A novel loss-of-function DDAH1 promoter polymorphism is associated with increased susceptibility to thrombosis stroke and coronary heart disease.
BACKGROUND
Asymmetrical dimethylarginine (ADMA), an endogenous arginine analogue, inhibits nitric oxide synthases and plays an important role in endothelial dysfunction.


OBJECTIVE
In the present study, we tested whether a novel genetic variant in dimethylarginine dimethylaminohydrolase 1 (DDAH1), an important ADMA hydrolyzing gene, was associated with stroke and coronary heart disease (CHD) susceptibility in the Chinese Han population.


RESULTS
By resequencing, we identified a novel 4-nucleotide deletion/insertion variant in the DDAH1 promoter. The insertion allele disrupted binding of metal-regulatory transcription factor 1, which resulted in significant reduction of in vitro DDAH1 transcriptional activity and in vivo DDAH1 mRNA level, and in turn, increased plasma ADMA level and the ratio of ADMA to L-arginine. We initially genotyped the polymorphism in 1388 stroke patients and 1027 controls as well as 576 CHD patients and 557 controls and then replicated our study in additional independent case-control cohorts comprising 961 stroke patients and 822 controls and 482 CHD patients and 1072 controls. We identified that the -396 4N ins allele was significantly associated with increased risk of thrombosis stroke and CHD after adjusting for environmental factors in both samples for both diseases (thrombosis stroke discovery set: odds ratio [OR]=1.35, P=0.032; replication set: OR=1.51, P=0.006; CHD discovery set: OR=1.45, P=0.035; replication set: OR=1.47, P=0.003).


CONCLUSIONS
Our results suggest that the DDAH1 loss-of-function polymorphism is associated with both increased risk of thrombosis stroke and CHD.
Ding
Hu
H
Department of Internal Medicine-Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095# Jiefang Ave., Wuhan, People's Republic of China.
Wu
Bin
B
Wang
Hu
H
Lu
Zhilan
Z
Yan
Jiangtao
J
Wang
Xiaojing
X
Shaffer
John R
JR
Hui
Rutai
R
Wang
Dao Wen
DW
D000368:Aged; D000581:Amidohydrolases / Q000235:genetics* / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood; D044466:Asian People; D001665:Binding Sites; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D002478:Cells, Cultured; D016009:Chi-Square Distribution; D002681:China; D003324:Coronary Artery Disease / Q000201:enzymology / Q000208:ethnology / Q000235:genetics*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D016017:Odds Ratio; D010641:Phenotype; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D018570:Risk Assessment; D012307:Risk Factors; D017384:Sequence Deletion; D020521:Stroke / Q000201:enzymology / Q000208:ethnology / Q000235:genetics*; D013927:Thrombosis / Q000201:enzymology / Q000208:ethnology / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D000097809:Transcription Factor MTF-1
D000581:Amidohydrolases; D001120:Arginine; D015415:Biomarkers; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D000097809:Transcription Factor MTF-1; C018524:N,N-dimethylarginine; C059999:dimethylargininase