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Nutrient-Gene Interactions

Dietary Modifications and Gene Polymorphisms Alter Serum Paraoxonase Activity in Healthy Women¹

Maire Rantala, Marja-Leena Silaste², Anu Tuominen, Jari Kaikkonen^*, Jukka T. Salonen^*, Georg Alfthan, Antti Aro and Y. Antero Kesäniemi

Department of Internal Medicine and Biocenter Oulu, University of Oulu, FIN-90014 Oulu, Finland; ^* Research Institute of Public Health, University of Kuopio, FIN-70211 Kuopio, Finland; and National Public Health Institute (KTL), FIN-00300 Helsinki, Finland

²To whom correspondence should be addressed. E-mail: Marja-Leena.Silaste{at}oulu.fi.

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Paraoxonase-1 (PON1), a HDL-associated enzyme, may protect against the development of atherosclerosis. Serum PON1 activity and PON1-mediated capacity of HDL to prevent lipoprotein oxidation are modulated by two common polymorphisms at positions 192 (GlnArg) and 55 (LeuMet) of the PON1 gene. We studied the effect of dietary modifications on PON1 activity and the role of PON1 gene polymorphisms in the response. A controlled, crossover dietary intervention of two 5-wk periods was conducted in 37 healthy, nonsmoking women. The two study diets were either low or high in vegetables, and thus in natural antioxidants, with some differences in fatty acid contents. The mean plasma total (-8%, P < 0.001), LDL (-7%, P < 0.01) and HDL (-7%, P < 0.001%) cholesterol, and apolipoprotein A-I (-8%, P < 0.001) concentrations were lower after the high vegetable diet period than after the low vegetable diet period. Also, the serum PON1 activity was lower (P < 0.05) after the high vegetable compared with the low vegetable diet period. The reduction of PON1 activity correlated with the reduction in HDL cholesterol (r = 0.35, P < 0.05). High baseline PON1 activity was related to the presence of the PON1_192Arg allele (P < 0.001) and PON1_55Leu/Leu genotype (P < 0.001). The reduction of PON1 activity due to the high vegetable diet was greatest among the women with the PON1_192Arg allele (P < 0.05) and PON1_55Leu/Leu genotype (P < 0.05). In conclusion, a diet high in vegetables, berries and fruit reduces PON1 activity, and the response is modulated by the genetic variance of PON1.

KEY WORDS: • antioxidant • diet • humans • paraoxonase • polymorphism

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Diet has an important role among the main risk factors for atherosclerosis and coronary heart disease (CHD)³ because it regulates the levels of plasma lipids and lipoproteins, blood pressure, energy balance, thrombogenesis and the oxidative modification or protection of plasma lipids and lipoproteins. The extent to which diet affects the plasma concentrations of lipids and lipoproteins is relatively well documented, even though there is substantial interindividual variation in dietary responsiveness (1 ,2 ). Information on the effect of diet on serum antioxidative enzymes, such as paraoxonase-1 (PON1), is limited.

On the basis of experimental data, PON1, a HDL-associated enzyme, is believed to protect against the development of atherosclerosis. PON1 has the ability to retard the oxidation of LDL by hydrolyzing LDL-associated oxidized phospholipids and cholesteryl-ester hydroperoxides and destroying the proinflammatory molecules involved in the initiation and progression of atherosclerotic lesions (3 –7 ). Serum levels of PON1 vary widely among individuals, but are relatively constant in an individual (8 ). Polymorphisms of the PON1 gene are at least partly responsible for the interindividual differences in enzyme activities (9 ). Because PON1 may play a central role in the development of atherosclerosis, studies concerning dietary modifications of serum PON1 activity in humans are warranted. The purpose of this study was to investigate the effect of diet on serum PON1 activity, and to examine the role of PON1 gene polymorphisms on responsiveness of PON1 activity to dietary manipulation.

	SUBJECTS AND METHODS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Subjects.

The study subjects were healthy, nonsmoking women working at the University Hospital of Oulu. A medical examination, screening laboratory tests and an interview by a dietitian were performed during the baseline period, and the subjects were considered eligible for inclusion in the study if they fulfilled the following criteria: 1) no gastrointestinal, renal or hepatic disease; 2) normal blood glucose and lipid concentrations; 3) body mass index (BMI) between 20 to 29 kg/m²; 4) no alcoholism; 5) not a current smoker; 6) no use of supplemental vitamins and/or minerals for at least 6 mo before the onset of the study; 7) no food allergy; and 8) not pregnant or lactating. Altogether 37 women were selected. Six women used oral contraceptives, and three were receiving postmenopausal estrogen/progestin supplementation. The study was carried out in accordance with the instructions of the Declaration of Helsinki. Informed consent was obtained from each participant. The study was approved by the Ethical Committee of the Faculty of Medicine, University of Oulu.

Study design.

This crossover dietary study consisted of a baseline period (2 wk) and of two intervention diet periods (5 wk each) with a washout period (3 wk) in between. During the baseline and washout periods, the women consumed their habitual diets. At the end of the baseline period, they were randomly assigned to two groups. Half of the women (n = 18) first consumed a low vegetable diet followed by a high vegetable diet, whereas the other half (n = 19) consumed the two intervention diets in reverse order.

Diets.

Both diets were designed on the basis of the regular hospital meals (a 5-wk menu) and contained conventional foods and beverages. The foods were prepared, packaged and delivered to the subjects by the hospital kitchen. During working days, the lunches and dinners were served at the hospital cafeteria. The participants could also take the dinner meals home. On weekends, the subjects consumed the lunches and dinners at the hospital cafeteria or took the weekend meals home on Friday.

Both study diets were energy-balanced and designed by a nutritionist to be low in dietary cholesterol (<200 mg/d) and saturated fat [10% of total energy (E%)]. During both diet periods, the quantity and quality of dietary fat was controlled by using low fat meat and dairy products, low fat cooking methods, and vegetable oil and margarine. Rapeseed and sunflower oils were used in the salad dressings during the low and high vegetable diet periods, respectively. Different soft, vegetable oil margarines were also used during the low and high vegetable diet periods. These fat and oil modifications resulted in differences in the dietary intake of vitamin E. The vegetable oil margarines contained no trans fatty acids.

The low vegetable diet contained one serving of both fresh vegetables and fresh fruit or fruit juice per day. During the high vegetable diet period, the intake of dietary antioxidants was increased by increasing the consumption of fresh vegetables, citrus fruits and berries to result in mean daily intakes of 430 mg of vitamin C, 18 mg of carotenoids, 17 mg of vitamin E and 600 µg of folate.

The same experienced dietitian (M.-L.S.) interviewed all study participants concerning their eating and exercise habits and determined an isocaloric energy intake level for each. During the intervention, the women were weighed daily before lunch, and their dietary energy intake was adjusted, when necessary, to maintain their body weights throughout the study. Alcohol consumption was estimated at the baseline by interviewing the subjects. The amount of alcohol consumed was negligible as assessed by the dietary records. The women were advised to restrict their use of alcohol to <4 drinks/wk during the study, and alcohol was therefore not included in the calculations of the nutrient contents of diets.

Laboratory methods.

Blood samples were drawn from the women into EDTA-containing tubes after overnight fasts for the measurement of plasma lipids and lipoproteins, carotenoids, tocopherols and vitamin C concentrations at baseline and at the end of each intervention period. All measurements were made on the same plasma sample each time. The plasma total, LDL and HDL cholesterol, and triacylglycerol concentrations were measured twice at the end of each diet period in samples obtained within a 1-wk interval. The means of these two samples are presented. The samples were assayed immediately or kept at -70°C until analysis.

To measure the plasma lipids and lipoproteins, plasma was separated by centrifugation at 1200 x g for 15 min (4°C). The plasma total cholesterol and triacylglycerol concentrations were determined using fresh plasma with enzymatic colorimetric methods (kits by Boehringer Mannheim, GmbH, Mannheim, Germany, cat. # 236691 and 701912, respectively) using a Gilford IMPACT 400E Clinical Chemistry Analyzer (Gilford Instruments, Oberlin, OH). The plasma HDL cholesterol concentration was determined after precipitation of the plasma with heparin-manganese chloride (10 ). The LDL cholesterol concentration was calculated according to the Friedewald formula (11 ). The concentration of apolipoprotein (apo)A-I was determined with the liquid-precipitate technique using the nephelometric method (Turbox-kit; Orion Diagnostica, Espoo, Finland). Tocopherols were analyzed using tocol as an internal standard and a Supelco (Bellefonte, PA) C18 column for separation. Carotenoids were analyzed using echinenone as an internal standard and a Waters (Millford, MS) Nova-Pak column for separation. Ascorbic acid was determined by an automated fluorometric method (12 ).

PON1 activity was measured in serum on the basis of its capacity to hydrolyze paraoxon. The formation of p-nitrophenol was monitored at 405 nm in Tris-HCl buffer, pH 8.0, in the presence of Ca²⁺ (13 ).

DNA was extracted from blood cells using standard procedures (14 ). PON1₅₅ and PON1₁₉₂ genotyping was performed using polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis as previously described (15 ) with slight modifications. Two sets of primers were designed to flank the polymorphic sites. The primers used for the amplification of the 169-bp DNA fragment for PON1₅₅ polymorphism were 5'-GAAGAGTGATGTTATAGCCCCAG-3' and 5'-ACTCACAGAGCTAATGAAAGCCA-3'. The 99-bp DNA fragment encompassing the PON1₁₉₂ polymorphism was obtained using the primers 5'-TATTGTTGCTGTGGGACCTGAG-3' and 5'-CACGCTAAACCCAAATACATCTC-3'. PCR mixture (25 µL) contained 10 mmol/L Tris-HCl, pH 8.3, 50 mmol/L KCL, 1.5 mmol/L MgCl₂, 0.05 mmol/L dNTP for the PON1₅₅ polymorphism and 0.4 mmol/L dNTP for the PON1₁₉₂ polymorphism, 0.25 µmol/L of each primer, 1 U of DyNAzyme II DNA polymerase (Finnzymes, Espoo, Finland) and 125 ng of DNA template. The PCR reaction for the amplification of both polymorphic regions was carried out with initial denaturation at 95°C for 5 min, followed by 35 cycles, each consisting of three 1-min steps: denaturation at 95°C, annealing at 61°C and extension at 72°C. The reaction was completed with a final extension at 72°C for 10 min. The PON1₅₅ (169-bp) PCR product was digested with 5 U of NlaIII (New England Biolabs, Beverley, MA) at 37°C for 3 h. Digestion resulted in 127- and 42-bp fragments for the PON1_{55 Met} (methionine) allele and a nondigested 169-bp fragment for the PON1_55Leu (leucine) allele. The PON1₁₉₂ (99-bp) PCR product was digested with 2 U of AlwI (New England Biolabs) at 37°C for 5 h. Digestion with AlwI resulted in 63- and 36-bp fragments for the PON1_192Arg (arginine) allele and a nondigested 99-bp fragment for the PON1_192Gln (glutamine) allele. The digested fragments were separated and visualized on a UV transilluminator after electrophoresis on a 5% low-melting-point agarose gel (4:1 NuSieve; BioWhittaker Molecular Applications, Rockland, ME) containing nucleic acid gel stain (GelStar; BioWhittaker).

Dietary analyses.

Four-day diet records were collected during the baseline diet period after the first visit to our laboratory, and their nutrient contents were calculated using the Nutrica software (Social Insurance Institution, Helsinki, Finland). The dietary intake during the intervention periods was analyzed (Agricultural Research Center of Finland, Jokioinen, Finland) from duplicate portions collected daily and pooled for each period. The nutrient analysis included total energy, total fat, carbohydrate, fiber, fatty acids, dietary cholesterol, potassium, calcium, iron, -carotene, ß-carotene, ascorbic acid and -tocopherol.

The fatty acid composition of the diets was analyzed by gas chromatography. The lipids of freeze-dried sample (1 g) were extracted using 30 mL of chloroform/methanol for 5 min in a magnetic stirrer. The sample was filtered through a separation funnel and 5 mL of water was added to the filtrate. The organic phase was separated and evaporated in a rotary evaporator. The sample was transferred to a test tube and the residual organic solvent was evaporated by a flow of nitrogen. Saponification of lipids was accomplished by 0.5 mol/L sodium hydroxide in methanol (85°C, 7 min). To the cooled sample, 2 mL of 10% boron trifluoride in methanol (Fluka, Milwaukee, WI) was added for preparing methyl esters of fatty acids. After incubation for 12 min at 85°C the cooled-down sample was extracted using 1 mL of hexane (16 ). Fatty acid methyl esters were analyzed by a Hewlett-Packard (Avondale, PA) 5890 series gas chromatograph equipped with a 5970 series mass selective detector used in scan mode. For quantification, relative response ratios of different fatty acids were determined using Nu-Chek Prep (Elysian, MN) standards GLC-68A and GLC-85. The analytical column used was a Hewlett-Packard HP-5MS (30 m x 0.25 mm) with helium as a carrier gas (0.5 mL/min). Other analytical conditions were as follows: injector 250°C, oven temperature program 110°C (1.5 min), 110–150°C (15°C/min), 150°C (0.5 min), 150–250°C (5 C°/min), 250°C (0.5 min), 250–290°C (15°C/min), transfer line 280°C, 1 µL injected in split less mode.

Statistical analyses.

Because only five women were homozygous for the mutation Gln Arg of the PON1₁₉₂, all of the women with the PON1_192Arg allele were treated as one group. Also, the women (n = 2) homozygous for the PON1_55Met allele were included with the women with the PON_55Leu/Met genotype for statistical analyses.

The distribution of variables was tested by the Saphiro-Wilk test. The differences in the plasma antioxidant concentrations after each of the intervention periods were tested by the Sign test (carotenoids) and Student’s t test for paired samples (-tocopherol and vitamin C). The plasma lipids (total cholesterol, HDL cholesterol, LDL cholesterol) and apoA-I differences within groups were tested by Student’s t test for paired samples and those between groups by Student’s t test for independent samples. Antioxidant and lipid concentrations are presented as means ± SD. For serum PON1 activity, the differences within groups were tested by the nonparametric Sign test and those between groups by the Mann-Whitney test. Serum PON1 activity is expressed as median (minimum, maximum). Because the change in the serum PON1 activity of each genotype was normally distributed, changes within genotypes are presented as means ± SD. Spearman correlation coefficients were determined to test associations between variables. Differences were considered significant at P < 0.05. The SPSS 8.0 software (SPSS, Chicago, IL) was used in the statistical analyses.

	RESULTS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
The PON1_{192 Arg} allele frequency was 0.37 and the PON1_{55 Met} allele frequency 0.32; the genotype distributions were not different from the Hardy-Weinberg prediction. The age of the women ranged from 22 to 57 y and their BMI from 20 to 29 kg/m², with means of 23.7, 23.2 and 23.3 kg/m² during the baseline, low vegetable diet and high vegetable diet periods, respectively. The genotype groups did not differ from one another in age or BMI (Table 1 ). Plasma lipid and lipoprotein concentrations also did not differ among the genotypes at baseline (Table 1) . The women with the PON1_192Arg allele had higher (P < 0.001) serum PON1 activity at baseline than those with the PON1_192Gln/Gln genotype (Table 1) . Also, women with the PON_55Leu/Leu genotype had a higher (P < 0.001) serum PON1 activity at the baseline than the than those with the PON1_55Met allele (Table 1) .

View this table: [in this window] [in a new window]   TABLE 3 Plasma concentrations of -carotene, ß-carotene, ß-cryptoxanthin, lutein + zeaxanthin, lycopene, vitamin C and -tocopherol of the women at baseline and after consumption of low and high vegetable diets

View larger version (14K): [in this window] [in a new window]   FIGURE 1 Plasma total, LDL, and HDL cholesterol (C) and apolipoprotein (apo)A-I concentrations of women who consumed low and high vegetable diets in a crossover design. Values are means ± SD, n = 37. *P < 0.01, **P < 0.001; different from the low vegetable diet period (paired t test).

View larger version (14K): [in this window] [in a new window]   FIGURE 2 Differences in paraoxonase 1 (PON1) activity between the low and high vegetable diet periods in women stratified by PON1192 and PON155 genotypes. Values are mean ± SD. PON1192Gln indicates glutamine and PON1192Arg, arginine, at position; 192 of the PON1 gene. PON155Leu indicates leucine and PON155Met, methionine, at position 55 of the PON1 gene. *P < 0.05, different from the PON1192Gln/Gln (Mann-Whitney test). P < 0.05, different from the PON1192Leu/Leu (Mann-Whitney test).

	DISCUSSION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

Oxidative modification of LDL is an important contributor to atherosclerosis (17 ,18 ). HDL can protect LDL from oxidative damage (19 ); the protective effect is related to PON1, a HDL-associated enzyme capable of hydrolyzing lipid peroxides and destroying proinflammatory molecules formed by the oxidation of LDL (20 ). In addition to PON1, two other members of the paraoxonase family, PON2 and PON3, have been identified. PON3 has been cloned and characterized recently (21 ), and it does not have activity against the synthetic substrate of PON1, namely, paraoxon. In experimental studies, PON1 has been considered antiatherogenic (7 ,13 ,22 –24 ). Some epidemiologic studies have shown an association between reduced serum PON1 activity and an increased risk for atherosclerosis (25 –28 ). Whether low serum PON1 activity in humans is causative of the development of atherosclerosis or is associated with other risk factors for atherosclerotic disease warrants future studies. For example, reduced serum PON1 activity and an increased CHD risk may both be related to the atherosclerosis-promoting abnormalities of lipid metabolism. More interestingly, some environmental factors, such as dietary habits, may regulate PON1 activity and explain at least in part the reduced PON1 activities among CHD patients. Thus, the effect of diet on PON1 activity should be clarified.

The effect of dietary modifications on serum PON1 activity has been studied in laboratory animals. An atherogenic diet reduced PON1 activity in mice (3 ,23 ), rabbits (29 , 30 ) and rats (31 ) and the diet-induced reduction of PON1 activity correlated with the reduction of plasma HDL cholesterol and apoA-I concentrations. To our knowledge, data from only a few human intervention studies are available. Pomegranate juice supplementation to the habitual diets of 13 healthy men increased their serum PON1 activity by 20% (32 ). Serum PON1 activity increased and lipid peroxidation decreased in three subjects, although their plasma lipids and lipoproteins did not change significantly (32 ). In another study, 3 wk of daily moderate alcohol consumption increased serum PON1 activity (33 ), and that increase correlated strongly with the coincident increases of the plasma HDL cholesterol and apoA-I concentrations. Also, in the present study, the reduction of serum PON1 activity correlated with the reduction of the plasma HDL cholesterol concentration.

The intakes of total fat, protein and carbohydrate were essentially the same during the low vegetable and high vegetable diet periods. However, the quality of dietary fat was somewhat different because the oils and margarines were changed to alter the dietary intake of vitamin E. The high vegetable diet contained 3 E% more PUFA than the low vegetable diet. Large amounts of dietary PUFA lower the plasma HDL cholesterol concentration and, furthermore, may increase the oxidizability of lipoproteins and potentially exacerbate atherogenesis (34 ). However, in the present study, the small increase in PUFA intake in the high vegetable diet is unlikely to explain the decreased plasma HDL cholesterol concentration. More likely, the higher intake of dietary fiber (40 g/d) in the high vegetable diet decreased the plasma total and HDL cholesterol concentrations (35 ). Whether the reduction in HDL cholesterol associated with the reduction of PON1 activity has clinical importance in the development of atherosclerosis among humans has to be confirmed in future studies.

In a recently published study (36 ), low serum PON1 activity was reported to be associated with a high intake of vegetables, i.e., a dietary pattern commonly regarded as an indicator of a "healthy" diet. In that study, the serum PON1 activity was especially low in the highest vegetable intake quartile and the negative correlation between the intake of vegetables and the serum PON1 activity was particularly strong among women (36 ). In our study, the high vegetable diet containing large amounts of vegetables, fruit and berries decreased serum PON1 activity. Thus, the findings of the correlation study (36 ) and our intervention study are similar.

The mechanism by which diet can modify PON1 activity has been studied in animal models. The altered synthesis, secretion or clearance of HDL cholesterol induced by dietary fatty acids explains at least in part the change in serum PON activity (23 , 30 ,31 ). Also, an immune mechanism has been proposed to explain diet-induced changes in PON1 activity (3 ). However, diet-induced changes are not regulated by altered gene transcription because the gene expressions of PON1 and apoA-I are unaffected (3 ). The reduced oxidative stress after dietary modification (32 ), antioxidant supplementation (37 ), moderate alcohol intake (33 ) or drug treatment (38 ) may preserve or even increase PON1 activity.

The physiologic substrate of PON1 in humans is unknown. The ability of different alloenzymes to hydrolyze nonphysiologic substrates, such as paraoxon, varies. PON1_192Arg and PON1_55Leu hydrolyze paraoxon faster than PON1_192Gln and PON1_55Met (9 ,39 ). Alleles with high enzyme activity are associated with an impaired capacity of HDL to protect LDL from oxidative modification (40 ) and an increased risk of cardiovascular diseases (20 ). The treatment-induced increase in PON1 activity in patients with familial hypercholesterolemia was independent of PON1 polymorphisms (38 ). In our study, the alleles associated with high enzyme activity also were associated with a more extensive reduction in serum PON1 activity, a finding that supports the hypothesis that the PON1 gene polymorphism is one additional factor to help explain gene-diet interaction in atherosclerosis.

In conclusion, dietary modifications alter serum PON1 activity and the response to dietary modification may be genetically regulated. The role of HDL cholesterol metabolism and possibly also apoA-I seems to be important in the dietary regulation of serum PON activity. We should therefore explore in more detail the potential importance of the relationship between PON1 activity and diet for the development of atherosclerosis to be able to give more specific dietary recommendations.

	ACKNOWLEDGMENTS

 
The authors thank Saija Kortetjärvi, Liisa Mannermaa, Sirpa Rannikko and Eila Saarikoski for skillful laboratory assistance during the study.

	FOOTNOTES

 
¹ Supported in part by the Research Council for Health of the Academy of Finland and the Finnish Foundation for Cardiovascular Research.

³ Abbreviations used: apo, apolipoprotein; BMI, body mass index; CHD, coronary heart disease; E%, percentage of total energy; PCR, polymerase chain reaction; PON1, paraoxonase-1; PUFA, polyunsaturated fatty acids.

Manuscript received 25 March 2002. Initial review completed 25 April 2002. Revision accepted 14 June 2002.

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