Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications.
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.
Tong
Zongzhong
Z
Department of Ophthalmology and Visual Sciences, Eccles Institute of Human Genetics.
Yang
Zhenglin
Z
Patel
Shrena
S
Chen
Haoyu
H
Gibbs
Daniel
D
Yang
Xian
X
Hau
Vincent S
VS
Kaminoh
Yuuki
Y
Harmon
Jennifer
J
Pearson
Erik
E
Buehler
Jeanette
J
Chen
Yuhong
Y
Yu
Baifeng
B
Tinkham
Nicholas H
NH
Zabriskie
Norman A
NA
Zeng
Jiexi
J
Luo
Ling
L
Sun
Jennifer K
JK
Prakash
Manvi
M
Hamam
Rola N
RN
Tonna
Stephen
S
Constantine
Ryan
R
Ronquillo
Cecinio C
CC
Sadda
SriniVas
S
Avery
Robert L
RL
Brand
John M
JM
London
Nyall
N
Anduze
Alfred L
AL
King
George L
GL
Bernstein
Paul S
PS
Watkins
Scott
S
Jorde
Lynn B
LB
Li
Dean Y
DY
Aiello
Lloyd Paul
LP
Pollak
Martin R
MR
Zhang
Kang
K
D000483:Alleles; D000818:Animals; D002460:Cell Line; D015331:Cohort Studies; D003928:Diabetic Nephropathies / Q000150:complications* / Q000235:genetics*; D003930:Diabetic Retinopathy / Q000150:complications* / Q000235:genetics*; D004921:Erythropoietin / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000378:metabolism / Q000473:pathology
D012333:RNA, Messenger; D004921:Erythropoietin; D008156:Luciferases