TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis.
TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis.
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DOI：
10.1038/nature11307
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发表时间：
2012-08-23
期刊：
影响因子：
64.8
通讯作者：
Fugger, Lars
中科院分区：
文献类型：
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作者：
Gregory, Adam P.;Dendrou, Calliope A.;Attfield, Kathrine E.;Haghikia, Aiden;Xifara, Dionysia K.;Butter, Falk;Poschmann, Gereon;Kaur, Gurman;Lambert, Lydia;Leach, Oliver A.;Proemel, Simone;Punwani, Divya;Felce, James H.;Davis, Simon J.;Gold, Ralf;Nielsen, Finn C.;Siegel, Richard M.;Mann, Matthias;Bell, John I.;McVean, Gil;Fugger, Lars
尽管使用全基因组关联研究（GWAS）鉴定与常见疾病相关的遗传变异方面取得了很大的成功，但很难证明哪些变体是因果关系，以及它们在疾病中的作用。疾病风险提出了有关其医学相关性的问题。编码TNF受体1（TNFR1），通过GWAS发现与多发性硬化症（MS）相关，但与其他自身免疫性疾病（如类风湿关节炎（RA），牛皮癣），牛皮癣和Crohn氏病有关。我们提供了1000个基因组项目数据，我们提供了遗传证据，这些证据强烈暗示该SNP为RS1800693，作为TNFRSF1A的因果变体地区。与RS1800693没有关联的自身免疫性疾病的治疗。 RS1800693的关联，并且MS相关的TNFR1变体模仿TNF阻断药物的影响，我们的研究表明，可以通过比较常见的GWAS来了解临床实践变化。
Although there has been much success in identifying genetic variants associated with common diseases using genome-wide association studies (GWAS), it has been difficult to demonstrate which variants are causal and what role they play in disease. Moreover, the modest contribution these variants make to disease risk has raised questions regarding their medical relevance. We have investigated a single nucleotide polymorphism (SNP) in the TNFRSF1A gene, that encodes TNF receptor 1 (TNFR1), which was discovered through GWAS to be associated with multiple sclerosis (MS), but not with other autoimmune conditions such as rheumatoid arthritis (RA), psoriasis and Crohn’s disease. By analyzing MS GWAS data in conjunction with the 1000 Genomes Project data we provide genetic evidence that strongly implicates this SNP, rs1800693, as the causal variant in the TNFRSF1A region. We further substantiate this through functional studies showing that the MS risk allele directs expression of a novel, soluble form of TNFR1 that can block TNF. Importantly, TNF blocking drugs can promote onset or exacerbation of MS, but they have proven highly efficacious in the treatment of autoimmune diseases for which there is no association with rs1800693. This indicates that the clinical experience with these drugs parallels the disease association of rs1800693, and that the MS-associated TNFR1 variant mimics the effect of TNF blocking drugs. Hence, our study demonstrates that clinical practice can be informed by comparing GWAS across common autoimmune diseases and by investigating the functional consequences of the disease-associated genetic variation.
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影响因子：
30.8
作者：
Marchini, Jonathan;Howie, Bryan;Donnelly, Peter
通讯作者：
Donnelly, Peter
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影响因子：
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Brambilla, Roberta;Ashbaugh, Jessica Jopek;Bethea, John R.
通讯作者：
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通讯作者：
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影响因子：
30.8
作者：
通讯作者：
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