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

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 loge (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. 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 loge (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. Paraoxonase 1 (PON1) (arylesterase; EC 3.1.1.2) is an HDL-associated enzyme that hydrolyzes organophosphate compounds and fatty acid lactones (1Costa L.G. Cole T.B. Furlong C.E. Paraoxonase (PON1): from toxicology to cardiovascular medicine.Acta Biomed. 2005; 76: 50-57PubMed Google Scholar, 2Gaidukov L. Tawfik D.S. The development of human sera tests for HDL-bound serum PON1 and its lipolactonase activity.J. Lipid Res. 2007; 48: 1637-1646Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 3Mackness M. Mackness B. Paraoxonase 1 and atherosclerosis: is the gene or the protein more important?.Free Radic. Biol. Med. 2004; 37: 1317-1323Crossref PubMed Scopus (134) Google Scholar–4James R.W. A long and winding road: defining the biological role and clinical importance of paraoxonases.Clin. Chem. Lab. Med. 2006; 44: 1052-1059Crossref PubMed Scopus (72) Google Scholar). PON1 activity has been inversely associated with cardiovascular disease (5Bhattacharyya T. Nicholls S.J. Topol E.J. Zhang R. Yang X. Schmitt D. Fu X. Shao M. Brennan D.M. Ellis S.G. et al.Relationship of paraoxonase 1 (PON1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk.JAMA. 2008; 299: 1265-1276Crossref PubMed Scopus (439) Google Scholar), and PON1-deficient mice are more prone to develop atherosclerosis (6Shih D.M. Xia Y.R. Wang X.P. Miller E. Castellani L.W. Subbanagounder G. Cheroutre H. Faull K.F. Berliner J.A. Witztum J.L. et al.Combined serum paraoxonase knockout/apolipoprotein E knockout mice exhibit increased lipoprotein oxidation and atherosclerosis.J. Biol. Chem. 2000; 275: 17527-17535Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar). In human studies, PON1 activity is significantly lower in subjects with the metabolic syndrome (7Senti M. Tomas M. Fito M. Weinbrenner T. Covas M.I. Sala J. Masia R. Marrugat J. Antioxidant paraoxonase 1 activity in the metabolic syndrome.J. Clin. Endocrinol. Metab. 2003; 88: 5422-5426Crossref PubMed Scopus (143) Google Scholar). PON1 activity was recently shown to be reduced in subjects with type 1 and type 2 diabetes mellitus (T1DM and T2DM) (8Deakin S.P. James R.W. Genetic and environmental factors modulating serum concentrations and activities of the antioxidant enzyme paraoxonase-1.Clin. Sci. (Lond.). 2004; 107: 435-447Crossref PubMed Scopus (227) Google Scholar) and was inversely associated with glucose concentrations in subjects with type 1 diabetes (9Hofer S.E. Bennetts B. Chan A.K. Holloway B. Karschimkus C. Jenkins A.J. Silink M. Donaghue K.C. Association between PON 1 polymorphisms, PON activity and diabetes complications.J. Diabetes Complications. 2006; 20: 322-328Crossref PubMed Scopus (58) Google Scholar). Subjects with the Arg192 allele of the PON1 gene had an odds ratio of 3.21 for the presence of retinopathy and/or nephropathy compared with subjects who were homozygous for the Gln192 allele in a Japanese cohort. The Japanese are known to have a higher frequency of the minor Arg192 allele compared with Caucasians (10Murata M. Maruyama T. Suzuki Y. Saruta T. Ikeda Y. Paraoxonase 1 Gln/Arg polymorphism is associated with the risk of microangiopathy in Type 2 diabetes mellitus.Diabet. Med. 2004; 21: 837-844Crossref PubMed Scopus (28) Google Scholar). Hofer et al. (9Hofer S.E. Bennetts B. Chan A.K. Holloway B. Karschimkus C. Jenkins A.J. Silink M. Donaghue K.C. Association between PON 1 polymorphisms, PON activity and diabetes complications.J. Diabetes Complications. 2006; 20: 322-328Crossref PubMed Scopus (58) Google Scholar) reported that homozygosity for the minor A allele of the PON1 A(-162)G promoter polymorphism was associated with microalbuminuria in an adolescent Australian cohort of subjects with T1DM. Furthermore, several studies have reported the association of PON1 gene variants with increased diabetic complications in T1DM (11Kao Y. Donaghue K.C. Chan A. Bennetts B.H. Knight J. Silink M. Paraoxonase gene cluster is a genetic marker for early microvascular complications in type 1 diabetes.Diabet. Med. 2002; 19: 212-215Crossref PubMed Scopus (51) Google Scholar) and in T2DM (10Murata M. Maruyama T. Suzuki Y. Saruta T. Ikeda Y. Paraoxonase 1 Gln/Arg polymorphism is associated with the risk of microangiopathy in Type 2 diabetes mellitus.Diabet. Med. 2004; 21: 837-844Crossref PubMed Scopus (28) Google Scholar, 12Letellier C. Durou M.R. Jouanolle A.M. Le Gall J.Y. Poirier J.Y. Ruelland A. Serum paraoxonase activity and paraoxonase gene polymorphism in type 2 diabetic patients with or without vascular complications.Diabetes Metab. 2002; 28: 297-304PubMed Google Scholar). We have reported that the PON2 polymorphism Ala148Gly is associated with diabetes in a cohort of Aboriginal Canadians (13Hegele R.A. Connelly P.W. Scherer S.W. Hanley A.J. Harris S.B. Tsui L.C. Zinman B. Paraoxonase-2 G148 variant in an aboriginal Canadian girl with non-insulin-dependent diabetes.Lancet. 1997; 350: 785Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 14Hegele R.A. Connelly P.W. Scherer S.W. Hanley A.J. Harris S.B. Tsui L.C. Zinman B. Paraoxonase-2 gene (PON2) G148 variant associated with elevated fasting plasma glucose in noninsulin-dependent diabetes mellitus.J. Clin. Endocrinol. Metab. 1997; 82: 3373-3377Crossref PubMed Scopus (89) Google Scholar). In a prospective study of 3,374 predominantly Caucasian subjects (the United Kingdom Prospective Diabetes Study), with a median duration of diabetes of 14 years, it was found that heterozygotes for PON2 Ala148Gly polymorphism had a 1.25 relative risk for the development of microalbuminuria (15Calle R. McCarthy M.I. Banerjee P. Zeggini E. Cull C.A. Thorne K.I. Wiltshire S. Terra S. Meyer D. Richmond J. et al.Paraoxonase 2 (PON2) polymorphisms and development of renal dysfunction in type 2 diabetes: UKPDS 76.Diabetologia. 2006; 49: 2892-2899Crossref PubMed Scopus (14) Google Scholar). However, there are no previous studies of PON2 polymorphisms and PON1 mass. Relatively little information is available regarding circulating PON1 mass in subjects with and without diabetic complications (16Ikeda Y. Suehiro T. Inoue M. Nakauchi Y. Morita T. Arii K. Ito H. Kumon Y. Hashimoto K. Serum paraoxonase activity and its relationship to diabetic complications in patients with non-insulin-dependent diabetes mellitus.Metabolism. 1998; 47: 598-602Abstract Full Text PDF PubMed Scopus (135) Google Scholar, 17Mackness B. Durrington P.N. Abuashia B. Boulton A.J. Mackness M.I. Low paraoxonase activity in type II diabetes mellitus complicated by retinopathy.Clin. Sci. (Lond.). 2000; 98: 355-363Crossref PubMed Google Scholar). This issue is of interest due to the hypothesized role of oxidative stress in the development of the complications of diabetes (18Nishikawa T. Edelstein D. Brownlee M. The missing link: a single unifying mechanism for diabetic complications.Kidney Int. Suppl. 2000; 77: S26-S30Abstract Full Text Full Text PDF PubMed Scopus (407) Google Scholar). Furthermore, we are unaware of any studies of PON1 mass and diabetic complications among Aboriginal populations, who are at high risk for diabetes and associated sequelae (19Dyck R.F. Tan L. Rates and outcomes of diabetic end-stage renal disease among registered native people in Saskatchewan.CMAJ. 1994; 150: 203-208PubMed Google Scholar, 20Young T.K. Kaufert J.M. McKenzie J.K. Hawkins A. O'Neil J. Excessive burden of end-state renal disease among Canadian Indians: a national survey.Am. J. Public Health. 1989; 79: 756-758Crossref PubMed Scopus (34) Google Scholar). In particular, it is well documented that Aboriginal Canadian subjects with diabetes have high rates of microalbuminuria and end stage renal disease (19Dyck R.F. Tan L. Rates and outcomes of diabetic end-stage renal disease among registered native people in Saskatchewan.CMAJ. 1994; 150: 203-208PubMed Google Scholar, 20Young T.K. Kaufert J.M. McKenzie J.K. Hawkins A. O'Neil J. Excessive burden of end-state renal disease among Canadian Indians: a national survey.Am. J. Public Health. 1989; 79: 756-758Crossref PubMed Scopus (34) Google Scholar–21Hanley A.J. Harris S.B. Mamakeesick M. Goodwin K. Fiddler E. Hegele R.A. Spence J.D. House A.A. Brown E. Schoales B. et al.Complications of type 2 diabetes among Aboriginal Canadians: prevalence and associated risk factors.Diabetes Care. 2005; 28: 2054-2057Crossref PubMed Scopus (57) Google Scholar), suggesting that kidney dysfunction may be the predominant microvascular complication of diabetes in this population. Our objective, therefore, was to determine the association of PON1 mass with cystatin C, a marker of renal function, in a sample of Aboriginal Canadians with T2DM. The methodology of the Sandy Lake Diabetes Complications Study (2001–2002) has been presented in detail previously (21Hanley A.J. Harris S.B. Mamakeesick M. Goodwin K. Fiddler E. Hegele R.A. Spence J.D. House A.A. Brown E. Schoales B. et al.Complications of type 2 diabetes among Aboriginal Canadians: prevalence and associated risk factors.Diabetes Care. 2005; 28: 2054-2057Crossref PubMed Scopus (57) Google Scholar). Briefly, the research project was in with a Canadian Aboriginal high rates of with an early of disease and high rates of complications (21Hanley A.J. Harris S.B. Mamakeesick M. Goodwin K. Fiddler E. Hegele R.A. Spence J.D. House A.A. Brown E. Schoales B. et al.Complications of type 2 diabetes among Aboriginal Canadians: prevalence and associated risk factors.Diabetes Care. 2005; 28: 2054-2057Crossref PubMed Scopus (57) Google Scholar, S.B. J. Hanley A. A. J. A. Zinman B. The prevalence of and associated risk factors in native Care. 1997; 20: PubMed Scopus Google Scholar). known to have T2DM were to of subjects were Serum were available for the of PON1 mass for of subjects was from and the study was by the Sandy Lake and the were to nephropathy as previously (21Hanley A.J. Harris S.B. Mamakeesick M. Goodwin K. Fiddler E. Hegele R.A. Spence J.D. House A.A. Brown E. Schoales B. et al.Complications of type 2 diabetes among Aboriginal Canadians: prevalence and associated risk factors.Diabetes Care. 2005; 28: 2054-2057Crossref PubMed Scopus (57) Google Scholar). nephropathy was by the ratio in a single sample Diabetes Association Canadian Diabetes Association for the and of Diabetes in J. 2003; Scholar) the had been of a for the Chem. PubMed Scopus Google Scholar). was the R. of the Clin. 1994; PubMed Scopus Google Scholar). and creatinine concentrations were The was for estimated glomerular filtration rate (eGFR) of creatinine from serum PubMed Scopus Google Scholar). and waist and duration of diabetes, and of diabetes and were as previously (21Hanley A.J. Harris S.B. Mamakeesick M. Goodwin K. Fiddler E. Hegele R.A. Spence J.D. House A.A. Brown E. Schoales B. et al.Complications of type 2 diabetes among Aboriginal Canadians: prevalence and associated risk factors.Diabetes Care. 2005; 28: 2054-2057Crossref PubMed Scopus (57) Google Scholar). C, a of G. A. Le C. A. C as a marker of and 2005; PubMed Scopus Google Scholar), was the C and the to The cystatin was the as Le C. C. C. P. C. H. of kidney in patients with Care. 2007; PubMed Scopus Google Scholar). PON1 mass was and with PON1 as the and as the P.W. D. of an with to paraoxonase 1 in serum and Lipid Res. 2008; 49: Full Text Full Text PDF PubMed Scopus Google Scholar) and was with the of was A serum was human of PON1 Gln192 and A(-162)G polymorphisms and PON2 Ala148Gly polymorphism were (9Hofer S.E. Bennetts B. Chan A.K. Holloway B. Karschimkus C. Jenkins A.J. Silink M. Donaghue K.C. Association between PON 1 polymorphisms, PON activity and diabetes complications.J. Diabetes Complications. 2006; 20: 322-328Crossref PubMed Scopus (58) Google Scholar, R.A. Connelly P.W. A polymorphism of the paraoxonase gene associated with in plasma in a genetic Biol. PubMed Scopus Google Scholar, S. Harris S.B. T.K. Hanley A.J. Zinman B. Connelly P.W. Hegele R.A. Association between PON1 polymorphism and plasma in Canadian aboriginal Chem. Lab. Med. 2000; PubMed Scopus Google Scholar). were PON1 mass as well as the of and were to for the of and of PON1 A(-162)G and PON2 Ala148Gly were as between were and between were of PON1 with the outcomes cystatin C and were with included previous analysis of diabetic kidney complications in this (21Hanley A.J. Harris S.B. Mamakeesick M. Goodwin K. Fiddler E. Hegele R.A. Spence J.D. House A.A. Brown E. Schoales B. et al.Complications of type 2 diabetes among Aboriginal Canadians: prevalence and associated risk factors.Diabetes Care. 2005; 28: 2054-2057Crossref PubMed Scopus (57) Google Scholar). were study were of the duration of diabetes was and metabolic was In and were significantly with and PON1, and with cystatin C and PON1 no with of Sandy Lake Complications and of diabetes ratio C of in renal disease mass of in renal disease in a of PON1, and and metabolic risk factors with estimated glomerular filtration and cystatin of in renal disease of in renal disease in a mass The minor allele of PON1 acid polymorphisms and and promoter polymorphism A(-162)G were and The minor allele frequency of the PON2 acid polymorphism Ala148Gly was The PON1 A(-162)G and PON2 Ala148Gly but association was to be for PON1 and were not significantly associated with PON1 mass not of the of the minor allele for PON1 Arg192 and PON1 polymorphisms in this sample of Aboriginal polymorphisms were not However, of PON1 A(-162)G and PON2 Ala148Gly polymorphisms were significantly associated with PON1 mass The PON2 polymorphism had been previously shown to be associated with diabetes in this cohort (13Hegele R.A. Connelly P.W. Scherer S.W. Hanley A.J. Harris S.B. Tsui L.C. Zinman B. Paraoxonase-2 G148 variant in an aboriginal Canadian girl with non-insulin-dependent diabetes.Lancet. 1997; 350: 785Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 14Hegele R.A. Connelly P.W. Scherer S.W. Hanley A.J. Harris S.B. Tsui L.C. Zinman B. Paraoxonase-2 gene (PON2) G148 variant associated with elevated fasting plasma glucose in noninsulin-dependent diabetes mellitus.J. Clin. Endocrinol. Metab. 1997; 82: 3373-3377Crossref PubMed Scopus (89) Google Scholar), and among the genetic it had the relationship with PON1 analysis of PON1 mass by PON2 Ala148Gly and PON1 A(-162)G in a the of PON1 mass, regression analysis was with as or 1 presence or of and was with age, loge (ln) duration of diabetes, ln HbA1c, waist high density lipoprotein cholesterol (HDLC), and ln cystatin C. was that the of duration of diabetes was with subjects had diabetes of analysis is reported with to subjects with duration of diabetes The of PON1 mass was the presence of the PON2 genotype, for of the in PON1 mass, by HDLC, ln cystatin C, and ln duration of diabetes The not at the The of the was the the analysis was for subjects with duration of diabetes duration of diabetes was no the analysis was with PON1 the presence of the PON1 was the of mass, for of the in PON1 mass, by HDLC, ln cystatin C, and ln duration of diabetes were included in the the PON2 the of PON1 mass, the PON1 had a analysis of PON1 mass including PON2 cystatin cystatin in a analysis of PON1 mass including PON1 A(-162)G cystatin cystatin in a The of this study it to a relationship between the was that are the of cystatin The of cystatin C were by regression analysis with for the cohort and with to subjects with duration of diabetes age, ln HbA1c, and waist circumference as the for and of the in cystatin C for the cohort. The of the subjects with duration of diabetes is in subjects are included in the duration the regression model at the are it is not PON1 mass for a in and for the cohort and subjects with duration years, but has a for the analysis to subjects with duration of diabetes of there was no relationship of PON2 with cystatin analysis with ln cystatin C as the dependent not in a not et al. Le C. C. C. P. C. H. of kidney in patients with Care. 2007; PubMed Scopus Google Scholar) reported that the for cystatin in the of in the high ml/min per 1.73 and ml/min per 1.73 the were with subjects as or ml/min per 1.73 stage 3 kidney disease J. E. A. J. G. for kidney and Med. 2003; PubMed Scopus Google Scholar) of subjects by was of to concentrations in variance in plasma PON1 concentrations for the cohort and for subjects with a duration of diabetes analysis with ln PON1 as the dependent and cystatin C as than or than in a several previous have documented of PON1 gene polymorphisms with diabetic complications (9Hofer S.E. Bennetts B. Chan A.K. Holloway B. Karschimkus C. Jenkins A.J. Silink M. Donaghue K.C. Association between PON 1 polymorphisms, PON activity and diabetes complications.J. Diabetes Complications. 2006; 20: 322-328Crossref PubMed Scopus (58) Google Scholar, M. Maruyama T. Suzuki Y. Saruta T. Ikeda Y. Paraoxonase 1 Gln/Arg polymorphism is associated with the risk of microangiopathy in Type 2 diabetes mellitus.Diabet. Med. 2004; 21: 837-844Crossref PubMed Scopus (28) Google Scholar, Y. Donaghue K.C. Chan A. Bennetts B.H. Knight J. Silink M. Paraoxonase gene cluster is a genetic marker for early microvascular complications in type 1 diabetes.Diabet. Med. 2002; 19: 212-215Crossref PubMed Scopus (51) Google C. Durou M.R. Jouanolle A.M. Le Gall J.Y. Poirier J.Y. Ruelland A. Serum paraoxonase activity and paraoxonase gene polymorphism in type 2 diabetic patients with or without vascular complications.Diabetes Metab. 2002; 28: 297-304PubMed Google Scholar), information is available from studies circulating concentrations of PON1, and no previous study of subjects with diabetes has at the relationship of PON1 mass and cystatin C. In the we a association of PON1 mass with cystatin C, a marker of kidney function, in Aboriginal subjects with type 2 was found that this was explained by lower PON1 mass for subjects with a <60 ml/min per 1.73 m2 compared with subjects with >60 ml/min per 1.73 m2. research PON1 and diabetic kidney disease has microalbuminuria (10Murata M. Maruyama T. Suzuki Y. Saruta T. Ikeda Y. Paraoxonase 1 Gln/Arg polymorphism is associated with the risk of microangiopathy in Type 2 diabetes mellitus.Diabet. Med. 2004; 21: 837-844Crossref PubMed Scopus (28) Google Scholar, Y. Donaghue K.C. Chan A. Bennetts B.H. Knight J. Silink M. Paraoxonase gene cluster is a genetic marker for early microvascular complications in type 1 diabetes.Diabet. Med. 2002; 19: 212-215Crossref PubMed Scopus (51) Google Scholar). We not an association between PON1 mass and ratio in The for an of association of PON1 mass with microalbuminuria is the duration of diabetes in this with a median of years, compared with 14 for Serum cystatin C concentrations are an of glomerular filtration rate and with Le C. C. C. P. C. H. of kidney in patients with Care. 2007; PubMed Scopus Google Scholar, J. S.E. of cystatin C compared to serum creatinine for the of renal dysfunction in and 2007; PubMed Scopus Google Scholar, E. S. S. E. G. of cystatin C are more accurate than in renal in type 1 Care. 2008; PubMed Scopus Google C. E. S. A. Jenkins et of cystatin C and for and kidney disease in diabetes.Diabet. Med. 2007; PubMed Scopus Google Scholar). are several for the association of PON1 mass and of the ratio of with as by plasma cystatin C PON1 has been reported to be reduced by and R.A. C. Paraoxonase activity in the serum and the 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). et al. S. C.A. Harris T.B. and of in without kidney the and Int. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar) reported a between cystatin C and in an as reduced renal and reduced PON1 Serum PON1 is with in subjects and is found in and X. S. James R.W. of and its to enzyme activity and to oxidative Lipid Res. 2008; 49: Full Text Full Text PDF PubMed Scopus Google Scholar). Association of PON1 with has been shown to be for the of the enzyme L. Tawfik D.S. and activity of serum paraoxonase PON1 with 2005; 44: PubMed Scopus Google Scholar), and in studies have that this is for PON1 associated with compared with X. S. James R.W. of and its to enzyme activity and to oxidative Lipid Res. 2008; 49: Full Text Full Text PDF PubMed Scopus Google Scholar). Subjects with diabetes have been reported to have lower concentrations T. D. K. and disease in Full Text PDF PubMed Scopus Google Scholar), has been reported to be reduced in subjects with renal with or without diabetes J. A. P. J. M. A. J. et lipoprotein in diabetic patients with and without renal of Metab. 19: Google Scholar). We have recently shown that the PON1 knockout has an vascular D.S. T. B. P. Connelly P.W. in mice to vascular oxidative and in the of 2008; PubMed Scopus Google Scholar). there is for an between the and metabolic of diabetes to in lower serum The to the lower PON1 and the in anti-inflammatory of contribute to vascular and renal to be The genetic polymorphisms of the paraoxonase gene are R.A. Paraoxonase and Med. PubMed Scopus Google Scholar, J. J. M. et of the PON gene PON1 oxidative and vascular Lipid Res. 2006; 47: Full Text Full Text PDF PubMed Scopus Google Scholar). not the PON1 but between PON1 and the PON2 The PON1 promoter polymorphism at has been to of PON1 J. J. M. et of the PON gene PON1 oxidative and vascular Lipid Res. 2006; 47: Full Text Full Text PDF PubMed Scopus Google Scholar). The of this polymorphism with the PON2 Ala148Gly polymorphism from the genetic PON1 to a single However, the of an association between the PON1 and PON2 polymorphisms and cystatin C that genetic of PON1 are not renal function, the of the sample The relative risk of 1.25 for the development of microalbuminuria for heterozygotes for the PON2 Ala148Gly polymorphism in the United Kingdom Prospective Diabetes Study (15Calle R. McCarthy M.I. Banerjee P. Zeggini E. Cull C.A. Thorne K.I. Wiltshire S. Terra S. Meyer D. Richmond J. et al.Paraoxonase 2 (PON2) polymorphisms and development of renal dysfunction in type 2 diabetes: UKPDS 76.Diabetologia. 2006; 49: 2892-2899Crossref PubMed Scopus (14) Google Scholar) is with at the to for diabetic nephropathy. However, would that the of renal PON1 is of a significantly than that of the of genetic renal has been that PON1 activity is lower in subjects compared with J. L. P. G. C. of serum paraoxonase activity in renal 1998; Google Scholar). In PON1 activity was not from in kidney patients J. L. P. G. C. of serum paraoxonase activity in renal 1998; Google Scholar). This is with renal in reduced PON1 and that PON1 is a of renal The of in PON1 is to be as it has been reported that lower PON1 mass higher in patients Y. Suehiro T. T. Y. H. Inoue M. Arii K. Hashimoto K. serum paraoxonase cardiovascular in 2007; PubMed Scopus Google Scholar) and lower PON1 activity of cardiovascular end (5Bhattacharyya T. Nicholls S.J. Topol E.J. Zhang R. Yang X. Schmitt D. Fu X. Shao M. Brennan D.M. Ellis S.G. et al.Relationship of paraoxonase 1 (PON1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk.JAMA. 2008; 299: 1265-1276Crossref PubMed Scopus (439) Google Scholar). The PON1 mass, for age, duration of diabetes, and HDLC, was for the subjects with the PON2 and <60 ml/min per 1.73 m2 compared with for the subjects with the PON2 and >60 ml/min per 1.73 m2 This in PON1 mass is to that in patients et in patients with diabetic but without renal the presence of the PON2 is associated with a metabolic that is from renal In we have found a association of PON1 with cystatin C, a marker of studies of subjects at risk for vascular disease be to determine the association of PON1 with is of a including renal The are to the and of Sandy Lake for their and in this

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