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Mol. Hum. Reprod. Advance Access published online on October 22, 2004
Molecular Human Reproduction, doi:10.1093/molehr/gah116
© 2004 by Oxford University Press
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Received August 16, 2004
Revised September 7, 2004
Accepted September 12, 2004

Article

Haplotypic association of DDAH1 with susceptibility to pre-eclampsia

Fareeza Akbar 1, Seppo Heinonen 2, Mia Pirskanen 3, Pekka Uimari 3, Tomi-Pekka Tuomainen 4, and Jukka T. Salonen 5*

1 Department of Obstetrics and Gynaecology, Kuopio University Hospital, Kuopio, Finland; Research Institute of Public Health, University of Kuopio, Kuopio, Finland
2 Department of Obstetrics and Gynaecology, Kuopio University Hospital, Kuopio, Finland
3 Oy Jurilab Ltd, Clinical Trial Centre, University of Kuopio, Kuopio, Finland
4 Research Institute of Public Health, University of Kuopio, Kuopio, Finland; Atherosclerosis Research Unit, Clinical Trial Centre, University of Kuopio, Kuopio, Finland
5 Research Institute of Public Health, University of Kuopio, Kuopio, Finland; Oy Jurilab Ltd, Clinical Trial Centre, University of Kuopio, Kuopio, Finland

* To whom correspondence should be addressed.
Jukka T. Salonen, E-mail: jukka.salonen{at}uku.fi or jukka.salonen@jurilab.com


  Abstract

Association between pre-eclampsia (PEE1) and the dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2 genes, which play a role in the regulation of nitric oxide synthesis and release, was studied. In a case-control study design single nucleotide polymorphisms (SNPs) were determined at eight sites in the DDAH1 gene and at one site (Pro231Pro) in the DDAH2 gene from 132 women with pre-eclampsia and 112 healthy controls. Three SNPs in the DDAH1 gene were associated with pre-eclampsia, showing complete linkage disequilibrium with each other, but none of the associations in the allele or genotype data reached statistical significance in either of the genes after the correction for multiple testing. Haplotype frequencies were estimated using a population based on a maximum likelihood method (EM algorithm). Four common DDAH1 haplotypes were present and a significant association of haplotypes H2 and H3 with pre-eclampsia (P=0.03) was found. The risk of pre-eclampsia was greatest in individuals (odds ratio: 3.93; 95% confidence interval: 1.54-9.99) who had two copies of the high-risk haplotypes (H2 or H3). The observed haplotypic association provides the first evidence of the importance of DDAH1 polymorphisms in pre-eclampsia susceptibility.

Keywords: DDAH1; association; pre-eclampsia; relative risk; haplotype.
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