編碼一種神經(jīng)生長(zhǎng)因子（NGF）。據(jù)英國(guó)關(guān)節(jié)炎研究學(xué)會(huì)（Arthritis Research U）醫(yī)學(xué)部主任Alan Silman介紹,，過(guò)去,，曾有報(bào)道顯示用抗神經(jīng)生長(zhǎng)因子的抗體治療骨關(guān)節(jié)炎患者可以明顯減輕患者的疼痛并且改善疾病。隨著MCF2L基因突變與骨關(guān)節(jié)炎發(fā)病相關(guān)性的揭示,，人們開(kāi)始逐漸意識(shí)到神經(jīng)生長(zhǎng)因子的功能異?？赡苁菍?dǎo)致骨關(guān)節(jié)炎的重要病因。MCF2L基因的編碼產(chǎn)物可能在軟骨關(guān)節(jié)行使正常功能時(shí)發(fā)揮作用,，因此,，該基因的突變導(dǎo)致了骨關(guān)節(jié)炎的發(fā)病。
下一步,，研究人員將深入挖掘這1 000份基因組數(shù)據(jù),，以期更充分地揭示骨關(guān)節(jié)炎的病因，為研發(fā)新的治療方案提供線索,。(生物谷Bioon.com)
doi:10.1016/j.ajhg.2011.08.001
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A Variant in MCF2L Is Associated with Osteoarthritis
Aaron G. Day-Williams1, Lorraine Southam1, 2, Kalliope Panoutsopoulou1, Nigel W. Rayner2, Tonu Esko3, 4, 5, Karol Estrada6, 7, Hafdis T. Helgadottir8, Albert Hofman9, Throvaldur Ingvarsson10, 11, Helgi Jonsson11, 12, Aime Keis13, 14, Hanneke J.M. Kerkhof6, 7, Gudmar Thorleifsson8, Nigel K. Arden15, 16, Andrew Carr17, Kay Chapman17, Panos Deloukas1, John Loughlin18, Andrew McCaskie18, 19, William E.R. Ollier20, Stuart H. Ralston21, Timothy D. Spector22, Gillian A. Wallis23, J. Mark Wilkinson24, 25, Nadim Aslam26, Fraser Birell18, 27, Ian Carluke27, John Joseph28, Ashok Rai29, Mike Reed27, Kirsten Walker27, arcOGEN Consortium, Sally A. Doherty30, Ingileif Jonsdottir8, 11, Rose A. Maciewicz31, Kenneth R. Muir32, Andres Metspalu3, 4, 5, Fernando Rivadeneira6, 7, 9, Kari Stefansson8, 11, Unnur Styrkarsdottir8, Andre G. Uitterlinden6, 7, 9, Joyce B.J. van Meurs6, 7, Weiya Zhang30, Ana M. Valdes22, Michael Doherty30 and Eleftheria Zeggini1
Osteoarthritis (OA) is a prevalent, heritable degenerative joint disease with a substantial public health impact. We used a 1000-Genomes-Project-based imputation in a genome-wide association scan for osteoarthritis (3177 OA cases and 4894 controls) to detect a previously unidentified risk locus. We discovered a small disease-associated set of variants on chromosome 13. Through large-scale replication, we establish a robust association with SNPs in MCF2L (rs11842874, combined odds ratio [95% confidence interval] 1.17 [1.11–1.23], p = 2.1 × 10?8) across a total of 19,041 OA cases and 24,504 controls of European descent. This risk locus represents the third established signal for OA overall. MCF2L regulates a nerve growth factor (NGF), and treatment with a humanized monoclonal antibody against NGF is associated with reduction in pain and improvement in function for knee OA patients.
