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

Zongzhong Tong, Zhenglin Yang, Shrena Patel, Haoyu Chen, Daniel Gibbs, Xian Yang, Vincent S. Hau, Yuuki Kaminoh, Jennifer Harmon, Erik Pearson, Jeanette Buehler, Yuhong Chen, Baifeng Yu, Nicholas H. Tinkham, Norman A. Zabriskie, Jiexi Zeng, Ling Luo, Jennifer K. Sun, Manvi Prakash, Rola N. HamamStephen Tonna, Ryan Constantine, Cecinio C. Ronquillo, Srini Vas Sadda, Robert L. Avery, John M. Brand, Nyall London, Alfred L. Anduze, George L. King, Paul S. Bernstein, Scott Watkins, Xiang Ma, D. Joshua-Cameron, Melvin Rabena, Alex Goldfarb-Rumyantzev, Nick Banerjee, Hilary-Keenan, Nick Mamalis, Charles Perez, Bradley J. Katz, Lynn B. Jorde, Dean Y. Li, Lloyd Paul Aiello, Martin R. Pollak, Kang Zhang

Research output: Contribution to journalArticle

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 × 10-3; Genetics of Kidneys in Diabetes (GoKinD) Study: P = 2.66 × 10-8; and Boston: P = 2.1 × 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.

Original languageEnglish (US)
Pages (from-to)6998-7003
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number19
DOIs
StatePublished - May 13 2008
Externally publishedYes

Fingerprint

Diabetic Retinopathy
Erythropoietin
Chronic Kidney Failure
Kidney
Alleles
Diabetes Complications
Genes
Genotype
Vitreous Body
Angiogenesis Inducing Agents
Luciferases
Human Body
Single Nucleotide Polymorphism
Diabetes Mellitus
Binding Sites
Morbidity
Mortality
Incidence

Keywords

  • Association
  • Diabetic microvascular complication
  • End stage renal disease
  • Proliferative diabetic retinopathy
  • SNP

ASJC Scopus subject areas

  • General

Cite this

Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications. / Tong, Zongzhong; Yang, Zhenglin; Patel, Shrena; Chen, Haoyu; Gibbs, Daniel; Yang, Xian; Hau, Vincent S.; Kaminoh, Yuuki; Harmon, Jennifer; Pearson, Erik; Buehler, Jeanette; Chen, Yuhong; Yu, Baifeng; Tinkham, Nicholas H.; Zabriskie, Norman A.; Zeng, Jiexi; Luo, Ling; Sun, Jennifer K.; Prakash, Manvi; Hamam, Rola N.; Tonna, Stephen; Constantine, Ryan; Ronquillo, Cecinio C.; Sadda, Srini Vas; Avery, Robert L.; Brand, John M.; London, Nyall; Anduze, Alfred L.; King, George L.; Bernstein, Paul S.; Watkins, Scott; Ma, Xiang; Joshua-Cameron, D.; Rabena, Melvin; Goldfarb-Rumyantzev, Alex; Banerjee, Nick; Hilary-Keenan; Mamalis, Nick; Perez, Charles; Katz, Bradley J.; Jorde, Lynn B.; Li, Dean Y.; Aiello, Lloyd Paul; Pollak, Martin R.; Zhang, Kang.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 19, 13.05.2008, p. 6998-7003.

Research output: Contribution to journalArticle

Tong, Z, Yang, Z, Patel, S, Chen, H, Gibbs, D, Yang, X, Hau, VS, Kaminoh, Y, Harmon, J, Pearson, E, Buehler, J, Chen, Y, Yu, B, Tinkham, NH, Zabriskie, NA, Zeng, J, Luo, L, Sun, JK, Prakash, M, Hamam, RN, Tonna, S, Constantine, R, Ronquillo, CC, Sadda, SV, Avery, RL, Brand, JM, London, N, Anduze, AL, King, GL, Bernstein, PS, Watkins, S, Ma, X, Joshua-Cameron, D, Rabena, M, Goldfarb-Rumyantzev, A, Banerjee, N, Hilary-Keenan, Mamalis, N, Perez, C, Katz, BJ, Jorde, LB, Li, DY, Aiello, LP, Pollak, MR & Zhang, K 2008, 'Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications', Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 19, pp. 6998-7003. https://doi.org/10.1073/pnas.0800454105
Tong, Zongzhong ; Yang, Zhenglin ; Patel, Shrena ; Chen, Haoyu ; Gibbs, Daniel ; Yang, Xian ; Hau, Vincent S. ; Kaminoh, Yuuki ; Harmon, Jennifer ; Pearson, Erik ; Buehler, Jeanette ; Chen, Yuhong ; Yu, Baifeng ; Tinkham, Nicholas H. ; Zabriskie, Norman A. ; Zeng, Jiexi ; Luo, Ling ; Sun, Jennifer K. ; Prakash, Manvi ; Hamam, Rola N. ; Tonna, Stephen ; Constantine, Ryan ; Ronquillo, Cecinio C. ; Sadda, Srini Vas ; Avery, Robert L. ; Brand, John M. ; London, Nyall ; Anduze, Alfred L. ; King, George L. ; Bernstein, Paul S. ; Watkins, Scott ; Ma, Xiang ; Joshua-Cameron, D. ; Rabena, Melvin ; Goldfarb-Rumyantzev, Alex ; Banerjee, Nick ; Hilary-Keenan ; Mamalis, Nick ; Perez, Charles ; Katz, Bradley J. ; Jorde, Lynn B. ; Li, Dean Y. ; Aiello, Lloyd Paul ; Pollak, Martin R. ; Zhang, Kang. / Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 19. pp. 6998-7003.
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title = "Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications",
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 × 10-3; Genetics of Kidneys in Diabetes (GoKinD) Study: P = 2.66 × 10-8; and Boston: P = 2.1 × 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.",
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author = "Zongzhong Tong and Zhenglin Yang and Shrena Patel and Haoyu Chen and Daniel Gibbs and Xian Yang and Hau, {Vincent S.} and Yuuki Kaminoh and Jennifer Harmon and Erik Pearson and Jeanette Buehler and Yuhong Chen and Baifeng Yu and Tinkham, {Nicholas H.} and Zabriskie, {Norman A.} and Jiexi Zeng and Ling Luo and Sun, {Jennifer K.} and Manvi Prakash and Hamam, {Rola N.} and Stephen Tonna and Ryan Constantine and Ronquillo, {Cecinio C.} and Sadda, {Srini Vas} and Avery, {Robert L.} and Brand, {John M.} and Nyall London and Anduze, {Alfred L.} and King, {George L.} and Bernstein, {Paul S.} and Scott Watkins and Xiang Ma and D. Joshua-Cameron and Melvin Rabena and Alex Goldfarb-Rumyantzev and Nick Banerjee and Hilary-Keenan and Nick Mamalis and Charles Perez and Katz, {Bradley J.} and Jorde, {Lynn B.} and Li, {Dean Y.} and Aiello, {Lloyd Paul} and Pollak, {Martin R.} and Kang Zhang",
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T1 - Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications

AU - Tong, Zongzhong

AU - Yang, Zhenglin

AU - Patel, Shrena

AU - Chen, Haoyu

AU - Gibbs, Daniel

AU - Yang, Xian

AU - Hau, Vincent S.

AU - Kaminoh, Yuuki

AU - Harmon, Jennifer

AU - Pearson, Erik

AU - Buehler, Jeanette

AU - Chen, Yuhong

AU - Yu, Baifeng

AU - Tinkham, Nicholas H.

AU - Zabriskie, Norman A.

AU - Zeng, Jiexi

AU - Luo, Ling

AU - Sun, Jennifer K.

AU - Prakash, Manvi

AU - Hamam, Rola N.

AU - Tonna, Stephen

AU - Constantine, Ryan

AU - Ronquillo, Cecinio C.

AU - Sadda, Srini Vas

AU - Avery, Robert L.

AU - Brand, John M.

AU - London, Nyall

AU - Anduze, Alfred L.

AU - King, George L.

AU - Bernstein, Paul S.

AU - Watkins, Scott

AU - Ma, Xiang

AU - Joshua-Cameron, D.

AU - Rabena, Melvin

AU - Goldfarb-Rumyantzev, Alex

AU - Banerjee, Nick

AU - Hilary-Keenan,

AU - Mamalis, Nick

AU - Perez, Charles

AU - Katz, Bradley J.

AU - Jorde, Lynn B.

AU - Li, Dean Y.

AU - Aiello, Lloyd Paul

AU - Pollak, Martin R.

AU - Zhang, Kang

PY - 2008/5/13

Y1 - 2008/5/13

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 × 10-3; Genetics of Kidneys in Diabetes (GoKinD) Study: P = 2.66 × 10-8; and Boston: P = 2.1 × 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.

AB - 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 × 10-3; Genetics of Kidneys in Diabetes (GoKinD) Study: P = 2.66 × 10-8; and Boston: P = 2.1 × 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.

KW - Association

KW - Diabetic microvascular complication

KW - End stage renal disease

KW - Proliferative diabetic retinopathy

KW - SNP

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U2 - 10.1073/pnas.0800454105

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