Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications

@article{citeulike:2796228, abstract = {Significant morbidity and mortality among patients with diabetes mellitus result largely from a greatly increased incidence of microvascular complications. Proliferative diabetic retinopathy (PDR) and end stage renal disease (ESRD) are two of the most common and severe microvascular complications of diabetes. A high concordance exists in the development of PDR and ESRD in diabetic patients, as well as strong familial aggregation of these complications, suggesting a common underlying genetic mechanism. However, the precise gene(s) and genetic variant(s) involved remain largely unknown. Erythropoietin (EPO) is a potent angiogenic factor observed in the diabetic human and mouse eye. By a combination of case-control association and functional studies, we demonstrate that the T allele of SNP rs1617640 in the promoter of the EPO gene is significantly associated with PDR and ESRD in three European-American cohorts [Utah: P = 1.91 x 10-3; Genetics of Kidneys in Diabetes (GoKinD) Study: P = 2.66 x 10-8; and Boston: P = 2.1 x 10-2]. The EPO concentration in human vitreous body was 7.5-fold higher in normal subjects with the TT risk genotype than in those with the GG genotype. Computational analysis suggests that the risk allele (T) of rs1617640 creates a matrix match with the EVI1/MEL1 or AP1 binding site, accounting for an observed 25-fold enhancement of luciferase reporter expression as compared with the G allele. These results suggest that rs1617640 in the EPO promoter is significantly associated with PDR and ESRD. This study identifies a disease risk-associated gene and potential pathway mediating severe diabetic microvascular complications. 10.1073/pnas.0800454105}, author = {Tong, Zongzhong and Yang, Zhenglin and Patel, Shrena and Chen, Haoyu and Gibbs, Daniel and Yang, Xian and Hau, Vincent S. and Kaminoh, Yuuki and Harmon, Jennifer and Pearson, Erik and Buehler, Jeanette and Chen, Yuhong and Yu, Baifeng and Tinkham, Nicholas H. and Zabriskie, Norman A. and Zeng, Jiexi and Luo, Ling and Sun, Jennifer K. and Prakash, Manvi and Hamam, Rola N. and Tonna, Stephen and Constantine, Ryan and Ronquillo, Cecinio C. and Sadda, Srinivas and Avery, Robert L. and Brand, John M. and London, Nyall and Anduze, Alfred L. and King, George L. and Bernstein, Paul S. and Watkins, Scott and Genetics and Jorde, Lynn B. and Li, Dean Y. and Aiello, Lloyd P. and Pollak, Martin R. and Zhang, Kang }, citeulike-article-id = {2796228}, doi = {10.1073/pnas.0800454105}, journal = {Proceedings of the National Academy of Sciences}, keywords = {dn, epo, snp}, month = {May}, number = {19}, pages = {6998--7003}, posted-at = {2008-05-15 09:50:12}, priority = {2}, title = {Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications}, url = {http://dx.doi.org/10.1073/pnas.0800454105}, volume = {105}, year = {2008} }

TY - JOUR ID - citeulike:2796228 L3 - citeulike-article-id:2796228 TI - Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications JF - Proceedings of the National Academy of Sciences VL - 105 IS - 19 SP - 6998 EP - 7003 N2 - Significant morbidity and mortality among patients with diabetes mellitus result largely from a greatly increased incidence of microvascular complications. Proliferative diabetic retinopathy (PDR) and end stage renal disease (ESRD) are two of the most common and severe microvascular complications of diabetes. A high concordance exists in the development of PDR and ESRD in diabetic patients, as well as strong familial aggregation of these complications, suggesting a common underlying genetic mechanism. However, the precise gene(s) and genetic variant(s) involved remain largely unknown. Erythropoietin (EPO) is a potent angiogenic factor observed in the diabetic human and mouse eye. By a combination of case-control association and functional studies, we demonstrate that the T allele of SNP rs1617640 in the promoter of the EPO gene is significantly associated with PDR and ESRD in three European-American cohorts [Utah: P = 1.91 x 10-3; Genetics of Kidneys in Diabetes (GoKinD) Study: P = 2.66 x 10-8; and Boston: P = 2.1 x 10-2]. The EPO concentration in human vitreous body was 7.5-fold higher in normal subjects with the TT risk genotype than in those with the GG genotype. Computational analysis suggests that the risk allele (T) of rs1617640 creates a matrix match with the EVI1/MEL1 or AP1 binding site, accounting for an observed 25-fold enhancement of luciferase reporter expression as compared with the G allele. These results suggest that rs1617640 in the EPO promoter is significantly associated with PDR and ESRD. This study identifies a disease risk-associated gene and potential pathway mediating severe diabetic microvascular complications. 10.1073/pnas.0800454105 KW - dn KW - epo KW - snp AU - Tong, Zongzhong AU - Yang, Zhenglin AU - Patel, Shrena AU - Chen, Haoyu AU - Gibbs, Daniel AU - Yang, Xian AU - Hau, Vincent AU - Kaminoh, Yuuki AU - Harmon, Jennifer AU - Pearson, Erik AU - Buehler, Jeanette AU - Chen, Yuhong AU - Yu, Baifeng AU - Tinkham, Nicholas AU - Zabriskie, Norman AU - Zeng, Jiexi AU - Luo, Ling AU - Sun, Jennifer AU - Prakash, Manvi AU - Hamam, Rola AU - Tonna, Stephen AU - Constantine, Ryan AU - Ronquillo, Cecinio AU - Sadda, Srinivas AU - Avery, Robert AU - Brand, John AU - London, Nyall AU - Anduze, Alfred AU - King, George AU - Bernstein, Paul AU - Watkins, Scott AU - Genetics AU - Jorde, Lynn AU - Li, Dean AU - Aiello, Lloyd AU - Pollak, Martin AU - Zhang, Kang PY - 2008/05/13/ UR - http://dx.doi.org/10.1073/pnas.0800454105 ER -