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Papers In Press, published online ahead of print June 1, 2009
J. Lipid Res., doi:10.1194/jlr.P800070-JLR200

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Journal of Lipid Research, Vol. 50, 1216-1222, June 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Patient-Oriented and Epidemiological Research

Association of the novel cardiovascular risk factors paraoxonase 1 and cystatin C in type 2 diabetes^*,

Philip W. Connelly^1,*,, Bernard Zinman, Graham F. Maguire^*, Mary Mamakeesick^**, Stewart B. Harris, Robert A. Hegele, Ravi Retnakaran and Anthony J. G. Hanley^,***

^* Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Canada
Departments of Medicine and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
Leadership Sinai Centre for Diabetes, Mount Sinai Hospital and Department of Medicine, University of Toronto, Toronto, Canada
^** Sandy Lake Health and Diabetes Project, Sandy Lake First Nation, Ontario, Canada
Centre for Studies in Family Medicine, University of Western Ontario, London, Ontario, Canada
Robarts Research Institute, University of Western Ontario, London, Ontario, Canada
^*** Department of Nutritional Sciences, University of Toronto, Toronto, Canada

^* This research has been supported through operating grants from the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Ontario (T5592 and T6389). A.J.G.H. holds a Canada Research Chair and is supported through a Canadian Diabetes Association Research Scholarship. S.B.H. holds the Ian McWhinney Chair for Studies in Family Medicine at the University of Western Ontario. B.Z. holds the Sam and Judy Pencer Family Chair in Diabetes Research at Mount Sinai Hospital and the University of Toronto. R.R. holds Canadian Institutes of Health Research New Investigator and Canadian Diabetes Association Clinician Scientist Awards. R.A.H. holds the Jacob J. Wolfe Distinguished Medical Research Chair and Edith Schulich Vinet Canada Research Chair (Tier 1) in Human Genetics.

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of two figures.

Published, JLR Papers in Press, January 18, 2009.

¹ To whom correspondence should be addressed. e-mail: connellyp{at}smh.toronto.on.ca

Paraoxonase 1 (PON1) has been reported to be associated with proteinuria in subjects with type 2 diabetes mellitus (T2DM). Plasma cystatin C is more accurate than creatinine for identifying stage 3 kidney disease in T2DM. We tested the hypothesis that PON1 and cystatin C would be associated in T2DM subjects from an Aboriginal Canadian community, who are at high risk for the development of nephropathy. PON1 A(-162)G and PON2 Ala148Gly genotypes, cystatin C, HbA1c, high density lipoprotein cholesterol (HDLC), waist circumference (waist), and duration of diabetes were included in the regression analysis with log_e (ln) of PON1 mass as the dependent variable. A regression model including PON2 Ala148Gly genotype, HDLC, and ln cystatin C explained 25.8% of the variance in PON1 mass. Conversely, waist, age, ln HbA1c, ln duration of diabetes, and ln PON1 mass, but not PON2 genotype, explained 38% of the variance in cystatin C. Subjects with cystatin C estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m² (stage 3 kidney disease) had significantly lower PON1 mass compared with subjects with cystatin C-eGFR >60 ml/min per 1.73 m². The lower mass of PON1, an anti-inflammatory HDL-associated enzyme, in T2DM with cystatin C-eGFR <60 ml/min per 1.73 m² may contribute to their increased risk for cardiovascular disease.

Supplementary key words estimated glomerular filtration rate • renal • high density lipoprotein • genotype • polymorphism • aboriginal

Abbreviations: apoAI, apolipoprotein AI; cysC, cystatin C; eGFR, estimated glomerular filtration rate; HDLC, high density lipoprotein cholesterol; ln, log_e; PON1, paraoxonase 1; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; TNF-, tumor necrosis factor-

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