Relationship between DDAH gene variants and serum ADMA level in individuals with type 1 diabetes ☆ Rhys D. Fogarty a, 1 , Sotoodeh Abhary a, 1 , Shahrbanou Javadiyan a , Nicholas Kasmeridis b , Nikolai Petrovsky b , Malcolm J. Whiting c , Jamie E. Craig a , Kathryn P. Burdon a, ⁎ a Department of Ophthalmology, Flinders Medical Centre and Flinders University, South Australia, Australia b Department of Endocrinology, Flinders Medical Centre and Flinders University, South Australia, Australia c Chemical Pathology Laboratory, SA Pathology, Adelaide, South Australia, Australia abstract article info Article history: Received 1 September 2011 Received in revised form 9 March 2012 Accepted 21 March 2012 Available online 20 April 2012 Keywords: DDAH1 DDAH2 ADMA Diabetes Asymmetric dimethylarginine (ADMA) levels are elevated in diabetes and likely contribute to diabetic complications such as retinopathy and nephropathy. The DDAH enzymes are primarily responsible for ADMA metabolism. Polymorphisms in the dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2 genes have been previously associated with serum ADMA levels in type 2 diabetes (T2DM). We sought to determine whether they are also associated with ADMA levels in individuals with type 1 diabetes (T1DM). Serum ADMA concentrations were measured in 196 individuals with T1DM. Twenty-six tag SNPs in the DDAH1 gene and 10 in the DDAH2 gene were genotyped. One SNP in the DDAH1 gene (rs3738111) and one in the DDAH2 gene (rs805293) showed a correlation with serum ADMA levels; however, neither survived correction for multiple testing. We found limited evidence that genetic polymorphisms in DDAH genes influence serum ADMA levels in individuals with T1DM. This differs to findings in T2DM and may be due to underlying differences in the cohorts or to fundamental differences in the pathogenesis of the two types of diabetes. © 2012 Elsevier Inc. All rights reserved. 1. Introduction Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase that contributes to endothelial dysfunction in conditions such as cardiovascular disease, hypertension, and diabetes mellitus. Nitric oxide (NO) plays a critical role in maintaining the health of the vascular endothelium. As well as its vasodilatory properties, NO also inhibits apoptosis of vascular endothelial cells (Dimmeler, Rippmann, Weiland, Haendeler, & Zeiher, 1997), limits platelet aggregation (Tymvios et al., 2009), and has anti-inflamma- tory properties (Rubio & Morales-Segura, 2004). Impairment of these processes leads to endothelial dysfunction which is associated with a variety of vascular diseases including complications of diabetes (Calles-Escandon & Cipolla, 2001). Serum ADMA levels are elevated in both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) (Abbasi et al., 2001; Altinova et al., 2007). The consequent reduction in NO production in vascular endothelial cells has been shown to play a role in the progression of both diabetic macrovascular and microvascular complications such as atheroscle- rosis, nephropathy, and retinopathy. A number of studies have also found elevation of serum ADMA associated with these conditions (Abhary et al., 2009; Hanai et al., 2009; Krzyzanowska et al., 2006; Malecki et al., 2007). The majority of ADMA is cleared through metabolism by the dimethylarginine dimethylaminohydrolase (DDAH) enzymes, DDAH1 and DDAH2 (Achan et al., 2003). Deletion of the Ddah1 gene in mice causes an accumulation of plasma ADMA, a reduction in NO, and abnormalities such as elevated blood pressure and vascular resistance arising from endothelial dysfunction (Leiper et al., 2007). Ding et al. (2010) found that a loss-of-function polymorphism in the promoter region of the DDAH1 gene was associated with increased plasma ADMA and increased risk of thrombosis stroke and coronary heart disease in humans. Another DDAH1 variant was shown by Valkonen, Tuomainen, and Laaksonen (2005) to correlate with elevated plasma ADMA and a 50-fold increase in risk of coronary heart disease. We have previously found associations between genetic poly- morphisms in both the DDAH genes and serum ADMA concentration in individuals with T2DM (Abhary et al., 2010). The current study sought to examine the relationship between serum ADMA levels and DDAH gene polymorphisms in individuals with T1DM. Journal of Diabetes and Its Complications 26 (2012) 195–198 ☆ This work was funded by the Ophthalmic Research Institute of Australia. JEC is the recipient of an NHMRC Practitioner Fellowship. KPB is the recipient of an NHMRC Career Development Award. ⁎ Corresponding author. Department of Ophthalmology, Flinders Medical Centre, Bedford Park, SA, Australia. Tel.: +61 8 82044094; fax: +61 8 82770899. 1 R. Fogarty and S. Abhary contributed equally to this work. 1056-8727/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.jdiacomp.2012.03.022 Contents lists available at SciVerse ScienceDirect Journal of Diabetes and Its Complications journal homepage: WWW.JDCJOURNAL.COM