The official journal of the Japan Atherosclerosis Society andthe Asian Pacific Society of Atherosclerosis and Vascular Diseases

Review

J Atheroscler Thromb, 2021; 28: 802-810. http://doi.org/10.5551/jat.RV17053

Current Diagnosis and Management of Tangier Disease
Masahiro Koseki 1, Shizuya Yamashita 2, Masatsune Ogura 3, Yasushi Ishigaki 4, Koh Ono 5,
Kazuhisa Tsukamoto 6, Mika Hori 3, Kota Matsuki 3, Shinji Yokoyama 7 and Mariko Harada-Shiba 8
on behalf of the Committee on Primary Dyslipidemia under the Research Program on Rare and Intractable
Disease of the Ministry of Health, Labour and Welfare of Japan †1

Division of Cardiovascular Medicine, Department of Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
Department of Cardiology, Rinku General Medical Center, Osaka, Japan3
Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan
4
Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan
5
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
6
Department of Internal Medicine, Teikyo University, Tokyo, Japan.
7
Institute for Biological Functions, Chubu University, Aichi, Japan
8
Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan
2†
The Committee on Primary Dyslipidemia under the Research Program on Rare and Intractable Disease of the Ministry of
Health, Labour and Welfare of Japan: Mariko Harada-Shiba (Department of Molecular Pathogenesis, National Cerebral andCardiovascular Center Research Institute, Osaka, Japan), Shun Ishibashi (Division of Endocrinology and Metabolism, Department
of Internal Medicine, School of Medicine, Jichi Medical University, Tochigi, Japan), Shinji Yokoyama (Institute for Biological
Functions, Chubu University, Aichi, Japan), Hitoshi Shimano (Department of Internal Medicine (Endocrinology and Metabolism),
Faculty of Medicine University of Tsukuba, Tsukuba, Japan), Koutaro Yokote (Department of Endocrinology, Hematology andGerontology, Chiba University Graduate School of Medicine, Chiba, Japan), Hideaki Bujo (Department of Clinical-Laboratory andExperimental-Research Medicine, Toho University Sakura Medical Center, Chiba, Japan), Shizuya Yamashita (Rinku General
Medical Center, Osaka, Japan), Kazuhisa Tsukamoto (Department of Internal Medicine, Teikyo University, Tokyo, Japan), Toshio
Hayashi (School of Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan), Katsunori Ikewaki (Divisionof Neurology, Anti-Aging, and Vascular Medicine, Department of Internal Medicine, National Defense Medical College, Saitama,
Japan), Takanari Gotoda (Department of Metabolic Biochemistry, Faculty of Medicine, Kyorin University, Tokyo, Japan), Kazushige
Dobashi (Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan), Yoshihiro Miyamoto (Open
Innovation Center, National Cerebral and Cardiovascular Center, Osaka, Japan), Misa Takegami (Department of Preventive
Medicine and Epidemiology, National Cerebral and Cardiovascular Center, Osaka, Japan), Yoshiki Sekijima (Department ofMedicine (Neurology & Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan), Yasushi Ishigaki (Division of
Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan), Hiroaki
Okazaki (Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan),Atsushi Nohara (Ishikawa Prefectural Central Hospital, Kanazawa, Japan), Shingo Koyama (Division of Neurology and Clinical
Neuroscience, Department of Internal Medicine III, Yamagata University Faculty of Medicine, Yamagata, Japan), Kyoko Inagaki(Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Nippon Medical School, Tokyo, Japan), Koh
Ono (Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan), Masahiro Koseki(Division of Cardiovascular Medicine, Department of Medicine, Osaka University Graduate School of Medicine, Osaka, Japan),
Hiroyuki Daida (Faculty of Health Science, Juntendo University, Juntendo University Graduate School of Medicine, Tokyo, Japan),
Manabu Takahashi (Division of Endocrinology and Metabolism, Department of Internal Medicine, Jichi Medical University,
Tochigi, Japan), Kimitoshi Nakamura (Department of Pediatrics, Kumamoto University Graduate School of Medical Sciences,
Kumamoto, Japan), Takashi Miida (Department of Clinical Laboratory Medicine, Juntendo University Graduate School of
Medicine, Tokyo, Japan), Masa-aki Kawashiri (Department of Cardiovascular Medicine, Graduate School of Medical Sciences,
Kanazawa University, Kanazawa, Japan), Tetsuo Minamino (Department of Cardiorenal and Cerebrovascular Medicine, Faculty of
Medicine, Kagawa University, Kagawa, Japan), Sachiko Okazaki (Division for Health Service Promotion, The University of Tokyo,
Tokyo, Japan), Hayato Tada (Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences,
Kanazawa, Japan), Jun Wada (Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University
Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan), Masatsune Ogura (Division of Lipid
Metabolism, Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute,
Osaka, Japan), Hirotoshi Ohmura (Department of Cardiovascular Medicine, School of Medicine, Juntendo University, Tokyo,
Japan), Mika Hori (Department of Endocrinology, Research Institute of Environmental Medicine, Nagoya University, Nagoya,Japan), Kota Matsuki (Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki,
Japan), Masashi Yamamoto (Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of802

Diagnosis and Management of Tangier Disease

Medicine, Chiba, Japan), Yasuo Takeuchi (Division of Nephrology, Kitasato University School of Medicine, Kanagawa, Japan),
Atsuko Nakatsuka (Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate
School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan), Daisaku Masuda (Department of Cardiology,
Health Care Center, Rinku Innovation Center for Wellness Care and Activities (RICWA), Rinku General Medical Center, Osaka,
Japan), Satoshi Hirayama (Department of Clinical Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo,
Japan), Masayuki Kuroda (Center for Advanced Medicine, Chiba University Hospital, Chiba University, Chiba, Japan), Takashi
Yamaguchi (Center of Diabetes, Endocrinology and Metabolism, Toho University Sakura Medical Center, Chiba, Japan), Takeyoshi
Murano (Clinical Laboratory Program, Faculty of Science, Toho University, Chiba, Japan).

Tangier disease is a genetic disorder characterized by an absence or extremely low level of high-density
lipoprotein (HDL)-cholesterol (HDL-C). It is caused by a dysfunctional mutation of the ATP-binding cassettetransporter A1 (ABCA1) gene, the mandatory gene for generation of HDL particles from cellular cholesterol andphospholipids, and it appears in an autosomal recessive hereditary profile. To date, 35 cases have been reported
in Japan and 109 cases outside Japan. With dysfunctional mutations in both alleles (homozygotes or compound
heterozygotes), the HDL-C level is mostly less than 5 mg/dL and there is 10 mg/dL or less of apolipoprotein A-I(apoA-I), the major protein component of HDL. In patients with Tangier disease, major physical findings areorange-colored pharyngeal tonsils, hepatosplenomegaly, corneal opacity, lymphadenopathy, and peripheral
neuropathy. Although patients tend to have decreased low-density lipoprotein (LDL)-cholesterol (LDL-C) levels,
premature coronary artery disease is frequently observed. No specific curative treatment is currently available, soearly identification of patients and preventing atherosclerosis development are crucial. Management of risk
factors other than low HDL-C is also important, such as LDL-C levels, hypertension and smoking. Additionally,treatment for glucose intolerance might be required because impaired insulin secretion from pancreatic beta cells
has occasionally been reported.
Key words: Tangier disease, HDL, Reverse cholesterol transport, ABCA1, Cholesterol efflux, Orange tonsil,
Atherosclerosis

Introduction
Tangier disease is an autosomal recessive diseasecharacterized by extremely low levels or absence ofhigh-density lipoprotein (HDL)-cholesterol (HDL-C)
and apolipoprotein A-I (apoA-I) 1). The disease wasnamed after Tangier Island in Chesapeake Bay,
Virginia, USA, where the first case was discovered in1960 and reported in 1961 2). In 1991, generation of
HDL particles through the direct action of helical
HDL apoproteins on cells was first reported 3), andthis was found to be deficient in cells derived from apatient with Tangier disease in 1995 4). Eventually,
ATP binding cassette transporter A1 (ABCA1) was
identified as the gene responsible for this action andfor Tangier disease in 1999 5-7). Sequential progress in
the investigation of HDL biosynthesis showed that
HDL particles generated through ABCA1-dependentinteraction of apolipoproteins with cells are the main

source of plasma HDL. Patients with homozygous orcompound heterozygous mutations in the ABCA1
gene display the phenotype of Tangier disease andheterozygotes have decreases in HDL-cholesterol tovarious extents.
1. Disease Frequency
The number of cases of Tangier disease reported
by 2020 was 35 in Japan and 109 in other countries(possibly including duplicates), indicating that it is arather rare disease 8, 9). However, the frequency ofdysfunctional mutations in the ABCA1 gene in thegeneral population is not clear. A recent article using
the Exome Aggregation Consortium database reported
that 1 in 400 individuals in the general population is aheterozygote for a loss-of-function variant in the
ABCA1 gene on the basis of allele frequencies(frameshift, nonsense and splicing only; not missense),
indicating a global prevalence of Tangier disease of at

Address for correspondence: Masahiro Koseki, Division of Cardiovascular Medicine, Department of Medicine, Osaka University Graduate School of Medicine,
2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
E-mail: koseki@cardiology.med.osaka-u.ac.jp
Received: March 18, 2021
Accepted for publication: March 21, 2021
Copyright©2021 Japan Atherosclerosis Society
This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.

803

Koseki et al .

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Fig. 1. Roles of ABCA1 in formation of HDL particles, reverse cholesterol transport and pathogenesis of Tangier diseaseleast 1 in 640,000 10). It therefore seems that asubstantial number of cases might go undiagnosed.
2. Genetic Backgrounds and Pathophysiology
ABCA1 is a member of the ATP-binding cassettetransporter membrane protein family. It is an essential
factor for generation of nascent HDL particles withextracellular helical apolipoproteins, through transportof cellular phospholipids and cholesterol (Fig. 1). This
process is the major source of plasma HDL and one of
the major mechanisms of cholesterol export from cells.
It may be essential for final processing of cholesterolin mammalian somatic cells that are unable tocatabolize cholesterol molecules. Peripheral cells sense
intra-cellular cholesterol levels and increase ABCA1
expression for its excretion 11), while it undergoes
804

bidirectional control in hepatocytes to prevent
cholesterol recovered from peripheral cells flowing
back into blood plasma 12, 13). With functional
deficiency in ABCA1, spherical HDL particles are notproduced resulting in extremely low plasma HDL-C
levels, which, in Tangier disease patients, are about
one third of the normal level. The reason for this is
unclear but it has been postulated that a substantial
portion of cholesterol molecules in LDL in humanplasma are those which have been acyl-esterified in
HDL and transferred to VLDL/LDL and that a severe
decrease in HDL cholesterol may lead to a decrease in
LDL-C level.
In Tangier disease patients, cellular cholesterol
export is impaired due to ABCA1 deficiency inperipheral cells, including macrophages and Schwann

Diagnosis and Management of Tangier Disease

Fig. 2. Orange-colored tonsils observed in male patient with Tangier disease in his 50s
Arrow heads indicate palatine tonsil (left panel) and lingual tonsil (right panel). Reproduced from reference [8].

cells. Cholesterol therefore accumulates in these cells,causing orange-colored pharyngeal tonsillar swelling,corneal opacity, hepatosplenomegaly, lymphadenopathy
and peripheral neuropathy. However, impairment of
the initial stage of reverse cholesterol transport should
be considered to be a risk for developing
atherosclerotic diseases even though plasma LDL-C
concentrations could be reduced.
ABCA1 appears to destabilize the raft structure,a cholesterol-rich domain of the plasma membrane 14, 15),
its deficiency leads to an increase in “lipid” rafts and it
has been suggested that this increases secretion of
inflammatory cytokines 16). It has also been reported
that the insulinogenic index decreases due tocholesterol accumulation in pancreatic β-cells, which
often accompanies glucose intolerance 17, 18). These
metabolic disorders are collectively involved in thedevelopment of premature coronary artery disease 8).
In early studies of Tangier disease, Schaefer et al.
revealed the kinetics of plasma lipoprotein metabolism
using externally labeled injected HDL and found thatthat apoA-I was catabolized at a much greater
fractional rate in patients 19). Their data, however,should be reinterpreted in terms of external HDL
catabolism on the basis of ABCA1 deficiency. A recent
study using human pluripotent stem cell-derived
hepatocytes has demonstrated that ABCA1 deficiency
increases angiopoietin-like protein 3 secretion, whichis consistent with increased triglyceride in the plasmaof Tangier patients 20).
3. Clinical Manifestations
3.1. Abnormal Plasma Lipoproteins
Plasma HDL-C is mostly low, at 5 mg/dL or less(mean of identified cases 3±3 mg/dL), and the apoA-I
concentration is 10 mg/dL or less 21). Plasma LDL-C isalso reduced, to around 37% of the average normal
level. The appearance of remnant lipoprotein particles(intermediate products between VLDL and LDL) richin triglycerides has been reported and this was found
to result in abnormal small, dense LDL particles 21). In
subjects with heterozygous mutations of the ABCA1
gene, plasma HDL-C and apoA-I levels are often
reduced to about 50% of that in normal subjects,
though the extent of HDL-C decline is not consistent.
3.2. Physical Findings
Impairment of HDL biogenesis results in
reduced cholesterol export, which leads to lipid
accumulation in cells. A typical finding of thisdisorder is orange-colored tonsils (Fig. 2) 8). The tonsilsof patients are lobulated and swollen and present abright orange or yellow-grey surface. A history ofrecurrent tonsillitis or tonsillectomy is often noted. In
addition, splenomegaly and associatedthrombocytopenia and/or reticulocyte hyperplasia
may be present (Fig. 3). Hepatomegaly is also
observed in about one-third of cases, but liver
dysfunction is not usually present 22). There is alsocholesterol accumulation in other organs, such as
lymph nodes, thymus, intestinal mucosa, and skin. Its
accumulation in the cornea causes corneal opacity.
3.3. Peripheral Neuropathy
Various peripheral neuropathies, ranging frommild to severe, have been reported. Sensory, motor ormixed disorders appear transiently or persistently.
Reduced deep perception and tendon reflexes are rare.
Peripheral neuropathy appears as a recurrent
asymmetric disorder of peripheral nerves including
cranial nerves, as neuropathy with symmetry in thelower limbs, or syringomyelia-like peripheral
neuropathy 23, 24).
3.4. Cardiovascular Diseases
It has been reported that 12 out of 35 patients
805

Koseki et al .

Fig. 3. Abdominal CT scan of splenomegaly in female patient with Tangier disease in her 40s
The photo was kindly provided by one of the co-authors, Prof. Yasushi Ishigaki (Iwate Medical University).

'(

Fig. 4. Advanced systemic atherosclerotic lesions in male patient with Tangier disease in his 50s
Arrows indicate stenosis or occlusion of the artery.
A: left coronary artery, B: right coronary artery, C: brachiocephalic artery, D: left iliac artery, E: right external iliac artery [8].

(34.3%) in Japan and 34 out of 109 patients (31.2%)
in other countries had some type of cardiovasculardisease, suggesting accelerated atherogenicity in
Tangier disease (Fig. 4) 8). A previous case study using
intravascular ultrasound (IVUS) revealed diffuse
calcified coronary artery lesions 25), which might havebeen affected by HDL deficiency and glucose
intolerance 17).

806

4. Diagnostic Criteria and Differential Diagnosis
Diagnostic criteria for Tangier disease are given
in Table 1 and the flow chart for differential diagnosisof hypo-HDL-cholesterolemia is shown in Fig. 5,
based on discussions by the Committee on Primary
Dyslipidemia under the Research Program on Rareand Intractable Diseases of Japan’s Ministry of Health,Labour and Welfare.
Inherited diseases that lead to hypo-HDL-Diagnosis and Management of Tangier Disease

Table 1. Diagnostic criteria
A. Required laboratory test results
1. Plasma (serum) HDL-cholesterol less than 25 mg/dL
2. Plasma (serum) apoA-I concentration less than 20 mg/dL
B. Clinical symptoms
1. Orange-colored tonsillar swelling
2. Hepatomegaly and/or splenomegaly
3. Corneal opacity
4. Peripheral neuropathy
5. Cardiovascular disease
C. Differential diagnosis
The following diseases should be excluded;
LCAT deficiency, apoA-I deficiency and secondary hypo-HDL-cholesterolemia＊
D. Genetic testing＊＊
Identification of pathogenic mutations in the ABCA1 gene
< Diagnostic category >Definite: Patients should satisfy both of required laboratory test results (A) AND at least one clinical symptom of (B)AND should be excluded for the diseases of differential diagnosis (C) AND should be positive for genetic testing (D).
Probable: Patients should satisfy both of required laboratory test results (A) AND at least two clinical symptoms of (B)AND should be excluded for the diseases of differential diagnosis (C).
Tangier disease can be diagnosed if patients are categorized “Definite” or “Probable”.
＊

Secondary hypo-HDL-cholesterolemia: After surgery, liver disorders (especially liver cirrhosis and severe hepatitis, including
convalescent stage), acute phase of systemic inflammatory disease, debilitating diseases such as cancer, history of oral probucol within
the past 6 months, and combined probucol and fibrate (including fibrate administration after discontinuation of probucol).
＊＊When differential diagnosis is difficult, genetic testing for ABCA1 mutations should be performed. The diagnosis can be definite
if pathogenic mutations in the ABCA1 gene are identified.

cholesterolemia (Familial hypoalphalipoproteinemia)
include classical lecithin: cholesterol acyltransferase(LCAT) deficiency, fish-eye disease, and familial
apoA-I deficiency. Corneal opacity is commonly
observed in these diseases, but tonsillar swelling andperipheral neuropathy are specific to Tangier disease,and xanthomas are found only in familial apoA-I
deficiency 24, 26).
Care should be taken to exclude secondary hypoHDL-cholesterolemia, such as in severe liver diseases,
especially liver cirrhosis, and drug-induced hypoHDL-cholesterolemia, most frequently due tocombination of probucol and fibrates. It should be
noted that probucol may continue to influence lipid
profiles for several months after discontinuation, so
HDL-C may be significantly reduced by switchingfrom probucol to fibrates or permafibrate, a selective
peroxisome proliferator-activated receptor alphamodulator (SPPARMα), in some cases.
5. Current Management of Tangier Disease
Based on the patients identified in Japan to date,there seem to be no distinct differences in clinical or
genetic profiles with patients in other countries 8, 9).
No curative treatment, such as gene therapy for the
ABCA1 gene, has yet been established. Since extremely

enhanced risk of atherosclerotic diseases is the majorclinical problem, patients should be carefully
monitored for presence of atherosclerotic lesions
through regular testing including exercise
electrocardiography, echocardiography and computedt o m o g r a p h y c o r o n a r y a n g i o g r a p h y 8). T h emanagement of atherosclerotic risk factors, such as
hypertension, smoking and diabetes mellitus, iscrucial, 27). Plasma LDL-C levels are generally low inpatients with Tangier disease but if this is not the case,they should be reduced through administration of
statins or other means. Impairment of theinsulinogenic index should be estimated using a 75 goral glucose tolerance test 17).
Conclusions and Future Perspectives
Gene therapy for ABCA1 gene may have thegreatest potential for Tangier disease. There is thepossibility that restoration of ABCA1 expression in
the liver would raise serum HDL-C levels but thismight not be enough to recover cellular cholesterol
efflux and suppress extra lipid accumulation in cells in
atherogenic lesions such as macrophages, smoothmuscle cells and endothelial cells. It may not be easy
to develop a fundamental therapy for Tangier disease.
807

Koseki et al .

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Acknowledgments andNotice of Grant Support
This work has been supported by Health, Labourand Welfare Sciences Research Grant for Research on
Rare and Intractable Diseases (H30-nanji-ippan-003).
Conflicts of Interest
Atsushi Nohara has nothing to disclose. Hayato
Tada has nothing to disclose. Masatsune Ogura has
808

received honoraria from Amgen Inc., Astellas Pharma
Inc. Sachiko Okazaki has received scholarship grants
from Minophagen Pharmaceutical Co., Ltd., Kowa
Company, Ltd. Koh Ono has nothing to disclose.
Hitoshi Shimano has nothing to disclose. Hiroyuki
Daida has received honoraria from Amgen Inc.,
Daiichi-Sankyo Co., Ltd., Kowa Co., Ltd., and MSD
K.K., Novartis Pharma K.K., Bayer Yakuhin, Ltd. andreceived clinical research funding from Canon Medical
Systems Corporation, Philips Japan, Ltd., Toho
Holdings Co., Ltd., Asahi Kasei Corporation, andDiagnosis and Management of Tangier Disease

Inter Reha Co., Ltd. HD has also received scholarshipgrants from Nippon Boehringer Ingelheim Co., Ltd.,
Otsuka Pharmaceutical Co., Ltd., Sanofi K.K., MSD
K.K., Daiichi-Sankyo Co., Ltd., Pfizer Co., Ltd.,
Mitsubishi Tanabe Pharma Corp., Astellas PharmaInc., Takeda Pharmaceutical Co., Ltd., Teijin Pharma,
Ltd., Shionogi & Co., Ltd., Actelion Pharmaceuticals,Ltd., Actelion Ltd., Kowa Co., Ltd., Bayer Yakuhin,Ltd. HD has also courses endowed by companies,
including Philips Japan, Ltd., ResMed, Fukuda
Denshi Co., Ltd., and Paramount Bed Co., Ltd.
Kazushige Dobashi has nothing to disclose. Toshio
Hayashi has nothing to disclose. Mika Hori has
nothing to disclose. Kota Matsuki has nothing todisclose. Tetsuo Minamino has nothing to disclose.
Shinji Yokoyama has nothing to disclose. Mariko
Harada-Shiba has received stock holdings or options
from Liid Pharma, honoraria from Amgen Inc.,
Astellas Pharma Inc., Sanofi, and scholarship grants
from Aegerion Pharmaceuticals, Inc., Recordati Rare
Diseases Japan, and Kaneka Corporation. Katsunori
Ikewaki has nothing to disclose. Yasushi Ishigaki has
nothing to disclose. Shun Ishibashi has received
honoraria from Kowa Co., Ltd., and a scholarshipgrant from Ono Pharmaceutical Co., Ltd. Kyoko
Inagaki has nothing to disclose. Hirotoshi Ohmura
has nothing to disclose. Hiroaki Okazaki has received
scholarship grants from Minophagen PharmaceuticalCo., Ltd., Kowa Company, Ltd. Masa-aki Kawashiri
has nothing to disclose. Masayuki Kuroda has nothing
to disclose. Masahiro Koseki has received clinicalresearch funding from Kowa Company, Ltd., Rohto
Pharmaceutical Co., Ltd. Takanari Gotoda has
nothing to disclose. Shingo Koyama has nothing todisclose. Yoshiki Sekijima has nothing to disclose.
Manabu Takahashi has nothing to disclose. Yasuo
Takeuchi has nothing to disclose. Misa Takegami has
nothing to disclose. Kazuhisa Tsukamoto has received
honoraria from Bayer Yakuhin, Ltd., MSD Ltd.,
Takeda Pharmaceutical Company Ltd., andscholarship grants from Mitsubishi Tanabe Pharma
Corporation., Bayer Yakuhin, Ltd., Sanofi K.K.
Atsuko Nakatsuka has nothing to disclose. Kimitoshi
Nakamura has nothing to disclose. Satoshi Hirayama
has nothing to disclose. Hideaki Bujo has nothing todisclose. Daisaku Masuda has received clinical researchfunding from MSD K.K., Ono Pharmaceutical Co.,
Ltd., Takeda Pharmaceutical Co., Ltd., Kowa Co.,
Ltd. Takashi Miida has nothing to disclose. Yoshihiro
Miyamoto has nothing to disclose. Takeyoshi Murano
has nothing to disclose. Takashi Yamaguchi has
nothing to disclose. Shizuya Yamashita has received
honoraria from Kowa Company, Ltd., MSD K.K.
Masashi Yamamoto has nothing to disclose. Koutaro

Yokote has received honoraria from Kowa Company,
Ltd., MSD K.K., Astellas Pharma Inc., Mitsubishi
Tanabe Pharma Corp., Amgen K.K., Takeda
Pharmaceutical Company Limited, Sanofi K.K., Ono
Pharmaceutical Co., Ltd., AstraZeneca K.K., DaiichiSankyo Co., Ltd., Novartis Pharma K.K., Sumitomo
Dainippon Pharma Co., Ltd., Kyowa Kirin Co., Ltd.,
Pfizer Japan Inc., Novo Nordisk Pharma Ltd., Nippon
Boehringer Ingelheim Co., Ltd., Eli Lilly Japan K.K.,
Taisho Pharmaceutical Co., Ltd., Janssen
Pharmaceutical K.K., and received clinical researchfunding from Taisho Pharmaceutical Co., Ltd. KY has
also received scholarship grants from Mitsubishi
Tanabe Pharma Corp., Takeda Pharmaceutical Co.,
Ltd., MSD K.K., Pfizer Japan Inc., Novo Nordisk
Pharma Ltd., Taisho Pharmaceutical Co., Ltd., Kao
Corporation, Ono Pharmaceutical Co., Ltd., Eli Lilly
Japan K.K., Sumitomo Dainippon Pharma Co., Ltd.,
Nippon Boehringer Ingelheim Co., Ltd., DaiichiSankyo Co., Ltd., Teijin Pharma, Ltd., Shionogi Co.,
Ltd., Bayer Yakuhin, Ltd. Jun Wada has nothing todisclose.
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2001; 8th ed. vol 2: 2937-2960
2) Fredrickson DS, Altrocchi PH, Avioli LV, Goodman DS,
Goodman HC. Tangier disease—Combined clinical staff
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Intern Med, 1961; 55: 1016-1031
3) Hara H, Yokoyama S. Interaction of free apolipoproteins
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