© 1997 American Heart Association, Inc.
Articles |
Genetic Cholesteryl Ester Transfer Protein Deficiency Is Extremely Frequent in the Omagari Area of Japan
Marked Hyperalphalipoproteinemia Caused by CETP Gene Mutation Is Not Associated With Longevity
From the Second Department of Internal Medicine, Osaka University Medical School (K-i.H., S.Y., T.A., T.M., Y.Y., M.I., N.S., K.K.-T., Y.M.), and the Nakajima Clinic, Akita (N.N.), Japan.
Correspondence to Ken-ichi Hirano, MD, PhD, Section of Gastroenterology, Department of Medicine, University of Chicago, 5841 S Maryland Ave, Chicago, IL 60637.
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Abstract |
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Abstract Low levels of HDL cholesterol have been clearly demonstrated to be associated with an increased incidence of coronary heart disease, strongly suggesting that HDL particles have an antiatherogenic function. However, little information has been available concerning the atherogenicity of a marked hyperalphalipoproteinemia (HALP). There is no agreement about whether plasma cholesteryl ester transfer protein (CETP) deficiency is associated with an antiatherogenic state or not, although this disorder was reported to be one of the major causes of marked HALP. In the current study, we have found a unique area (Omagari City, Akita Prefecture, Japan) where CETP deficiency caused by a G-to-A mutation at the 5' splice donor site of intron 14 in the CETP gene is extremely frequent. In Omagari City, the mutation was detected more than 20 times more frequently and the prevalence of a marked HALP with plasma HDL cholesterol
2.58 mmol/L (100 mg/dL) was 5 to 10 times higher than in other areas of Japan. This discovery has made it possible to perform a large population-based study concerning the atherogenicity of a marked elevation of HDL cholesterol in a genetically more homogeneous population. There was a statistically significant U-shaped relationship between HDL cholesterol levels and the incidence of ischemic changes in electrocardiograms. In cases of HDL cholesterol <1.81 mmol/L (70 mg/dL), the incidence increased in proportion to the levels of HDL cholesterol. The frequency of the CETP gene mutation was higher in patients with coronary heart disease than in healthy control subjects. In subjects aged >80 years, the prevalence of both marked HALP and the intron 14 splicing defect was significantly lower than in the younger generation. The current study indicated for the first time that a marked HALP caused by CETP gene mutation may not represent a longevity syndrome, suggesting the importance of reevaluation of the clinical significance and pathophysiology of a marked HALP.
Key Words: hyperalphalipoproteinemia • high-density lipoprotein • atherosclerosis • cholesteryl ester transfer protein deficiency • longevity syndrome
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Introduction |
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A number of epidemiological and experimental studies have suggested that HDL particles have an antiatherogenic function.1 2 Although a mild or moderate increase of plasma HDL cholesterol has been clearly demonstrated to be associated with a reduced incidence of CHD,3 there has been little information concerning the atherogenicity of a marked HALP. Some investigators have regarded a marked HALP as a beneficial state and designated it as a longevity syndrome.4 However, this view does not appear to be well grounded, since it was based on the results obtained from a relatively small number of genetically undefined subjects.5 Therefore, a large population-based study dealing with genetically homogeneous subjects may be necessary to elucidate the clinical significance of a marked HALP.
CETP is a plasma glycoprotein that transfers cholesteryl ester from HDL to apoB-containing lipoproteins and regulates plasma HDL cholesterol levels.6 Familial CETP deficiency was found in the Japanese subjects with a marked HALP.7 8 Several laboratories, including ours, have clarified the characteristics of the lipoprotein abnormalities in these subjects9 10 and identified several mutations in the CETP gene.11 12 13 Therefore, CETP deficiency is one of the marked HALPs for which biochemical and molecular bases have been extensively analyzed. We have also identified that a G-to-A substitution at the 5' splice donor site of intron 14 in the CETP gene is a common mutation associated with HALP patients with decreased plasma CETP activities12 and that it is relatively frequent in the Japanese general population.14
Although some investigators assume that CETP deficiency is a beneficial state, we have demonstrated that in many patients CETP deficiency was accompanied by atherosclerotic cardiovascular diseases. One case was reported15 16 in which, in spite of a marked HALP, the patient suffered from CHD accompanied by juvenile corneal opacification, which is often observed in patients with genetic HDL deficiencies.17 We found that this HALP patient was homozygous for a novel missense mutation in exon 15 of the CETP gene (D442: G)18 and that heterozygous CETP-deficient patients with low HTGL may be susceptible to atherosclerotic diseases.19
In the current study, we have found a unique area in which the intron 14 splicing defect in the CETP gene is extremely frequent. This discovery has provided an opportunity to perform a large population-based study in a genetically homogeneous group to clarify the clinical significance and pathophysiology of a marked HALP. We demonstrated that a marked HALP caused by CETP gene mutation is not associated with longevity and may be an atherogenic state.
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Methods |
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Population-Based Study
Since 1989, annual health examinations for the general population have been performed in Omagari City, Akita Prefecture, and its surrounding area, located in the northwest part of the main Japanese island (Fig 1
). It was revealed that the average life span had been shorter in Akita Prefecture than in other Japanese areas (Akita Prefecture: male, 75.3 years; female, 81.9 years versus all of Japan: male, 76.04 years; female, 82.27 years in 1990).20 In 1991, the measurement of HDL cholesterol was for the first time added to the protocol of the annual health examination to further clarify the lipoprotein profiles. The subjects in the current study were 39 567 men and 64 938 women (total 104 505), who underwent examinations in 1992. Their mean age was 58±10 years (mean±SD). Conventional measurements included body height, body weight, systolic and diastolic blood pressure, peripheral blood cell counts, plasma total cholesterol, HDL cholesterol, and liver function tests. Twelve-lead ECGs were also recorded at rest. To estimate the frequency of CHD, we determined the incidence of ST-segment depression of more than 1 mm. In the current study, a marked HALP was defined as plasma HDL cholesterol >2.58 mmol/L (100 mg/dL), according to the criteria of primary HALP proposed by the Japan Atherosclerosis Society.
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, Geographic location of Omagari City.In 1992, we surveyed the levels of HDL cholesterol and determined the frequency of a marked HALP in Osaka, another area in Japan. There were 28 818 subjects (male, 9060; female, 19 758). Their mean age was 54±12 years.
Analysis of CETP Gene Mutations
To investigate genetic background, we screened the two common mutations in the CETP gene by using the polymerase chain reaction–based restriction fragment length polymorphism methods developed previously,14 18 a G-to-A mutation at the +1 position of intron 14 and a missense mutation of exon 15 (D442: G), in the following groups.
Group A comprised 168 unrelated healthy control subjects, who were randomly assigned from the total 104 505 subjects and who consented to DNA analysis. Their HDL cholesterol levels were 1.51±0.41 mmol/L (mean±SD). A marked HALP with HDL cholesterol 2.58 mmol/L was observed in two subjects (1.3%). The distribution of HDL cholesterol levels was well matched to that in all subjects in the population-based study.
Group B comprised 25 unrelated subjects with a marked HALP (HDL cholesterol >2.58 mmol/L).
To clarify the relation of CETP gene mutation to CHD and longevity, we screened the mutations in the following two groups.
Group C comprised 45 CHD patients aged 66±12 years (mean±SD; 32 males and 13 females). CHD was diagnosed on the basis of angiographic findings. For patients in whom angiography could not be performed, we used the following criteria for coronary artery disease: Angina pectoris was diagnosed when a subject experienced recurrent chest discomfort that was brief in duration (<15 minutes), worsened by exertion or emotion, and relieved by rest or nitroglycerin. Myocardial infarction was diagnosed on the basis of at least two of three standard criteria (typical chest pain, QRS and ST-T changes on ECG, and the transient elevation of myocardial enzymes).
Group D comprised 67 unrelated elderly subjects >80 years old, who were living in a geriatric care center in Omagari and did not have annual health examinations.
As a control, we determined the frequency of CETP gene mutations in 512 healthy subjects who were randomly assigned from the total 28 818 subjects in Osaka. We also determined the frequency of mutations in 62 unrelated subjects with a marked HALP, 10 of whom were included in the 28 818 subjects and the remaining 52 of whom were not included in the population-based study but were referred to our lipid research clinic from hospitals in the Osaka area.
Miscellaneous Assays and Statistical Analysis
CETP activity was measured according to the method of Kato et al.21 Protein concentration was determined by the method of Lowry et al.22 Plasma total cholesterol was measured enzymatically. Plasma concentrations of HDL cholesterol were measured by the Mg2+/dextran sulfate precipitation method with minor modifications.23 Serum concentrations of apolipoproteins A-I, A-II, B, C-II, C-III, and E were measured by a single radial immunodiffusion method.24 All values were expressed as mean±SD. Statistical significance was evaluated by use of Student's t test for comparison of unpaired data or by ANOVA. To evaluate the relationship between HDL cholesterol levels and incidence of ischemic ECG changes, we assigned quantitative values to subjects with and without ST-segment depression of >1 mm (with the abnormal ECG change, 1; without the abnormal ECG change, 0) and performed logistic regression analysis.
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Results |
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The consecutive 3-year survey of HDL cholesterol revealed that the prevalence of a marked HALP with HDL cholesterol
2.58 mmol/L (100 mg/dL) was 0.98% to 1.15% of the total 104 505 subjects investigated in Omagari. The mean HDL cholesterol levels were 1.50±0.41 mmol/L in males and 1.52±0.42 mmol/L in females, respectively. The prevalence of a marked HALP in Omagari was >10 times higher than that in our previous results performed in Osaka,14 as shown in Table 1. The mean levels of HDL cholesterol were also remarkably higher in the Omagari area than in the other areas of Japan (data not shown). Table 1 also shows the prevalence of the two common CETP gene mutations in Omagari in comparison with that in Osaka. Of 168 healthy subjects (group A), 1 subject (0.6%) was detected to be homozygous and 46 subjects (27.3%) were revealed to be heterozygous for the intron 14 splicing defect. Of 25 unrelated subjects with a marked HALP (group B), 8 subjects (32%) were homozygous and 12 subjects (52%) were heterozygous for the intron 14 splicing defect. There was no significant difference in the frequency of the 442 D: G missense mutation between the Omagari and Osaka subjects. Several Japanese groups, including ours, independently reported that heterozygotes for the intron 14 splicing defect were observed in 
1% of the Japanese general population.14 25 26 Compared with these previous reports, it was clearly demonstrated that HALP caused by the intron 14 splicing defect was extremely frequent in the Omagari area.
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Fig 2 shows the distribution of plasma HDL cholesterol in Omagari compared with that in Osaka. Compared with Osaka (open bars in Fig 2), the distribution of plasma HDL cholesterol levels in the general population in Omagari (solid bars) was clearly demonstrated to be shifted to the right. This could partly be due to the contribution of heterozygous CETP-deficient subjects of the intron 14 splicing defect (hatched bars). These results indicate that the intron 14 splicing defect of the CETP gene accumulated markedly in the Omagari area and was considered to be the major cause of the higher prevalence of marked HALP.
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Because it is well known that chronic alcohol intake is one of the major determinants of acquired HDL cholesterol levels,27 28 we analyzed the relationship between daily alcohol intake and HDL cholesterol levels. As shown in Table 2, 70% of male subjects had a habitual daily intake of alcohol. In the range of alcohol intake from 0 to 90 g/d, there was a positive relationship between alcohol intake and HDL cholesterol levels. However, male subjects who drank >90 g of alcohol per day had significantly lower HDL cholesterol levels than those who drank 60 to 90 g of alcohol (P<.001). From the results of interviews, >99.9% of the female subjects did not have a habit of daily alcohol ingestion.
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Although previous population studies have shown that a mild or moderate increase in plasma HDL cholesterol is an independent negative coronary risk factor for CHD, less information has been available concerning the relationship between CHD and a marked HALP with HDL cholesterol >75 mg/dL. The reason for this may be that previous studies did not include a large enough number of subjects with a marked HALP.29 The current discovery of a unique area provided an opportunity to fill in this lack of information. As shown in Fig 3, the relationship between plasma HDL cholesterol levels and the incidence of ischemic ECG changes, which were designated as an ST-segment depression of >1 mm, exhibited a U-shaped curve. In the range of HDL cholesterol <1.81 mmol/L (70 mg/dL), there was an inverse relationship between plasma HDL cholesterol and the incidence of ischemic ECG changes, which was consistent with previous studies. However, in the group with HDL cholesterol 1.81 mmol/L (70 mg/dL), the incidence increased in proportion to the levels of HDL cholesterol. Logistic regression analysis indicated the statistically significant U-shaped relationship between HDL cholesterol levels and the incidence (
2=11.862, 2 df, P=.0027). This tendency was much more apparent in female subjects, 99.9% of whom did not have daily alcohol intake. There was no statistical significance in total cholesterol or the incidence of hypertension and diabetes mellitus between the subgroups divided by every 10 mg/dL of HDL cholesterol (data not shown).
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We investigated the prevalence of CETP gene mutations in 45 patients (group C; 32 males and 13 females) with apparent CHD. Thirty-six percent of the patients (38% in male, 31% in female) had CETP gene mutations. This frequency in each sex was higher than those in age- and sex-matched control subjects in Omagari (P<.05; 24% in male, 22% in female). Two of the patients with marked HALP of >2.58 mmol/L (100 mg/dL) were heterozygous for the intron 14 splicing defect. Table 3 shows the comparison of plasma lipids and apolipoproteins between CHD patients with and without CETP gene mutations. Patients without CETP gene mutations had lower levels of HDL cholesterol and apoA-I and higher levels of apoB compared with patients with CETP gene mutations and healthy control subjects. In contrast, patients with CETP gene mutations had higher levels of HDL cholesterol and apoA-I and lower levels of apoB compared with patients without the CETP gene mutations and control subjects. Although the number of patients investigated was relatively small and the study is preliminary, these results suggested that patients with CETP deficiency might be susceptible to CHD. These results also demonstrated that CHD patients in Omagari comprise two different groups, one including patients without CETP gene mutations who have lower HDL cholesterol levels, and the other patients with CETP gene mutations who have higher HDL cholesterol levels. This observation was thought to be consistent with the U-shaped relationship between HDL cholesterol and ischemic ECG changes (Fig 3
).
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Finally, most of the previous investigators had believed that HALP with genetic CETP deficiency might be associated with longevity.4 5 To further investigate whether a marked HALP is actually associated with longevity, we next examined the relationship of age to the prevalence of a marked HALP and CETP gene mutation. Fig 4A shows the prevalence of a marked HALP in every 10-year age group. In the elderly subjects aged >80 years, the prevalence of a marked HALP was lower than that in the younger subjects. This tendency was consistent in both sexes. Fig 4B shows the frequency of the intron 14 splicing defect in 10-year age groups. In the 67 elderly subjects aged >80 years (group D), 10 subjects (14.9%) were detected to be heterozygotes for the intron 14 splicing defect. No homozygote was identified in the elderly. The frequency of heterozygotes for the intron 14 splicing defect was significantly lower in the elderly subjects (14.9% in group D) than in the younger subjects <80 years old (P<.05, 2 test). Therefore, the intron 14 splicing defect was less frequent in the elderly subjects aged >80 years than in the younger subjects. These results clearly demonstrated that patients with the CETP deficiency caused by the intron 14 splicing defect may not be long lived compared with subjects without the mutation in Omagari.
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Discussion |
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Longevity has attracted much scientific attention during the past several decades,3 4 because it is thought to be an ultimate but unattainable landmark of medical science. Since HDL was shown to have an antiatherogenic function in vitro and in vivo,1 2 a marked HALP has been considered to be one of the possible conditions associated with longevity. There have been several studies that focused on plasma lipid levels, especially those of HDL cholesterol,4 30 in the elderly and long-lived subjects, who are thought to have escaped the major causes of death in the last decades of life. However, these studies provided controversial results, and it remains unknown whether a marked HALP is actually associated with a longevity syndrome or not. The reason for this lack of conclusive evidence may be that these studies were conducted on a rather small number of genetically undefined subjects. In the current study, we found a unique area in which a marked HALP due to the intron 14 splicing defect in the CETP gene is extremely frequent. Therefore, the Omagari study has, for the first time, made it possible to perform a large population-based study dealing with a genetically more homogeneous group to clarify whether a marked HALP denotes a longevity syndrome and to discover the pathophysiological significance of genetic CETP deficiency.
The current study also provided an opportunity to study the relationship between a marked elevation of HDL cholesterol and the incidence of CHD. Many previous studies have demonstrated that a mild or moderate increase in plasma HDL cholesterol levels was an independent and negative risk factor for CHD. We demonstrated for the first time that there was a U-shaped relationship between HDL cholesterol levels and the incidence of ischemic ECG changes. In the range of HDL cholesterol 70 mg/dL, the incidence of ischemic ECG changes tended to rise with the increment of HDL cholesterol levels. Though not a direct indicator, it was reported that abnormalities obtained from rest ECGs provide insightful information concerning long-term CHD risk.3 31 We speculate that the relationship observed may in part explain the reduced prevalence of a mark-ed HALP and the CETP gene mutation in the elderly subjects. The U-shaped relationship was more apparent in female subjects, 99.9% of whom do not have daily alcohol intake. The relationship in male subjects showed a complicated pattern. One of the reasons for this may be that HDL cholesterol levels in male subjects can be affected not only by the CETP gene mutation but also by the amount of daily alcohol intake.
There have been conflicting opinions as to whether CETP deficiency is antiatherogenic or not. Some investigators have considered that this disorder represents a longevity syndrome, since plasma lipid profiles in CETP deficiency are characterized by high plasma HDL cholesterol and relatively low LDL cholesterol levels.7 However, CETP plays a crucial role in reverse cholesterol transport,6 15 which is one of the major protective systems against atherosclerosis.32 We found that deficiency of CETP caused qualitative and quantitative abnormalities in LDL8 10 33 as well as HDL.9 34 35 Small and polydisperse LDL, observed in homozygous patients, had a reduced binding affinity for LDL receptors.33 Large and cholesteryl ester–rich HDL particles obtained from homozygotes of CETP deficiency could not prevent macrophages from accumulating cholesterol induced by acetylated LDL or remove cholesterol from lipid-laden macrophages.34 Moreover, we reported that the decrease in HDL cholesterol was closely correlated with the reduction in Achilles tendon thickness in patients with familial hypercholesterolemia during the treatment with probucol,15 which was shown to raise plasma CETP levels.36 Furthermore, the current study demonstrated that the frequency of CETP gene mutations was higher in patients with CHD than in healthy control subjects and that many heterozygous CETP-deficient patients, whose lipoprotein profiles were characterized by higher HDL cholesterol levels, suffered from apparent CHD. These results suggested that the lipoprotein abnormalities observed in CETP deficiency may reflect the impairment of the reverse cholesterol transport system.
The current results also demonstrated a lower frequency of the CETP gene mutation, as well as a decreased prevalence of a marked HALP with HDL cholesterol 100 mg/dL, in the elderly subjects aged >80 years. Considering that the average life span was relatively shorter in this area and that no homozygote for the CETP gene mutations was found in the elderly subjects, we speculate that a marked HALP caused by CETP gene mutation may not represent a longevity syndrome. The current study was designed as cross-sectional. To clarify the reason for the lower frequency of the CETP gene mutation in the elderly subjects and to further analyze the pathophysiology of CETP deficiency, a prospective follow-up study is in progress to evaluate the mortality, cause of death, and life span of patients diagnosed with genetic CETP deficiency.
It is still inconclusive whether CETP gene mutation is an independent positive coronary risk factor as are hypercholesterolemia, hypertension, and smoking. Recently, we have reported that patients with a concomitant reduction of CETP and HTGL are susceptible to CHD.19 We have also reported that chronic heavy alcohol intake decreases both activity and protein mass of CETP, which might cause atherogenic lipoprotein profiles.37 38 Recently, the introduction of the human CETP gene into apoC-III transgenic mice with hypertriglyceridemia has been reported to decrease early atherosclerotic lesions.39 Therefore, we speculate that the combination of CETP deficiency and some other factors, such as heavy alcohol intake and a low HTGL, would be very important in the development of atherosclerosis.
It remains to be investigated why the CETP gene mutation is extremely frequent in Omagari. Omagari is a rural area and had been rather isolated not only geographically but also by being snowbound in winter until a few decades ago. Therefore, we speculate that one of the Japanese ancestors who had the CETP gene mutation might have moved to the Omagari area and that the geographical isolation might have caused the marked accumulation of the genetic defect in the CETP gene, as has been observed with familial hypercholesterolemia in French Canadians living in Quebec40 and whites living in South Africa.
CETP deficiency has been found mostly in Japanese subjects. It may be quite interesting to investigate to what extent the current results, ie, that a marked HALP is not a beneficial state, can be generalized to other races and countries. Because plasma HDL cholesterol levels are known to be influenced by various genetic and environmental factors, a marked HALP is thought to be a heterogeneous syndrome. Most of the previous reports have shown that subjects with a marked HALP might be free from atherosclerotic cardiovascular diseases and exhibit a longevity syndrome, although their primary genetic defects were not identified. However, some hyperalphalipoproteinemic states were reported to be possibly associated with atherosclerosis. Genetic HTGL deficiency is sometimes accompanied by an elevation in HDL cholesterol, but there was a case associated with premature CHD.41 Weitzman and Vladutiu42 reported that a marked HALP, which was speculated to be caused by factors other than genetic, did not always signify the absence of CHD and an increase in life expectancy.
We conclude that a marked HALP caused by the CETP gene mutation is never associated with a longevity syndrome. Furthermore, it may be necessary to further analyze the molecular and biochemical basis for a marked HALP, besides CETP deficiency, and to reevaluate its clinical significance and pathophysiology.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by grants from the Japanese Ministry of Education (Nos. 4404085, 3557117, and 05670859), Research Grants for the Adult Disease, and HMG-CoA Reductase Research Fund (Sankyo Co, Japan). The authors thank Mayumi Koyama, Masako Masuda, and Sugako Okada for skillful technical assistance.
Received January 8, 1996; accepted July 31, 1996.
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