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1.
J Atheroscler Thromb ; 11(3): 110-21, 2004.
Article in English | MEDLINE | ID: mdl-15256762

ABSTRACT

Plasma cholesteryl ester transfer protein (CETP) facilitates the transfer of cholesteryl ester (CE) from high density lipoprotein (HDL) to apolipoprotein B-containing lipoproteins. Since CETP regulates the plasma levels of HDL cholesterol and the size of HDL particles, CETP is considered to be a key protein in reverse cholesterol transport (RCT), a protective system against atherosclerosis. The importance of plasma CETP in lipoprotein metabolism was demonstrated by the discovery of CETP-deficient subjects with marked hyperalphalipoproteinemia (HALP). Genetic CETP deficiency is the most important and common cause of HALP in the Japanese. Ten mutations of the CETP gene have been demonstrated as causes of HALP, including two common mutations: an intron 14 splicing defect (Int14 + 1 G --> A) and an exon 15 missense mutation (D442G). The subjects with CETP deficiency show a variety of abnormalities in the concentration, composition, and function of both HDL and low density lipoprotein (LDL). CETP deficiency is considered a physiological state of impaired RCT, which may possibly lead to the development of atherosclerosis despite high HDL cholesterol levels. However, the pathophysiological significance of CETP in terms of atherosclerosis has been controversial. Epidemiological studies in Japanese-Americans living in Hawaii and Japanese in the Omagari area, where HALP subjects with an intron 14 splicing defect of the CETP gene are markedly frequent, have shown a relatively increased incidence of coronary atherosclerosis in CETP deficiency. On the other hand, the TaqIB polymorphism-B2 allele with low CETP mass and increased HDL cholesterol has been related to a decreased risk for coronary heart disease (CHD) in many studies, including the Framingham Offspring Study. The current review focused on the characterization of the Japanese subjects with CETP deficiency, including our recent findings.


Subject(s)
Asian People/genetics , Glycoproteins/deficiency , Hyperlipoproteinemias/genetics , Metabolic Diseases/genetics , Adolescent , Adult , Arteriosclerosis/complications , Carrier Proteins/genetics , Cholesterol Ester Transfer Proteins , Female , Glycoproteins/genetics , Humans , Hyperlipoproteinemias/etiology , Japan , Lipid Metabolism , Male , Metabolic Diseases/complications , Middle Aged , Mutation/genetics , Polymorphism, Genetic/genetics , Severity of Illness Index
2.
Clin Gastroenterol Hepatol ; 3(6): 564-73, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15952098

ABSTRACT

BACKGROUND & AIMS: The relationship between single nucleotide polymorphisms (SNPs) and clinical outcomes has been intensively studied. We intended to determine SNPs of CYP2C19 and 23S rRNA of Helicobacter pylori by using rapid urease test (RUT)-positive gastric mucosal samples. METHODS: One hundred thirty-nine patients with H pylori -positive results based on RUT completed 1-week treatment with lansoprazole 30 mg twice a day, clarithromycin 200 mg 3 times daily, and amoxicillin 500 mg 3 times daily. SNPs from adenine to guanine at positions 2142 and 2143 of 23S rRNA of H pylori (A2142G and A2143G) and SNPs from guanine to adenine at positions 681 in exon 5 (* 2 ) and 636 in exon 4 (* 3 ) of CYP2C19 were determined by the serial invasive signal amplification reaction assay by using DNAs extracted from gastric tissue samples already used for RUT. Minimum inhibitory concentrations of clarithromycin for H pylori were determined by culture test. CYP2C19 genotypes were classified into the rapid metabolizer (* 1 /* 1 ), intermediate metabolizer (* 1 /* 2 or * 1 /* 3 ), and poor metabolizer (* 2 /* 2 , * 2 /* 3 , or * 3 /* 3 ) groups. RESULTS: H pylori strains with A2142G or A2143G mutation had higher minimum inhibitory concentrations for clarithromycin. Cure rates in rapid, intermediate, and poor metabolizer groups were 57.8% (95% confidence interval, 42.1%-72.4%), 88.2% (78.1%-94.8%), and 92.3% (74.9%-99.1%), respectively ( P < .001). Cure rates in strains with and without A2142G or A2143G mutation were 48.3% (29.4%-67.5%) and 87.3% (79.5%-92.7%), respectively ( P < .001). CONCLUSIONS: SNPs of CYP2C19 and 23S rRNA of H pylori using RUT-positive gastric mucosal samples could be predictable determinants for H pylori eradication by triple therapy.


Subject(s)
Anti-Infective Agents/therapeutic use , Aryl Hydrocarbon Hydroxylases/genetics , Gastric Mucosa/microbiology , Helicobacter Infections/drug therapy , Helicobacter pylori , Mixed Function Oxygenases/genetics , Polymorphism, Restriction Fragment Length , RNA, Ribosomal, 23S/genetics , 2-Pyridinylmethylsulfinylbenzimidazoles , Adolescent , Adult , Aged , Amoxicillin/therapeutic use , Aryl Hydrocarbon Hydroxylases/metabolism , Biopsy , Clarithromycin/therapeutic use , Colony Count, Microbial , Cytochrome P-450 CYP2C19 , Endoscopy, Gastrointestinal , Female , Gastric Mucosa/metabolism , Gastritis/drug therapy , Gastritis/metabolism , Gastritis/microbiology , Genotype , Helicobacter Infections/metabolism , Helicobacter Infections/microbiology , Helicobacter pylori/genetics , Helicobacter pylori/isolation & purification , Humans , Lansoprazole , Male , Middle Aged , Mixed Function Oxygenases/metabolism , Mutation , Omeprazole/analogs & derivatives , Omeprazole/therapeutic use , Polymerase Chain Reaction , RNA, Bacterial/drug effects , RNA, Bacterial/genetics , RNA, Ribosomal, 23S/drug effects , Treatment Outcome
3.
J Lipid Res ; 43(7): 1011-8, 2002 Jul.
Article in English | MEDLINE | ID: mdl-12091484

ABSTRACT

Cholesteryl ester transfer protein (CETP) deficiency is one of the most important and common causes of hyperalphalipoproteinemia (HALP) in the Japanese. CETP deficiency is thought to be a state of impaired reverse cholesterol transport, which may possibly lead to the development of atherosclerotic cardiovascular disease despite high HDL-cholesterol (HDL-C) levels. Thus, it is important to investigate whether HALP is caused by CETP deficiency. In the present study, we identified two novel missense mutations in the CETP gene among 196 subjects with a marked HALP (HDL-C > or = 2.59 mmol/l = 100 mg/dl). The two missense mutations, L151P (CTC-->CCC in exon 5) and R282C (CGC-->TGC in exon 9), were found in compound heterozygous subjects with D442G mutation, whose plasma CETP levels were significantly lower when compared with those in D442G heterozygous subjects. In COS-7 cells expressing the wild type and mutant CETP, these two mutant CETP showed a marked reduction in the secretion of CETP protein into media (0% and 39% of wild type for L151P and R282C, respectively). These results suggested that two novel missense mutations cause the decreased secretion of CETP protein into circulation leading to HALP. By using the Invader assay for seven mutations, including two novel mutations of the CETP gene, we investigated their frequency among 466 unrelated subjects with HALP (HDL-C > or = 2.07 mmol/l = 80 mg/dl). Two novel mutations were rare, but L151P mutation was found in unrelated subjects with a marked HALP. Furthermore, we demonstrated that CETP deficiency contributes to 61.7% and 31.4% of marked HALP and moderate HALP in the Japanese, respectively.


Subject(s)
Carrier Proteins/genetics , Glycoproteins , Hyperlipoproteinemias/genetics , Mutation, Missense/genetics , Adult , Aged , Amino Acid Sequence , Base Sequence , Carrier Proteins/chemistry , Cholesterol Ester Transfer Proteins , Cholesterol, HDL/blood , Female , Genotype , Humans , Hyperlipoproteinemias/blood , Hyperlipoproteinemias/ethnology , Japan/ethnology , Male , Middle Aged , Molecular Sequence Data
4.
J Lipid Res ; 43(8): 1236-43, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12177167

ABSTRACT

Plasma phospholipid transfer protein (PLTP) plays an important role in lipoprotein metabolism and reverse cholesterol transport. We have recently reported that plasma PLTP concentration correlates positively with plasma HDL cholesterol (HDL-C) but not with PLTP activity in healthy subjects. We have also shown that PLTP exists as active and inactive forms in healthy human plasma. In the present study, we measured plasma PLTP concentration and PLTP activity, and analyzed the distribution of PLTP in normolipidemic subjects (controls), cholesteryl ester transfer protein (CETP) deficiency, and hypo-alphalipoproteinemia (hypo-ALP). Plasma PLTP concentration was significantly lower (0.7 +/- 0.4 mg/l, mean +/- SD, n = 9, P < 0.001) in the hypo-ALP subjects, and significantly higher (19.5 +/- 4.3 mg/l, n = 17, P < 0.001) in CETP deficiency than in the controls (12.4 +/- 2.3 mg/l, n = 63). In contrast, we observed no significant differences in plasma PLTP activity between controls, hypo-ALP subjects, and CETP deficiency (6.2 +/- 1.3, 6.1 +/- 1.8, and 6.8 +/- 1.2 micro mol/ml/h, respectively). There was a positive correlation between PLTP concentration and plasma HDL-C (r = 0.81, n = 89, P < 0.001). By size exclusion chromatography analysis, we found that the larger PLTP containing particles without PLTP activity (inactive form of PLTP) were almost absent in the plasma of hypo-ALP subjects, and accumulated in the plasma of CETP deficiency compared with those of controls. These results indicate that the differences in plasma PLTP concentrations between hypo-ALP subjects, CETP deficiency, and controls are mainly due to the differences in the amount of the inactive form of PLTP.


Subject(s)
Carrier Proteins/blood , Cholesterol, HDL/blood , Hyperlipoproteinemias/blood , Membrane Proteins/blood , Phospholipid Transfer Proteins , Adult , Aged , Blotting, Western , Chromatography, Gel , Electrophoresis, Polyacrylamide Gel , Female , Humans , Male , Middle Aged
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