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基因AFF3和ERBB4增加患糖尿病性肾病的风险

来源:生物谷 2012-10-09 11:22

2012年10月09日 电 /生物谷BIOON/ --肾病是一种常见、严重的糖尿病并发症,大大地增加了心脏病和中风的风险。在全世界,糖尿病性肾病现已成为肾衰竭的主要病因,肾衰竭没有治愈的药物,只能采用透析或肾移植,但药物能减缓肾衰竭的进展。目前,科学家和临床医生只认识到某些病人会患肾病,但不知道到为什么会患此病。如果能知道哪些病人患肾病并发症的风险最大,将更有助于糖尿病病人的监管。

为此,一个国际研究协会开展了一项最大型的研究,招募了4750例糖尿病性肾病患者和近7000例无肾病的糖尿病长期患者,经过对每位参与者200多万个DNA标志物进行分析,他们发现,基因AFF3和ERBB4的变化会增加患肾病的风险。这一发现不但使患者立即受益,从长远来看,可能会导致形成新的治疗方法,对医疗与经济形成冲击性影响,也将加速研发新的有效治疗方法。相关研究结果将发表在期刊PLoS Genetics上。(生物谷bioon.com)

原文链接:http://www.sciencedaily.com/releases/2012/10/121005092932.htm

New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes

Niina Sandholm, Rany M. Salem, Amy Jayne McKnight, Eoin P. Brennan, Carol Forsblom, Tamara Isakova, Gareth J. McKay, Winfred W. Williams, Denise M. Sadlier, Ville-Petteri M?kinen, Elizabeth J. Swan, Cameron Palmer, Andrew P. Boright, Emma Ahlqvist, Harshal A. Deshmukh, Benjamin J. Keller, Huateng Huang, Aila J. Ahola, Emma Fagerholm, Daniel Gordin, Valma Harjutsalo, Bing He, Outi Heikkil?, Kustaa Hietala, Janne Kyt?, P?ivi Lahermo, Markku Lehto, Raija Lithovius, Anne-May ?sterholm, Maija Parkkonen, Janne Pitk?niemi, Milla Roseng?rd-B?rlund, Markku Saraheimo, Cinzia Sarti, Jenny S?derlund, Aino Soro-Paavonen, Anna Syreeni, Lena M. Thorn, Heikki Tikkanen, Nina Tolonen, Karl Tryggvason, Jaakko Tuomilehto, Johan Wadén, Geoffrey V. Gill, Sarah Prior, Candace Guiducci, Daniel B. Mirel, Andrew Taylor, S. Mohsen Hosseini, Hans-Henrik Parving, Peter Rossing, Lise Tarnow, Claes Ladenvall, Fran?ois Alhenc-Gelas, Pierre Lefebvre, Vincent Rigalleau, Ronan Roussel, David-Alexandre Tregouet, Anna Maestroni, Silvia Maestroni, Henrik Falhammar, Tianwei Gu, Anna M?llsten, Danut Cimponeriu, Mihai Ioana, Maria Mota, Eugen Mota, Cristian Serafinceanu, Monica Stavarachi, Robert L. Hanson, Robert G. Nelson, Matthias Kretzler, Helen M. Colhoun, Nicolae Mircea Panduru, Harvest F. Gu, Kerstin Brismar, Gianpaolo Zerbini, Samy Hadjadj, Michel Marre, Leif Groop, Maria Lajer, Shelley B. Bull, Daryl Waggott, Andrew D. Paterson, David A. Savage, Stephen C. Bain, Finian Martin, Joel N. Hirschhorn, Catherine Godson, Jose C. Florez, Per-Henrik Groop, Alexander P. Maxwell.

Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising~2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3gene (P=1.2X10-8) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P= 2.0 X10-9). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-b1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P= 2.1X10-7), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression ofERBB4. All these detected associations represent new signals in the pathogenesis of DN.

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