Determinants of variation in human serum paraoxonase activity

被引:67
作者
Rainwater, D. L. [1 ]
Rutherford, S. [1 ]
Dyer, T. D. [1 ]
Rainwater, E. D. [1 ]
Cole, S. A. [1 ]
VandeBerg, J. L. [1 ,2 ]
Almasy, L. [1 ]
Blangero, J. [1 ]
MacCluer, J. W. [1 ]
Mahaney, M. C. [1 ,2 ]
机构
[1] SW Fdn Biomed Res, Dept Genet, San Antonio, TX 78245 USA
[2] SW Fdn Biomed Res, SW Natl Primate Res Ctr, San Antonio, TX 78245 USA
关键词
PON1; genetic; linkage analysis; Mexican Americans; MEXICAN-AMERICANS; LINKAGE ANALYSIS; CARDIOVASCULAR RISK; GENE POLYMORPHISMS; OXIDATIVE STRESS; TRANSGENIC MICE; ENZYME-ACTIVITY; PON1; HDL; LIPOPROTEINS;
D O I
10.1038/hdy.2008.110
中图分类号
Q14 [生态学(生物生态学)];
学科分类号
071012 ; 0713 ;
摘要
Paraoxonase-1 (PON1) is associated with high-density lipoprotein (HDL) particles and is believed to contribute to antiatherogenic properties of HDLs. We assessed the determinants of PON1 activity variation using different substrates of the enzyme. PON1 activity in serum samples from 922 participants in the San Antonio Family Heart Study was assayed using a reliable microplate format with three substrates: paraoxon, phenyl acetate and the lactone dihydrocoumarin. There were major differences among results from the three substrates in degree of effect by various environmental and genetic factors, suggesting that knowledge of one substrate activity alone may not provide a complete sense of PON1 metabolism. Three significant demographic covariates (age, smoking status and contraceptive usage) together explained 1-6% of phenotypic variance, whereas four metabolic covariates representing lipoprotein metabolism (apoAII, apoAI, triglycerides and non-HDL cholesterol) explained 4-19%. Genes explained 65-92% of phenotypic variance and the dominant genetic effect was exerted by a locus mapping at or near the protein structural locus (PON1) on chromosome 7. Additional genes influencing PON1 activity were localized to chromosomes 3 and 14. Our study identified environmental and genetic determinants of PON1 activity that accounted for 88-97% of total phenotypic variance, suggesting that few, if any, major biological determinants are unrepresented in the models.
引用
收藏
页码:147 / 154
页数:8
相关论文
共 43 条
[1]   Multipoint quantitative-trait linkage analysis in general pedigrees [J].
Almasy, L ;
Blangero, J .
AMERICAN JOURNAL OF HUMAN GENETICS, 1998, 62 (05) :1198-1211
[2]   Paraoxonases and cardiovascular diseases: pharmacological and nutritional influences [J].
Aviram, M ;
Rosenblat, M .
CURRENT OPINION IN LIPIDOLOGY, 2005, 16 (04) :393-399
[3]   Relationship of paraoxonase 1 (PON1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk [J].
Bhattacharyya, Tamali ;
Nicholls, Stephen J. ;
Topol, Eric J. ;
Zhang, Renliang ;
Yang, Xia ;
Schmitt, David ;
Fu, Xiaoming ;
Shao, Mingyuan ;
Brennan, Danielle M. ;
Ellis, Stephen G. ;
Brennan, Marie-Luise ;
Allayee, Hooman ;
Lusis, Aldons J. ;
Hazen, Stanley L. .
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2008, 299 (11) :1265-1276
[4]  
Blangero J, 1997, GENET EPIDEMIOL, V14, P959, DOI 10.1002/(SICI)1098-2272(1997)14:6<959::AID-GEPI66>3.0.CO
[5]  
2-K
[6]   Novel family-based approaches to genetic risk in thrombosis [J].
Blangero, J ;
Williams, JT ;
Almasy, L .
JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 2003, 1 (07) :1391-1397
[7]   Overexpression of apolipoprotein all in transgenic mice converts high density lipoproteins to proinflammatory particles [J].
Castellani, LW ;
Navab, M ;
VanLenten, BJ ;
Hedrick, CC ;
Hama, SY ;
Goto, AM ;
Fogelman, AM ;
Lusis, AJ .
JOURNAL OF CLINICAL INVESTIGATION, 1997, 100 (02) :464-474
[8]   A NOVEL SYSTEM FOR STORAGE OF SERA FROZEN IN SMALL ALIQUOTS [J].
CHENG, ML ;
WOODFORD, SC ;
HILBURN, JL ;
VANDEBERG, JL .
JOURNAL OF BIOCHEMICAL AND BIOPHYSICAL METHODS, 1986, 13 (01) :47-51
[9]   Modulation of paraoxonase (PON1) activity [J].
Costa, LG ;
Vitalone, A ;
Cole, TB ;
Furlong, CE .
BIOCHEMICAL PHARMACOLOGY, 2005, 69 (04) :541-550
[10]   The effect of the human serum paraoxonase polymorphism is reversed with diazoxon, soman and sarin [J].
Davies, HG ;
Richter, RJ ;
Keifer, M ;
Broomfield, CA ;
Sowalla, J ;
Furlong, CE .
NATURE GENETICS, 1996, 14 (03) :334-336