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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:3565-3569.)
© 1997 American Heart Association, Inc.

Articles

A ¹⁹²Arg Variant of the Human Paraoxonase (HUMPONA) Gene Polymorphism Is Associated With an Increased Risk for Coronary Artery Disease in the Japanese

Takeru Zama; Mitsuru Murata; Yumiko Matsubara; Koichi Kawano; Nobuo Aoki; Hideaki Yoshino; Gentaro Watanabe; Kyozo Ishikawa; ; Yasuo Ikeda

From the Department of Medicine, School of Medicine, Keio University, the Second Department of Medicine, Kyorin University (K.K., N.A., H.Y., K.I.), and Hibiya Medical Center, Sakura Bank (G.W.), Tokyo, Japan.

Correspondence to Mitsuru Murata, MD, Department of Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160, Japan. E-mail murata{at}mc.med.keio.ac.jp

	Abstract

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Abstract Recent reports have suggested that polymorphisms in the human paraoxonase (HUMPONA) gene may be a genetic risk factor for coronary artery disease (CAD) in white populations. However, this association has not yet been confirmed in other ethnic populations. We studied 75 Japanese patients with CAD, whose coronary lesions were confirmed by angiography, and 115 Japanese control subjects with no history of CAD and a normal resting electrocardiogram. The assays for genotyping the two polymorphisms in the HUMPONA gene (¹⁹²Arg/Gln and ⁵⁵Leu/Met) were based on changes in restriction enzyme digestion patterns. For codon 192, the frequencies of the Arg-coding allele (B allele) in both patients and control subjects were much higher than those from published results of whites (.26 to .31), and the difference between patients (.74) and control subjects (.59) was statistically significant (P=.002). The patient group had a higher proportion of Arg/Arg (B/B) homozygotes (52.0% vs 32.2%, P=.006). For codon 55, the frequencies of the Leu-coding allele in control subjects and patients were much higher (.91 and .93, respectively) than those published results for whites, but there was no difference between Japanese control subjects and Japanese patients. When subjects with the ⁵⁵Leu/Leu genotype only were analyzed, ¹⁹²Arg/Arg homozygotes were still significantly more frequent in the patients than in the control subjects (55.4% vs 37.2%, P=.024), and the frequency of the ¹⁹²Arg allele was also higher in patients than control subjects (P=.013). Logistic regression analysis including conventional coronary risk factors revealed that ¹⁹²Arg is an independent risk factor for CAD. Thus, in the Japanese, the association of CAD with the ¹⁹²Arg variant of HUMPONA (B-type enzyme) is similar to that reported for whites, although the allele frequencies for ¹⁹²Arg and ⁵⁵Leu are much higher in the former than the latter population.

Key Words: paraoxonase • coronary artery disease • genetics • angiography • risk factors

	Introduction

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Human paraoxonase is an HDL-associated enzyme that hydrolyzes some products of lipid peroxidation.¹ This enzyme has been shown to prevent LDL from oxidation in vitro,^{2 3 4} although no physiological substrate has been identified to date. The cDNA for HUMPONA has been cloned⁵ and the two polymorphic sites in the HUMPONA gene locus elucidated: one at codon 192 (G/A) and the other at codon 55 (T/A).^{6 7 8} (These sites are identical to positions 191 and 54, respectively, according to the numbering system of Adkins et al.⁸ ) There is a 10- to 40-fold difference in serum HUMPONA activity among individuals,^{6 9} as assessed by the enzyme's ability to hydrolyze exogenous, nonphysiological substrates. This difference is attributed to the presence of polymorphisms in the gene encoding HUMPONA.^{6 7 8}

The first polymorphism is an amino acid dimorphism (Gln/Arg) at position 192 (identical to the A and B polymorphisms used by other authors^{10 11 12 13} ), which has been shown to be involved in the development of CAD. The frequency of the G allele (the Arg-coding, or B, allele) was significantly higher in patients than in control subjects.^{10 11} In the French white NIDDM population, the frequencies of the Arg-coding allele in CAD patients and control subjects were .35 and .26, respectively,¹⁰ and in the US population, .44 and .31, respectively.¹¹ However, another study in the Finnish population failed to show any correlation between the ¹⁹²Arg/Gln polymorphism and CAD.¹²

The second polymorphism in HUMPONA involves a T/A transversion at codon 55, resulting in an Leu/Met amino acid substitution.^{6 7} In a recent study, Garin et al¹³ have suggested that the ⁵⁵Leu/Met polymorphism is responsible for the variation in plasma paraoxonase concentrations and that homozygosity for the Leu-encoding allele is an independent risk factor for CAD in NIDDM patients. In those studies, however, all of the subjects studied were white. Because allele frequencies might differ significantly between races and CAD occur under different environmental conditions, we performed an allelic-association study to investigate the correlation of the two polymorphisms (¹⁹²Arg/Gln and ⁵⁵Leu/Met) with the incidence of CAD in the Japanese population.

	Methods

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Study Population, Evaluation of CAD, and Lipid Measurements
The subjects in this study were all genetically unrelated Japanese and consisted of 115 control subjects and 75 patients with CAD (22 with angina pectoris and 53 with myocardial infarction). Mean age was 48.3±6.3 years for control subjects and 62.6±9.7 years for patients with CAD. The control subjects were all healthy volunteers with no history of CAD and a normal resting electrocardiogram. The patients were identified from the discharge records of Kyorin University Hospital in Tokyo, Japan. The qualifying conditions for entry into the study as a CAD patient were (1) admission for treatment of myocardial infarction or unstable angina, percutaneous transluminal coronary angioplasty, or coronary artery bypass graft or (2) stable angina with angiographic evidence of CAD. All patients (with both angina and myocardial infarction) had coronary artery lesions, as confirmed by angiography. A transluminal narrowing of 50% was defined as significant. The severity of CAD was determined by the number of coronary arteries 50% luminal diameter stenosis. Information on a variety of characteristics relevant to the assessment of conventional coronary risk factors, including diabetes mellitus, hypertension, cigarette smoking, body weight, height, hypercholesterolemia, and family history of CAD, was obtained from all subjects or their medical records. All subjects enrolled in the present study gave informed consent. Serum lipid levels were measured by automated enzymatic methods using an automatic analyzer (Hitachi 7450). The reagents used were Determiner L TG (lipoprotein lipase method, Kyowa Medex) for triglyceride, L Type Total Cholesterol (cholesterol oxidase method, Wako Chemicals) for total cholesterol, and Determiner L HDL-C (direct measurement with polyethylene glycol–modified enzymes, Kyowa Medex) for HDL cholesterol.

Genotyping
Blood was obtained from the peripheral veins of control subjects and patients after their informed consent was obtained. Genomic DNA was extracted from peripheral blood leukocytes as described.¹⁴ The assays for genotyping the two polymorphisms were based on changes in restriction enzyme digestion patterns as described by Humbert et al,⁶ with minor modifications. To examine the variants, two sets of primers were designed to encompass the polymorphic regions in the HUMPONA gene. All primers were used at a concentration of 0.5 µmol/L. For genotyping the ¹⁹²Arg/Gln polymorphism, an initial incubation of 5 minutes at 94°C preceded amplification of genomic DNA in the PCR by using a DNA thermal cycler (Perkin Elmer, Takara Biomedicals). Primers for amplification of a 99-bp DNA that contains the coding sequence for position 192 were 5'TATTGTTGCTGTGGGACCTGAG3' and 5'CACGCTAAACCCAAATACATCTC3'. PCR was carried out for 40 cycles, with each cycle consisting of 60 seconds of denaturation at 94°C, 45 seconds of annealing at 56°C, and 45 seconds of extension at 72°C. PCR products were digested with 8 U of Alw I for 3 hours at 37°C. The digested products were then subjected to 3.0% agarose gel electrophoresis and visualized with ethidium bromide staining. Two fragments, of 63 and 36 bp, were expected from the digested PCR products from an Arg-coding allele (one cutting site), whereas one 99-bp fragment from a Gln-coding allele (no cutting site) was anticipated. For genotyping the ⁵⁵Leu/Met polymorphism, PCR was carried out under the same conditions used above. Primers for amplification of 170-bp DNA containing a sequence encoding codon 55 were 5'GAAGAGTGATGTATAGCCCCA3' and 5'TTTAATCCAGAGCTAATGAAAGCC3'. PCR products were then digested with 3 U of Nla III for 3 hours at 37°C, and the digestion products were subjected to 3.0% agarose gel electrophoresis and visualized with ethidium bromide staining. The allele containing ⁵⁵Met was identified when the PCR products were digested with Nla III into two fragments of 126 and 42 bp, whereas the allele coding for ⁵⁵Leu was identified when the PCR products were not digested with Nla III.

Statistical Analysis
The size of the sample was established on the basis of our pilot studies which had indicated that the allele frequencies for ¹⁹²Arg would be .60 for control subjects and .75 for CAD patients. Thus, we set at 150 the number of alleles (number of subjects=75) required to detect a difference between the two groups, with a power (P)=.8 and a significance level (chance of a two-sided error)=.05. Age, BMI, and serum lipid levels were compared between the control subjects and patients by Student's t test. Statistical analyses of frequency counts were performed with use of the ² test or Fisher's exact test for small samples. Age, BMI, and serum lipid levels in CAD patients were compared between HUMPONA genotypes by ANOVA. A value of P<.05 was considered statistically significant. Logistic regression analysis was performed to evaluate the interaction between the HUMPONA ¹⁹²Arg/Gln genotypes and other variables in relation to the prevalence of CAD. Independent variables included in the analysis were age (quantitative); sex (male or female); ⁵⁵Leu/Met genotypes; smoking (yes or no); hypertension (yes or no); diabetes mellitus (yes or no); and serum levels of cholesterol (quantitative), triglyceride (quantitative), and HDL cholesterol (quantitative). The analysis was executed by the SAS statistical program version 6.10 for Macintosh.

	Results

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Study Populations, Lipid Measurements, and Conventional Risk Factors of Patients and Control Subjects
Table 1 shows age, BMI, lipid measurements, and conventional risk factors of the patient and control groups. Patients with CAD were older and had lower values of HDL cholesterol than the control subjects. There were no significant differences between the two groups with respect to BMI, total cholesterol and triglyceride levels, and smoking. The patient group had higher frequencies of hypertension and diabetes mellitus.

View this table: [in this window] [in a new window]   Table 1. Characteristics of Patients With CAD and of Control Subjects

Genotype Distribution and Allele Frequencies of the HUMPONA Gene in Patients With CAD and Control Subjects
The distributions of the two polymorphisms of the HUMPONA gene (⁵⁵Leu/Met and ¹⁹²Arg/Gln) among patients and control subjects are shown in Table 2. For codon 55, the frequency of the Leu-coding allele in 115 Japanese control subjects was .91, which is significantly higher than that reported in whites.⁶ There were no subjects with the Met/Met genotype in our study groups. The genotype distribution (P=.369) and allele frequencies (P=.391) were not significantly different between patients with CAD and control subjects. For codon 192, the Arg/Arg genotype was the most common in patients with CAD (39/75). In contrast, the Arg/Gln genotype was the most frequent in the control group (61/115). The Gln/Gln genotype was the rarest in both patients (3/75) and control subjects (17/115). The difference in genotype distribution between patients and control subjects was statistically significant, with Arg/Arg homozygosity being more frequent in patients (52.0%) than control subjects (32.2%, P=.006). The frequency of the G allele (¹⁹²Arg-coding allele) in the healthy control group (.59) was about twice as high as that reported in healthy white populations (.26 to .31).^{11 12} The difference in frequency of the G allele between patients (.74) and control subjects (.59) was statistically significant (P=.002). Because it has recently been shown that the ⁵⁵Leu/Met polymorphism is responsible for the variation in paraoxonase activity and its concentration in plasma and that in NIDDM patients, homozygosity for the Leu allele is an independent risk factor for the development of CAD,¹³ we next analyzed the effect of the ¹⁹²Arg/Gln polymorphism in subjects having the same genotype for codon 55. As shown in Table 2, when ⁵⁵Leu/Leu subjects only were compared, there was still a significant difference in the proportion of ¹⁹²Arg/Arg homozygotes between patients (55.4%) and control subjects (37.2%, P=.024). Also, the difference in allele frequency between patients (.75) and control subjects (.62) was statistically significant (P=.013).

View this table: [in this window] [in a new window]   Table 2. Distributions of the Two Polymorphisms (55Leu/Met and 192Arg/Gln) in the HUMPONA Gene in CAD Patients and Control Subjects

Association of the HUMPONA codon 192 polymorphism with CAD, standardized for age; sex; codon 55 polymorphism; and other coronary risk factors including smoking, hypertension, diabetes mellitus, and serum levels of cholesterol, triglyceride, and HDL cholesterol was analyzed by a logistic regression model. This model provided an OR of 3.02 (95% CI, 1.02 to 8.98; P<.05) for the relation between CAD and codon 192 polymorphism adjusted for all other variables, suggesting that the HUMPONA codon 192 polymorphism is an independent risk factor for CAD (not shown in tables). On the other hand, the ⁵⁵Leu/Met polymorphism was not statistically significant in relation to CAD in this model (OR=0.84; 95% CI, 0.17 to 5.75; P=.858). Other variables shown to be significant (P<.05) in this model were age (OR=1.23), smoking (OR=4.08), hypertension (OR=11.1), and diabetes (OR=6.49). Sex and serum levels of cholesterol, triglyceride, and HDL cholesterol were not significantly associated with CAD.

Relationship Between the HUMPONA ¹⁹²Arg/Gln Polymorphism and Cholesterol Levels, Subtypes, and Severity of CAD
Table 3 shows characteristics of the patients with CAD according to HUMPONA (¹⁹²Arg/Gln) genotype. Patients with the ¹⁹²Arg/Arg were younger (P=.035), but there was no statistically significant difference in mean BMI, total cholesterol levels, HDL cholesterol levels, triglycerides, or types of CAD (angina or myocardial infarction) between genotypes of CAD patients. When comparisons were made on the basis of the number of affected vessels, there was no statistically significant difference in genotype distribution or allele frequency of the ¹⁹²Arg/Gln polymorphism (Table 4).

View this table: [in this window] [in a new window]   Table 3. Baseline Characteristics of Patients With CAD, According to HUMPONA Genotype (192Arg/Gln)

View this table: [in this window] [in a new window]   Table 4. Relationships Between the Number of Affected Coronary Arteries and HUMPONA Genotypes

	Discussion

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Genetic factors in combination with a number of environmental risk factors are involved in a predisposition to CAD. The susceptibility to CAD is a complex trait,^{15 16} and recently one ¹⁹²Arg variant (B type) of the HUMPONA gene has been reported to be associated with the incidence of CAD in the French¹⁰ and US¹¹ populations of whites. However, another study in the Finnish population failed to show any correlation between this variant and CAD.¹² Moreover, a recent study has demonstrated a race-specific association between CAD and the ¹⁹²Arg variant of paraoxonase in Asian Indians but not in Chinese living in Singapore.¹⁷ Because allele frequencies might differ significantly between races, we performed an allelic-association study to confirm these findings in Japan, where the population is ethnically homogeneous and mostly of Mongolian origin.

In the present study, the two HUMPONA genotypes were determined in 115 control subjects and 75 patients with CAD confirmed by angiography. The evidence available indicated that for codon 192, the frequency of the Arg-coding allele was much higher in the Japanese population than that in whites,^{10 11 12} and that the ¹⁹²Arg variant was independently associated with an increased risk for CAD. In the Finnish study,¹² although the control individuals had no symptoms of CAD or any other disease, the mean ages of the men and women in the group were 37 and 36 years, respectively. Therefore, if one assumes that Finland has one of the highest mortality rates for CAD in the world among middle-aged populations,¹⁸ then it is possible that the control group contained some individuals who may have had CAD. This might account for a negative association. Also, differences in the criteria used to select the patients may explain the discrepancy among the three studies, two of which show a positive association^{10 11} and one, a negative association.¹² In the study by Ruiz et al,¹⁰ the subjects with CAD were all NIDDM patients, whereas in the Finnish study by Antikainen et al,¹² subjects with a history of diabetes, current regular smoking, and dyslipidemia were excluded. Furthermore, whereas in the studies by Ruiz et al¹⁰ and Serrato and Marian,¹¹ males accounted for 79% and 71%, respectively, of the patient group, in the Finnish study all of the patients with CAD were male.^{12 19} In our study, 57 patients with CAD (76%) and 104 subjects in the control group (90%) were male. Twenty-six of 75 (35%) total patients with CAD had a history of diabetes. It should also be borne in mind that all of these studies were case-control in design and therefore that survival bias cannot be ruled out.

The mechanism underlying the association between HUMPONA genotype and CAD has so far remained elusive. Humbert et al⁶ and Adkins et al⁸ originally elucidated the two polymorphic sites in the HUMPONA gene locus. Only the ¹⁹²Arg/Gln polymorphism determined the activity of paraoxonase with paraoxon as an exogenous substrate, but there was no difference in enzyme activity toward other substrates such as phenylacetate or chlorpyrifos oxon.^{20 21 22} Paraoxonase activity toward the substrate paraoxon is higher with the enzyme containing ¹⁹²Arg (B type enzyme),²³ although current epidemiological evidence, including the present study, has suggested that paraoxonase with ¹⁹²Arg is a genetic risk factor for CAD. The paradox may be explained by the recent finding that the ¹⁹²Arg isozyme is less active against certain substrates, and when directly tested in vitro, HDL isolated from plasma from subjects with the ¹⁹²Arg polymorphism protected LDL from lipid peroxidation less effectively than did HDL from those with the ¹⁹²Gln polymorphism.²⁴

The present study showed a significant association between one variant of the HUMPONA gene (¹⁹²Arg) and the prevalence of CAD. On the contrary, we failed to detect any association between CAD and the ⁵⁵Leu/Met polymorphism, which was recently shown to be associated with the plasma concentration of paraoxonase and the development of CAD in NIDDM patients.¹³ One explanation for the discrepancy is the different allele frequencies between whites and Japanese. The Japanese have a much higher frequency of the ⁵⁵Leu allele than whites (91% for control subjects and 93% for CAD patients compared with 63% for the total study group in the published results on whites¹³ ). It is likely that in the Japanese, the ⁵⁵Leu-containing allele is too frequent to become a genetic risk factor. On the other hand, we have found an association between the ¹⁹²Arg/Gln polymorphism and CAD, even when only individuals homozygous for ⁵⁵Leu/Leu were analyzed. Thus, although the ⁵⁵Leu/Met polymorphism would be of central importance to paraoxonase activity and linkage disequilibrium has been shown to exist between the ⁵⁵Leu/Met and ¹⁹²Arg/Gln polymorphisms,¹³ these mechanisms do not explain the association between ¹⁹²Arg and CAD observed in the present study.

In conclusion, we have examined the association of the HUMPONA genotypes with CAD in the Japanese population and have found a significant association between the ¹⁹²Arg variant and CAD. Although HUMPONA is known to have the capacity to prevent LDL from oxidation in studies in vitro,^{2 3 4 25} the physiological relevance and natural substrate of this enzyme have not been identified to date. Further studies are needed to identify the molecular mechanisms relevant to the association between the HUMPONA gene and susceptibility to CAD.

	Acknowledgments

 
The authors wish to thank Kanako Yagi for her excellent technical assistance.

Received May 2, 1997; accepted September 2, 1997.

	References

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