Rainwater DL

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Full name : Rainwater David L

First name : David L

Mail : Department of Genetics, Texas Biomedical Research Institute, P.O. Box 760549, San Antonio, TX 78245-0549

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Country : USA

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References (10)

Title : Novel associations of nonstructural Loci with paraoxonase activity - Quillen_2012_J.Lipids_2012_189681
Author(s) : Quillen EE , Rainwater DL , Dyer TD , Carless MA , Curran JE , Johnson MP , Goring HH , Cole SA , Rutherford S , MacCluer JW , Moses EK , Blangero J , Almasy L , Mahaney MC
Ref : J Lipids , 2012 :189681 , 2012
Abstract : The high-density-lipoprotein-(HDL-) associated esterase paraoxonase 1 (PON1) is a likely contributor to the antioxidant and antiatherosclerotic capabilities of HDL. Two nonsynonymous mutations in the structural gene, PON1, have been associated with variation in activity levels, but substantial interindividual differences remain unexplained and are greatest for substrates other than the eponymous paraoxon. PON1 activity levels were measured for three substrates-organophosphate paraoxon, arylester phenyl acetate, and lactone dihydrocoumarin-in 767 Mexican American individuals from San Antonio, Texas. Genetic influences on activity levels for each substrate were evaluated by association with approximately one million single nucleotide polymorphism (SNPs) while conditioning on PON1 genotypes. Significant associations were detected at five loci including regions on chromosomes 4 and 17 known to be associated with atherosclerosis and lipoprotein regulation and loci on chromosome 3 that regulate ubiquitous transcription factors. These loci explain 7.8% of variation in PON1 activity with lactone as a substrate, 5.6% with the arylester, and 3.0% with paraoxon. In light of the potential importance of PON1 in preventing cardiovascular disease/events, these novel loci merit further investigation.
ESTHER : Quillen_2012_J.Lipids_2012_189681
PubMedSearch : Quillen_2012_J.Lipids_2012_189681
PubMedID: 22577559

Title : Determinants of variation in human serum paraoxonase activity - Rainwater_2009_Heredity.(Edinb)_102_147
Author(s) : Rainwater DL , Rutherford S , Dyer TD , Rainwater ED , Cole SA , Vandeberg JL , Almasy L , Blangero J , MacCluer JW , Mahaney MC
Ref : Heredity (Edinb) , 102 :147 , 2009
Abstract : 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.
ESTHER : Rainwater_2009_Heredity.(Edinb)_102_147
PubMedSearch : Rainwater_2009_Heredity.(Edinb)_102_147
PubMedID: 18971955

Title : Vitamin E dietary supplementation significantly affects multiple risk factors for cardiovascular disease in baboons - Rainwater_2007_Am.J.Clin.Nutr_86_597
Author(s) : Rainwater DL , Mahaney MC , Vandeberg JL , Wang XL
Ref : Am J Clin Nutr , 86 :597 , 2007
Abstract : BACKGROUND: Oxidative stress is a widely accepted risk factor for cardiovascular disease (CVD), but the CVD benefit of dietary antioxidants, such as vitamin E, is controversial. OBJECTIVE: Therefore, we have investigated, in the baboon model, the effects of dietary vitamin E supplementation on risk factors for CVD. DESIGN: Pedigreed baboons (n = 251) were fed 2 atherogenic diets, high in fat and cholesterol, that differed in vitamin E concentrations. After 7 wk on each diet, blood samples were taken, and a panel of CVD risk factor traits (ie, indicators of lipoprotein metabolism and oxidative stress) were measured.
RESULTS: Vitamin E supplementation caused significantly higher total antioxidant status (TAS) and lower oxidized LDL as expected. In addition, vitamin E caused 2 paradoxical effects on HDL metabolism: higher apolipoprotein A-I (apo A-I) concentrations and lower HDL sizes. We calculated a difference (Delta) variable for each trait as the value on the high-vitamin E diet minus that on the low-vitamin E diet and determined that several HDL concentration Delta variables were significantly correlated with Delta TAS, but only one, Delta apo A-I, was independently correlated. Genetic analyses showed that 2 Delta variables, Delta paraoxonase and Delta HDL(2), were significantly heritable, but that neither Delta TAS nor Delta apo A-I were heritable.
CONCLUSIONS: Thus, our data show that dietary vitamin E improves TAS and LDL quality. They also show 2 apparently paradoxical effects on HDL metabolism: lower HDL(2), which is mediated by genes, and higher apo A-I, which is not. These effects have contrasting associations with CVD risk and may help account for the mixed results from clinical trials of dietary vitamin E.
ESTHER : Rainwater_2007_Am.J.Clin.Nutr_86_597
PubMedSearch : Rainwater_2007_Am.J.Clin.Nutr_86_597
PubMedID: 17823422

Title : Decreased bone mineral density is correlated with increased subclinical atherosclerosis in older, but not younger, Mexican American women and men: the San Antonio Family Osteoporosis Study - Shaffer_2007_Calcif.Tissue.Int_81_430
Author(s) : Shaffer JR , Kammerer CM , Rainwater DL , O'Leary DH , Bruder JM , Bauer RL , Mitchell BD
Ref : Calcif Tissue Int , 81 :430 , 2007
Abstract : An association has been reported between cardiovascular disease (CVD) and osteoporosis, perhaps attributable to the presence of common risk factors. To assess this possibility, we measured areal bone mineral density (BMD) and carotid artery intimal medial thickness (IMT), a measure of preclinical atherosclerosis, in 535 women and 335 men from the San Antonio Family Osteoporosis Study. Variance decomposition methods were used to determine whether cross-sectional measures of areal BMD (measured by dual-energy X-ray absorptiometry) of the total hip, spine, and forearm were correlated with IMT, serum lipids, and/or C-reactive protein (CRP), a marker of inflammation, after accounting for known environmental factors. We observed significant inverse correlations of IMT and BMD at all bone sites in women >60 years of age (P < 0.001) and modest positive correlations (not significant) of IMT on hip BMD (P < 0.1) in women <60 years of age. Similarly, we observed negative correlations between IMT and forearm BMD in men >60 years of age (P < 0.001) and positive correlations in men <60 years of age (P = 0.05). Variation in risk factors for CVD, including serum levels of low- and high-density lipoprotein cholesterol, low-density lipoprotein particle size, triglycerides, paraoxonase 1 activity, and CRP did not account for the relationship between BMD and IMT in either older or younger men or women. In summary, our results demonstrate that decreased BMD is correlated with increased IMT in older (but not younger) Mexican American men and women, independent of serum CVD risk factors.
ESTHER : Shaffer_2007_Calcif.Tissue.Int_81_430
PubMedSearch : Shaffer_2007_Calcif.Tissue.Int_81_430
PubMedID: 17992559

Title : Sex-specific QTL effects on variation in paraoxonase 1 (PON1) activity in Mexican Americans - Winnier_2007_Genet.Epidemiol_31_66
Author(s) : Winnier DA , Rainwater DL , Cole SA , Williams JT , Dyer TD , Blangero J , MacCluer JW , Mahaney MC
Ref : Genet Epidemiol , 31 :66 , 2007
Abstract : Paraoxonase 1 (PON1), a high-density lipoprotein-associated enzyme known to protect against cellular damage from toxic agents, may also have antioxidant properties. PON1 activity levels have been reported to differ by sex in human and animal studies with females exhibiting higher basal levels. We measured PON1 activity frozen serum for 1,406 individuals in over 40 extended pedigrees from the San Antonio Family Heart Study (SAFHS). We used a maximum likelihood-based, variance decomposition approach implemented in SOLAR to test for genotype-by-sex (G x S) interaction on variation in PON1 activity and to determine if any of the four PON1 quantitative trait loci (QTL) previously reported by us for this population might account for sex differences in PON1 activity levels. The residual additive genetic correlation (rho(G) = 0.82) between males and females is significantly different from 1 (P = 0.009), suggesting that some of the genes that influence PON1 activity act differently in females and males or, possibly, that a different combination of genes influences this trait in each sex. In addition to the QTL at or near the PON structural locus on 7q21-22, three other potential QTLs were evaluated for sex-specific effects: one each on chromosomes 12, 17 and 19. The QTL on chromosome 17 (LOD = 2.32, P = 0.0003; flanked by microsatellite marker loci D17S974 and D17S969) shows a significant (P = 0.005) sex-specific effect on PON1 activity; accounting for 6% of the additive genetic variance in males and 20% in females. This study represents the first formal statistical genetic test for G x S interactions on normal quantitative variation in PON1 activity in humans.
ESTHER : Winnier_2007_Genet.Epidemiol_31_66
PubMedSearch : Winnier_2007_Genet.Epidemiol_31_66
PubMedID: 17136774

Title : Collaborative meta-analysis of individual participant data from observational studies of Lp-PLA2 and cardiovascular diseases - Ballantyne_2007_Eur.J.Cardiovasc.Prev.Rehabil_14_3
Author(s) : Ballantyne C , Cushman M , Psaty B , Furberg C , Khaw KT , Sandhu M , Oldgren J , Rossi GP , Maiolino G , Cesari M , Lenzini L , James SK , Rimm E , Collins R , Anderson J , Koenig W , Brenner H , Rothenbacher D , Berglund G , Persson M , Berger P , Brilakis E , McConnell JP , Sacco R , Elkind M , Talmud P , Cannon CP , Packard C , Barrett-Connor E , Hofman A , Kardys I , Witteman JC , Criqui M , Corsetti JP , Rainwater DL , Moss AJ , Robins S , Bloomfield H , Collins D , Wassertheil-Smoller S , Ridker P , Danesh J , Gu D , Nelson JJ , Thompson S , Zalewski A , Zariffa N , Di Angelantonio E , Kaptoge S , Thompson A , Walker M , Watson S , Wood A
Ref : Eur J Cardiovasc Prev Rehabil , 14 :3 , 2007
Abstract : BACKGROUND: A large number of observational epidemiological studies have reported generally positive associations between circulating mass and activity levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) and the risk of cardiovascular diseases. Few studies have been large enough to provide reliable estimates in different circumstances, such as in different subgroups (e.g., by age group, sex, or smoking status) or at different Lp-PLA2 levels. Moreover, most published studies have related disease risk only to baseline values of Lp-PLA2 markers (which can lead to substantial underestimation of any risk relationships because of within-person variability over time) and have used different approaches to adjustment for possible confounding factors. OBJECTIVES: By combination of data from individual participants from all relevant observational studies in a systematic 'meta-analysis', with correction for regression dilution (using available data on serial measurements of Lp-PLA2), the Lp-PLA2 Studies Collaboration will aim to characterize more precisely than has previously been possible the strength and shape of the age and sex-specific associations of plasma Lp-PLA2 with coronary heart disease (and, where data are sufficient, with other vascular diseases, such as ischaemic stroke). It will also help to determine to what extent such associations are independent of possible confounding factors and to explore potential sources of heterogeneity among studies, such as those related to assay methods and study design. It is anticipated that the present collaboration will serve as a framework to investigate related questions on Lp-PLA2 and cardiovascular outcomes. METHODS: A central database is being established containing data on circulating Lp-PLA2 values, sex and other potential confounding factors, age at baseline Lp-PLA2 measurement, age at event or at last follow-up, major vascular morbidity and cause-specific mortality. Information about any repeat measurements of Lp-PLA2 and potential confounding factors has been sought to allow adjustment for possible confounding and correction for regression dilution. The analyses will involve age-specific regression models. Synthesis of the available observational studies of Lp-PLA2 will yield information on a total of about 15 000 cardiovascular disease endpoints.
ESTHER : Ballantyne_2007_Eur.J.Cardiovasc.Prev.Rehabil_14_3
PubMedSearch : Ballantyne_2007_Eur.J.Cardiovasc.Prev.Rehabil_14_3
PubMedID: 17301621
Gene_locus related to this paper: human-PLA2G7

Title : Identification of promoter variants in baboon endothelial lipase that regulate high-density lipoprotein cholesterol levels - Cox_2007_Circulation_116_1185
Author(s) : Cox LA , Birnbaum S , Mahaney MC , Rainwater DL , Williams JT , Vandeberg JL
Ref : Circulation , 116 :1185 , 2007
Abstract : BACKGROUND: High-density lipoprotein cholesterol (HDL) levels are a major risk factor for cardiovascular disease. Previously we identified a quantitative trait locus on baboon chromosome 18 that regulates HDL. From positional cloning studies and expression studies, we identified the endothelial lipase gene (LIPG) as the primary candidate gene for the quantitative trait locus. The mechanism by which LIPG variation influences HDL levels has not been determined. METHODS AND
RESULTS: We identified 164 LIPG polymorphisms in a panel of sibling baboons discordant for HDL1 and genotyped putative regulatory polymorphisms in a population of 951 pedigreed baboons. With the use of quantitative trait nucleotide analysis we identified 3 polymorphisms in the LIPG promoter associated with variation in serum HDL1 levels. In addition, we demonstrated that these 3 polymorphisms affect LIPG promoter activity in vitro. In silico analysis was used to identify putative transcription factors that differentially bind the functional promoter polymorphisms.
CONCLUSIONS: These results reveal LIPG variants that specifically contribute to HDL1 levels and demonstrate mechanisms by which these polymorphisms may regulate LIPG promoter activity. Results from the present study provide a mechanism, namely variation in LIPG promoter activity possibly caused by altered transcription factor binding, by which LIPG variation affects HDL levels.
ESTHER : Cox_2007_Circulation_116_1185
PubMedSearch : Cox_2007_Circulation_116_1185
PubMedID: 17709635
Gene_locus related to this paper: papha-a7ld44

Title : Multiple QTLs influence variation in paraoxonase 1 activity in Mexican Americans - Winnier_2006_Hum.Biol_78_341
Author(s) : Winnier DA , Rainwater DL , Cole SA , Dyer TD , Blangero J , MacCluer JW , Mahaney MC
Ref : Hum Biol , 78 :341 , 2006
Abstract : Paraoxonase 1 (PON1), a high-density-lipoprotein-associated enzyme known to protect against cellular damage from toxic agents, may also have antioxidant properties. Although the importance of the influence of the PON1 structural locus on chromosome 7q21-22 for variation in the concentration and activity of the enzyme is well-documented, the contribution of other loci is poorly understood. Based on the recent observations of at least one additional quantitative trait locus (QTL) for PON1 activity in pedigreed baboons, we conducted a whole-genome linkage screen for QTLs other than the PON1 structural locus that may influence PON1 activity in humans. We measured PON1 activity in frozen serum for 1,406 individuals in more than 40 extended pedigrees from the San Antonio Family Heart Study (SAFHS). We used a maximum-likelihood-based variance decomposition approach implemented in SOLAR to test for QTLs that may influence PON1 activity. In addition to a QTL for which we detected the strongest, significant evidence (LOD = 31.41) at or near the PON1 structural locus on chromosome 7q21-22, we also localized at least one additional significant QTL on chromosome 12 (LOD = 3.56). Furthermore, we detected suggestive evidence for two more PON-related QTLs on chromosomes 17 and 19. We have provided evidence that other genes, in addition to the well-known ones on chromosome 7, play a role in influencing normal variation in PON1 activity.
ESTHER : Winnier_2006_Hum.Biol_78_341
PubMedSearch : Winnier_2006_Hum.Biol_78_341
PubMedID: 17216806

Title : Determinants of variation in serum paraoxonase enzyme activity in baboons - Rainwater_2005_J.Lipid.Res_46_1450
Author(s) : Rainwater DL , Mahaney MC , Wang XL , Rogers J , Cox LA , Vandeberg JL
Ref : J Lipid Res , 46 :1450 , 2005
Abstract : Paraoxonase (PON), an HDL-associated enzyme, is one of many circulating antioxidants thought to play a vital protective role. To better understand the determinants of quantitative variation in serum PON activity, we assayed PON in samples from 611 pedigreed baboons fed three diets. PON was measured enzymatically; the main determinant of variation was genetic and consisted of at least three components: two loci detected by linkage analyses and a residual polygenic component. Multipoint linkage analyses gave peak log of the odds (LOD) scores on the baboon homolog of human chromosome 7q21-22 (near PON1, the structural gene) of 9.1 on the low-cholesterol, high-fat diet and 4.1 on the high-cholesterol, high-fat diet (genome-wide P values were 1 x 10(-8) and 0.0018, respectively). Surprisingly, a second locus on the baboon homolog of human chromosome 12q13 gave a LOD score of 2.9 on the high-cholesterol, high-fat diet (genome-wide P value was 0.032). We identified several significant covariates, including age, sex, diet, and apolipoprotein A-I concentrations. We estimate that 53% of total trait variation in baboons is explained by genes and 17% by covariates, thus accounting for approximately 70% of total variation in baboon PON. Although the generation of free radicals is influenced primarily by environmental factors, our findings suggest strong genetic regulation of one component in the antioxidant defense system that plays a major role in susceptibility to atherosclerosis.
ESTHER : Rainwater_2005_J.Lipid.Res_46_1450
PubMedSearch : Rainwater_2005_J.Lipid.Res_46_1450
PubMedID: 15834129

Title : Joint linkage and association analysis of the hepatic lipase promoter polymorphism and lipoprotein size phenotypes - Almasy_2005_Hum.Biol_77_17
Author(s) : Almasy L , Rainwater DL , Cole S , Mahaney MC , Vandeberg JL , Hixson JE , Stern MP , MacCluer JW , Blangero J
Ref : Hum Biol , 77 :17 , 2005
Abstract : The hepatic lipase gene (LIPC) has been implicated as a potential regulator of HDL-cholesterol concentration and HDL and LDL particle size. Studies have centered on a C to T transition in the promoter region of LIPC, 514 base pairs upstream from the transcription initiation site. We performed a genome-wide linkage screen for several lipoprotein size phenotypes and tested for association of these traits with LIPC -514C-T in 798 individuals from the San Antonio Family Heart Study. Median diameters were measured for HDL particles stained for apoA1 (A1), apoA2 (A2), unesterified cholesterol (UC), and esterified cholesterol (EC) and for LDLs stained for EC. The median diameter of all phenotypes exhibited evidence of linkage to the LIPC region of chromosome 15 (LODs of 1.78 to 3.79). Linkage was also observed for HDL-EC size on chromosome 5p (LOD = 3.50). Association with the LIPC -514C-T polymorphism was detected for HDL-A1, HDL-A2, HDL-UC, and HDL-EC median diameters (p < 0.001) but not for LDL-EC size. Linkage analyses of HDL sizes conditional on the -514C-T polymorphism reduced the LOD scores in the LIPC region only slightly, suggesting that this polymorphism does not explain the observed linkage of lipoprotein sizes to chromosome 15. These results indicate the presence of a lipoprotein size locus in the LIPC region but suggest that -514C-T is not the primary functional variant in this region, implying that additional functional mutations influencing HDL and potentially LDL size variation occur in or near LIPC.
ESTHER : Almasy_2005_Hum.Biol_77_17
PubMedSearch : Almasy_2005_Hum.Biol_77_17
PubMedID: 16114813