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(Stroke. 1997;28:2417-2420.)
© 1997 American Heart Association, Inc.

Articles

A Mutation in Plasma Platelet-Activating Factor Acetylhydrolase (Val²⁷⁹Phe) is a Genetic Risk Factor for Stroke

Makoto Hiramoto, MD; Hidemi Yoshida, PhD; Tadaatsu Imaizumi, MD; Nobuhiro Yoshimizu, MD; Kei Satoh, MD

From the Department of Pathological Physiology (M.H., H.Y., T.I., K.S.), Institute of Neurological Diseases, Hirosaki University School of Medicine, Hirosaki, Japan, and the Department of Neurosurgery (N.Y.), the Yokohama General Hospital, Yokohama, Japan.

Correspondence to Kei Satoh, MD, Department of Pathological Physiology, Institute of Neurological Diseases, Hirosaki University School of Medicine, 5-Zaifucho, Hirosaki 036, Japan. E-mail pathophy{at}cc.hirosaki-u.ac.jp

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Platelet-activating factor (PAF) is a phospholipid with multiple actions that include thrombosis and inflammation. It is inactivated by a plasma enzyme, PAF acetylhydrolase. Deficiency of this enzyme in plasma is caused by a missense mutation in the gene (Val²⁷⁹Phe). We have studied a possible association of this mutation with the risk of stroke.

Subjects and Methods We studied 120 consecutive patients with cerebral thrombosis. The control group consisted of 134 patients matched for age and sex with minor complaints but without stroke. Genomic DNA was analyzed for the mutant allele by a specific polymerase-chain reaction. Plasma PAF acetylhydrolase activity was determined by the method of Stafforini et al.

Results The prevalence of the mutant gene was 43.4% in stroke patients (39.2% heterozygotes and 4.2% homozygotes), which was significantly higher than the 25.4% in control subjects (22.4% heterozygotes and 3.0% homozygotes) (²=9.22, P<.01). The prevalence was slightly higher in stroke patients without hypertension than those with hypertension, but the difference was not significant. The patients with family histories of stroke had a slightly higher but not a significant prevalence of the mutant gene as compared with those without family histories of stroke. Plasma PAF acetylhydrolase activity was higher in patients than in control subjects, in normal subjects, or patients with a heterozygous genotype.

Conclusions These results suggest that plasma PAF acetylhydrolase deficiency may be a risk factor for stroke. This may explain the relatively high prevalence of stroke in Japan, as the mutation is more common among Japanese than Caucasians.

Key Words: cerebral thrombosis • platelet-activating factor • mutation • risk factors

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Platelet-activating factor (PAF) is a phospholipid with the molecular structure of 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine. It has a wide variety of activities and has been implicated in many diseases.¹ PAF is inactivated by the enzyme PAF acetylhydrolase, which removes the sn-2 acetyl group. Deficiency of this enzyme was described first by Miwa et al,² who have shown a higher prevalence of inherited deficiency of plasma PAF acetylhydrolase among children with bronchial asthma than among less severe patients or normal subjects. Stafforini et al³ have identified recently a point mutation in the gene as the cause of this abnormality. They have analyzed blood samples from 1000 Japanese^{3 4} and found the same mutation in 4% of the subjects who completely lacked the enzyme activity in the plasma. Although the clinical significance of this mutation was not clear in these studies, the complete absence of plasma PAF acetylhydrolase may be associated with a risk for certain diseases in which PAF is involved. Studies to the present indicate that the mutation does not seem to occur in Caucasians.³ We studied the possible association of plasma PAF acetylhydrolase deficiency with stroke, which is the second most common cause of mortality in Japan. In our previous studies,^{5 6 7} we found that plasma PAF acetylhydrolase activity is higher than normal in patients with hypertension or ischemic stroke; this was considered to result from the enhanced PAF generation in these abnormalities and the subsequent induction of the enzyme.⁸ The inability of deficient subjects to respond properly to PAF generation may result in a higher risk for the occurrence of vascular complications in hypertension. This hypothesis was addressed by analyzing the incidence of the gene for PAF acetylhydrolase deficiency in patients with stroke in which hypertension was the most important risk factor. Age and arterial hypertension are major risk factors for stroke⁹ ; stroke, however, is a multifactorial disorder, and a detailed understanding of its cause is important, particularly for societies like those of Japan in which the management of hypertension is established and population aging is proceeding rapidly.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects
We studied 120 consecutive patients with cerebral thrombosis (average age, 64±11 years), who were admitted to the Yokohama General Hospital from March 1995 to October 1996. A computed tomography scan was performed in all patients. The type of stroke was determined according to the Classification of Cerebrovascular Diseases III,¹⁰ and patients diagnosed as having cardiogenic embolic stroke were excluded from this study. Eighty-eight patients were regarded as hypertensive either because of their histories of hypertension before the stroke or because hypertension was observed 2 months after the stroke. Fifty-seven patients had hyperlipidemia (plasma total cholesterol 220 mg/100 mL and/or triglyceride 150 mg/100 mL). Coronary heart disease (myocardial infarction or angina pectoris) was present in 7 patients and diabetes mellitus in 2 patients. Reliable family histories were available in 80 patients; 43 of the patients had family histories of stroke among their relatives in the first generation. The control subjects consisted of 134 individuals selected from those patients with minor complaints who visited the same hospital during the same period. The average age of the control group was 64±10 years old. They were free of abnormalities in physical findings, blood-screening tests, ECG, and chest x-rays. Fasting blood samples were obtained with EDTA-2Na as an anticoagulant, and plasma and blood cells were stored separately at -80°C. Informed consent was obtained from all subjects.

Genotype Determination
Total blood genomic DNA was extracted and amplified with a single-tube PCR kit (Takara Biomedicals). The PCR reactions were performed essentially as described previously³ with three different sets of the sense A and antisense primers B, C, or D as follows:

Sense primer A, 5'-CTATAAATTTATATCATGCTT-3'

Antisense primer B, 5'-TTTACTATTCTCTTGCTTTAC-3'

Antisense primer C, 5'-TCACTAAGAGTCTGAATAAC-3'

Antisense primer D, 5'-TCACTAAGAGTCTGAATAAA-3'

The PCR products were analyzed by electrophoresis on a 3% NuSieve® agarose (FMC BioProducts). The set of primers A and B amplifies the entire exon 9 of the PAF acetylhydrolase gene, a positive control for the PCR reaction. The primer sets A and C are specific for the normal allele, and primers A and D are specific for the mutant allele.

Mae II Studies
In 50 cases selected randomly, the genotype for PAF acetylhydrolase was confirmed also by the digestion of PCR products with the restriction endonuclease Mae II (Boehringer Mannheim). The products amplified with the sense primer A and antisense primer B were subjected to Mae II digestion as described previously.³ The digestion products were analyzed by electrophoresis in a similar manner.

Assay for PAF Acetylhydrolase Activity
Plasma PAF acetylhydrolase activity was determined as described by Stafforini et al.¹¹

Statistics
Data are expressed in terms of mean±SD, and statistical analysis was performed by the ² test and the Mann-Whitney U-test. The frequencies of the mutant allele were compared by calculating odds ratio. All probability values were based on two-tailed tests.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Representative cases with three different genotypes, as determined by specific amplification of the mutant allele, are shown in Fig 1. In all of the 50 samples selected randomly, the genotypes determined by this technique agreed completely with those determined by Mae II digestion. Representative patterns in the Mae II digestion study are shown in Fig 2.

View larger version (83K): [in this window] [in a new window]   Figure 1. Plasma PAF acetylhydrolase genotyping by allele-specific amplification. M indicates molecular markers. Lanes 1 to 3; entire exon 9 (lane 1), amplified fragment of normal allele (lane 2), and fragment of mutant allele (lane 3) of normal genotype. Lanes 4 to 5; exon 9 (lane 4), normal allele (lane 5), and mutant allele (lane 6) of a heterozygote. Lanes 7 to 9; exon 9 (lane 7), normal allele (lane 8), and mutant allele (lane 9) of a homozygote. Normal type lacks the mutant allele (lane 3) and homozygous type lacks the normal allele (lane 8).

View larger version (94K): [in this window] [in a new window]   Figure 2. Plasma PAF acetylhydrolase genotype determined by Mae II digestion. M indicates molecular markers. Lanes 1 and 2; normal genotype before (lane 1) and after (lane 2) Mae II digestion. Lanes 3 and 4; a heterozygote before (lane 3) and after (lane 4) digestion. Lanes 5 and 6; a homozygote before (lane 5) and after (lane 6) digestion. Note that in a heterozygote normal allele, digested fragments with molecular size of 95 and 82 bp are detected after Mae II digestion (lane 4). In a homozygote only two digested fragments are present (lane 6).

The prevalence of the mutant gene for PAF acetylhydrolase deficiency in stroke patients and control subjects are summarized in Table 1. The prevalence of the mutant gene in control subjects was approximately the same among Japanese subjects as reported previously.³ The prevalence was significantly higher in stroke patients as compared with the control group (²=9.22, P<.01). Frequency of the mutant allele in patients was 23.8%, which was significantly higher than the 14.2% in control subjects (²=7.63, P<.01, odds ratio=1.89, P<.01).

Table 2 summarizes the prevalence of PAF acetylhydrolase deficiency in stroke patients when they were divided according to the presence or absence of hypertension, hyperlipidemia, or a family history of stroke. The prevalence of PAF acetylhydrolase deficiency or the frequency of the mutant gene was slightly higher in those patients without hypertension compared with those with hypertension; the difference, however, was not statistically significant. Similarly, the prevalence of PAF acetylhydrolase deficiency and the frequency of the mutant gene were higher in patients with a family history of stroke than those without such a history, but there was no statistical significance. The presence of hyperlipidemia did not affect the prevalence of PAF acetylhydrolase deficiency.

View this table: [in this window] [in a new window]   Table 2. Plasma PAF Acetylhydrolase Genotypes and Alleles in Stroke Patients With Other Risk Factors

The average values of plasma PAF acetylhydrolase activity in each group are shown in Table 3. Plasma PAF acetylhydrolase activity was significantly higher in stroke patients than in control subjects; this was true in both normal and heterozygous genotype subgroups (P<.01 and P<.05, respectively; based on Mann-Whitney U-test). PAF acetylhydrolase activity was virtually absent in plasma from homozygous patients and control subjects.

View this table: [in this window] [in a new window]   Table 3. Plasma PAF Acetylhydrolase Activity and Genotype

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
PAF has been regarded as a chemical mediator of many pathological conditions that include inflammation and thrombosis.¹ PAF is inactivated by the hydrolytic removal of the sn-2 acetyl group, and this reaction has been shown to control inflammatory reactions in experimental animals.^{12 13} In our previous studies, we showed that plasma PAF acetylhydrolase activity is higher in patients with stroke^{5 6} or hypertension.⁷ This was attributed to the increased PAF generation in these disorders because the production of this enzyme by hepatic cells is enhanced in response to the stimulation with PAF.⁸ Lower plasma PAF acetylhydrolase activity has been observed in patients with systemic lupus erythematosus,¹⁴ severe coronary heart disease,^{15 16} and sepsis^{17 18} ; PAF therefore may play an important role in these diseases. The higher risk for stroke in PAF acetylhydrolase deficiency could be caused by the high prevalence of the mutation in hypertensive patients. This, however, is unlikely because the frequency of the mutant allele among the stroke patients with hypertension was lower than those without hypertension. Also, PAF is a hypotensive factor,¹⁹ and our previous study showed higher plasma PAF acetylhydrolase activity in patients with hypertension.⁷

PAF acetylhydrolase deficiency could contribute to stroke in several ways. In addition to causing the activation of platelets and leukocytes, PAF is vasoactive and therefore causes dilation or constriction, depending on the vascular bed tested.^{20 21} It has been also shown to play a pivotal role in the vascular wall–blood cell interactions,²² which are initiating factors in atherogenesis.²³ PAF is neuroactive²⁴ and has been shown to serve as a mediator of nervous system injury in experimental animals.^{25 26} All of these factors may contribute to the higher risk of stroke in subjects with the PAF acetylhydrolase deficiency gene as plasma PAF acetylhydrolase activity in heterozygous group was approximately one-half of that in normal groups, and homozygous subjects completely lacked PAF acetylhydrolase activity. Although there were slight differences in the enzyme activity between stroke patients and control subjects with the same genotype, the difference in the genotype prevalence is more significant; and the results of the present study may imply that a marked decrease in plasma enzyme activity in heterozygote or homozygote subjects enhances the risk of stroke.

It has been suggested that family history is an independent risk factor of stroke^{27 28 29} ; the precise mechanism for the familial aggregation, however, is not clearly defined.^{30 31 32} In the present study, we found a trend toward a higher prevalence of PAF acetylhydrolase deficiency in patients who had family histories of stroke. This association, however, must be established by a large-scale study.

In summary, we found that a mutant allele for PAF acetylhydrolase was markedly increased in stroke patients compared with controls. The mutation in the degradation enzyme implies that these patients have increased levels of PAF, perhaps in the vascular wall where it serves to promote atherogenesis and thrombosis.³³ The results of the present study may suggest that plasma PAF acetylhydrolase deficiency is a genetic risk factor for stroke, and the recognition of this risk factor may yield new strategies for treating stroke patients by the replacement of the deficient enzyme or by blocking the effects of PAF by the administration of a receptor antagonist.

View this table: [in this window] [in a new window]   Table 1. Plasma PAF Acetylhydrolase Genotypes and Alleles in Stroke Patients and Control Subjects

	Acknowledgments

 
We thank Stephen M. Prescott of the University of Utah for advice and Kumiko Satoh for excellent technical assistance.

Received May 14, 1997; revision received September 22, 1997; accepted September 22, 1997.

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