A randomized phase II trial of cisplatin plus gemcitabine versus carboplatin plus gemcitabine in patients with completely resected non-small cell lung cancer: Hokkaido Lung Cancer Clinical Study Group Trial (HOT0703).

PURPOSE: This study evaluated the efficacy and safety of platinum plus gemcitabine (P/G) combinations as postoperative adjuvant chemotherapies for non-small cell lung cancer. METHODS: Patients with postoperative stage IB-IIIA non-small cell lung cancer were randomly assigned to receive either cisplatin plus gemcitabine (GP arm) or carboplatin plus gemcitabine (GC arm) every 3 weeks for four cycles. The primary endpoint was 2-year disease-free survival (DFS). Secondary endpoints were safety, feasibility, overall survival (OS), and biomarker analyses. RESULTS: A total of 102 patients were randomized (stage IB, 22%; II, 36%; IIIA, 42%; histology: 74% adenocarcinoma). Of the 51 patients in each arm, 37 (73%) completed 4 cycles. During follow-up (median 5.8 years; range 0.1-9.7 years), estimated DFS and OS rates at 2 years were 59.6% and 86.3% with GP and 68.0% and 86.3% with GC, respectively. No significant difference in DFS was noted between arms (P = 0.163), although 3-, 4-, and 5-year DFS rates were higher with GC. Hematological toxic effects were comparable and non-hematological toxic effects were infrequent. DFS was significantly higher in the excision repair cross-complementation group 1 (ERCC1)-low group than in the ERCC1-high group for the GP arm (P = 0.045). CONCLUSION: Both P/G combination regimens were feasible and well-tolerated, and thus may represent valid options for postoperative adjuvant treatment of non-small cell lung cancer. Although no significant differences in DFS were evident between regimens, the present data favor the adoption of GC for further evaluation. CLINICAL TRIAL REGISTRATION: UMIN-CTR ( https://www.umin.ac.jp/ctr/ ) identifier: UMIN000000913.

In vitro studies on mangiferin protection against cadmium-induced human renal endothelial damage and cell death via the MAP kinase and NF-κB pathways.

The therapeutic effects of the natural antioxidant mangiferin (a xanthonoid and potent oxygen free radical scavenger), which is widely distributed in mango fruit, against CdCl(2)-induced toxicity in human renal glomerulus endothelial cells (HRGEC) were investigated. The viability of HREGCs that were treated with CdCl(2) (25 µ mol) and co-treated with mangiferin (75 µ mol) for 24 h was measured by crystal violet dye. The exposure of human glomerulus renal endothelial cells to cadmium promotes a polarized apical secretion of IL-6 and IL-8, two pivotal proinflammatory cytokines known to play a significant role in renal inflammation. Proinflammatory cytokine secretion by human renal glomerulus endothelial cells could be the result of cadmium-induced IL-6 secretion via an NF-κB-dependent pathway. However, IL-8 secretion involves the phosphor-JNK phospho-p38 signaling pathway. The results of the current study reveal that mangiferin could prevent both cadmium-induced IL-6 and IL-8 secretion by human glomerulus endothelial cells and be used to prevent renal inflammation.

Kaempferol, a potential cytostatic and cure for inflammatory disorders.

Kaempferol (3,5,7-trihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) is a flavonoid found in many edible plants (e.g., tea, broccoli, cabbage, kale, beans, endive, leek, tomato, strawberries, and grapes) and in plants or botanical products commonly used in traditional medicine (e.g., Ginkgo biloba, Tilia spp, Equisetum spp, Moringa oleifera, Sophora japonica and propolis). Its anti-oxidant/anti-inflammatory effects have been demonstrated in various disease models, including those for encephalomyelitis, diabetes, asthma, and carcinogenesis. Moreover, kaempferol act as a scavenger of free radicals and superoxide radicals as well as preserve the activity of various anti-oxidant enzymes such as catalase, glutathione peroxidase, and glutathione-S-transferase. The anticancer effect of this flavonoid is mediated through different modes of action, including anti-proliferation, apoptosis induction, cell-cycle arrest, generation of reactive oxygen species (ROS), and anti-metastasis/anti-angiogenesis activities. In addition, kaempferol was found to exhibit its anticancer activity through the modulation of multiple molecular targets including p53 and STAT3, through the activation of caspases, and through the generation of ROS. The anti-tumor effects of kaempferol have also been investigated in tumor-bearing mice. The combination of kaempferol and conventional chemotherapeutic drugs produces a greater therapeutic effect than the latter, as well as reduces the toxicity of the latter. In this review, we summarize the anti-oxidant/anti-inflammatory and anticancer effects of kaempferol with a focus on its molecular targets and the possible use of this flavonoid for the treatment of inflammatory diseases and cancer.

Efficacy of pyruvate therapy in patients with mitochondrial disease: a semi-quantitative clinical evaluation study.

BACKGROUND: Disorders of oxidative phosphorylation (OXPHOS) cause an increase in the NADH/NAD(+) ratio, which impairs the glycolysis pathway. Treatment with pyruvate is expected to decrease the ratio and thereby restore glycolysis. There are some case reports on the efficacy of pyruvate treatment for mitochondrial diseases. However, few of these reports assessed their results using a standardized scale. METHODS: We monitored 4 bedridden patients with OXPHOS disorders who continued therapies of 0.5-1.0 g/kg/day of sodium pyruvate for more than 12 months. The efficacies of these treatments were evaluated with the Newcastle Pediatric Mitochondrial Disease Scale and the Gross Motor Function Measure with 88 items. RESULTS: The ages of the patients at the treatment initiation ranged from 8-100 months. Of the 4 patients, 3 exhibited improvements within 1-3 months from the initiation of treatment. Among these 3 patients, one maintained the improvement for over 2 years. The remaining 2 regressed 3-6 months after the initiation of treatment. The blood lactate/pyruvate ratios did not correlate with the efficacy of treatment. CONCLUSION: Pyruvate was effective even in bedridden patients with OXPHOS disorders, at least in the short term. Clinical trials with more patients and less severe disabilities are necessary to evaluate the long-term efficacy of this treatment. Biomarkers other than lactate and pyruvate need to be identified to biochemically monitor the efficacy of this treatment.

The vascular endothelium and human diseases.

Alterations of endothelial cells and the vasculature play a central role in the pathogenesis of a broad spectrum of the most dreadful of human diseases, as endothelial cells have the key function of participating in the maintenance of patent and functional capillaries. The endothelium is directly involved in peripheral vascular disease, stroke, heart disease, diabetes, insulin resistance, chronic kidney failure, tumor growth, metastasis, venous thrombosis, and severe viral infectious diseases. Dysfunction of the vascular endothelium is thus a hallmark of human diseases. In this review the main endothelial abnormalities found in various human diseases such as cancer, diabetes mellitus, atherosclerosis, and viral infections are addressed.

Development of an image processing support system based on fluorescent dye to prevent elderly people with dementia from wandering.

The wandering of elderly people with dementia is a significant behavioral problem and is a heavy burden on caregivers in residential and nursing homes. Thus, warning systems have been developed to prevent elderly people with dementia from leaving the premises. Some of these systems use radio waves. However, systems based on radio waves present several practical problems. For instance, the transmitter must be carried and may become lost; in addition, the battery of the transmitter must be changed. To solve these problems, we developed a support system that prevents elderly people with dementia from wandering. The system employs image processing technology based on fluorescent dye. The composition of the support system can be described as follows: fluorescent dye is painted in a simple shape on the clothes of an elderly person. The fluorescent color becomes visible by irradiation with a long wavelength of ultraviolet light. In the present paper, the relationship between the color of the dye and the cloth was investigated. A 3D video camera was used to acquire a 3D image and detect the simple shape. As a preliminary experiment, 3 colors (red, green and blue) of fluorescent dye were applied to cloths of 9 different colors. All fluorescent colors were detected on 6 of the cloths, but red and blue dye could not be detected on the other 3 cloths. In contrast, green dye was detectable on all 9 of the cloths. Additionally, we determined whether green dye could be detected in an actual environment. A rectangular shaped patch of green fluorescent dye was painted on the shoulder area of a subject, from the scapula to the clavicle. As a result, the green dye was detected on all 9 different colored cloths.

Immunomodulatory Effect of Mangiferin in Experimental Animals with Benzo(a)Pyrene-induced Lung Carcinogenesis.

The immunomodulatory activity of mangiferin was studied in various groups of animals. For this study, adult Swiss albino male mice were treated with benzo(a)pyrene, abbreviated as B(a)P, at 50 mg/kg body weight orally twice a week for 4 weeks; and mangiferin was also given orally (pre- and post-initiation of carcinoma) at 100 mg/kg body weight. Immunocompetence and immune complexes as measured by phagocyte index, avidity index, and soluble immune complex (SIC) levels (p<0.001), as well as NBT reduction, were decreased in the B(a)P-treated animals;whereas increased levels of immunocompetence were noted in the mangiferin-treated animals given B(a)P (p<0.001, p<0.05). The levels of immunoglobulins such as IgG and IgM were decreased considerably (p<0.001) in the B(a)P-treated animals compared with their levels in the control animals; whereas the IgA level was increased (p<0.001). In the mangiferin-treated experimental animals given B(a)P, the levels of IgG and IgM were significantly (p<0.001, p<0.05) increased whereas the IgA level was decreased compared with those for the B(a)P-treated mice. Oxidative changes in lymphocytes, neutrophils, and macrophages were also measured. The enhanced lipid peroxidation and decreased catalase and superoxide dismutase activities found in the lymphocytes, polymorphonuclear cells (PMN), and macrophages from B(a)P-treated mice were significantly reduced and increased, respectively, by the mangiferin treatment. This study confirms the immunomodulatory effect of mangiferin and shows an immunoprotective role arbitrated through a reduction in the reactive intermediate-induced oxidative stress in lymphocytes, neutrophils, and macrophages.

Extended screening for major mitochondrial DNA point mutations in patients with hereditary hearing loss.

Hearing loss (HL) is the most common sensory disorder in humans. Many patients with mitochondrial diseases have sensorineural HL (SNHL). The HL of these patients manifests as a consequence of either syndromic or nonsyndromic mitochondrial diseases. Furthermore, the phenotypes vary among patients even if they are carrying the same mutation. Therefore, these features make it necessary to analyze every presumed mutation in patients with hereditary HL, but the extensive analysis of various mutations is laborious. We analyzed 373 patients with suspected hereditary HL by using an extended suspension-array screening system for major mitochondrial DNA (mtDNA) mutations, which can detect 32 other mtDNA mutations in addition to the previously analyzed 29 mutations. In the present study, we detected 2 different mtDNA mutations among these 373 patients; m.7444G>A in the MT-CO1 gene and m.7472insC in the MT-TS1 gene in 1 patient (0.3%) for each. As these two patients had no clinical features other than HL, they had not been suspected of having mtDNA mutations. This extended screening system together with the previous one is useful for the genetic diagnosis and epidemiological study of both syndromic and nonsyndromic HL.

Association of a polymorphism of BTN2A1 with myocardial infarction in East Asian populations.

OBJECTIVE: We have performed a genome-wide association study (GWAS) to identify genetic variants that confer susceptibility to myocardial infarction (MI) in Japanese and Korean populations. METHODS: A total of 17,447 Japanese or Korean individuals from four independent subject panels was examined. Japanese subject panels A, B, and C comprised 134 individuals with MI and 137 controls, 1431 individuals with MI and 3161 controls, and 643 individuals with MI and 1347 controls, respectively, whereas the Korean population comprised 1880 individuals with MI and 8714 controls. A GWAS for MI was performed in Japanese subject panel A with the use of the Affymetrix GeneChip Human Mapping 500K Array Set. RESULTS: Seventy single nucleotide polymorphisms (SNPs) significantly (P<1.0×10(-7)) associated with MI by the GWAS were examined further in Japanese subject panel B, revealing two SNPs (rs6929846 of BTN2A1, rs2569512 of ILF3) to be significantly (P<0.0007) associated with MI. The rs6929846 SNP of BTN2A1, but not rs2569512 of ILF3, was also significantly associated with MI in Japanese subject panel C. However, the association of neither rs6929846 nor rs2569512 with MI was replicated in the Korean population. CONCLUSION: BTN2A1 may be a susceptibility gene for MI in Japanese individuals.

Mitochondrial haplogroups A and M7a confer a genetic risk for coronary atherosclerosis in the Japanese elderly: an autopsy study of 1,536 patients.

AIM: We previously reported significant associations between mitochondrial single nucleotide polymorphisms (mtSNPs) and myocardial infarction, atherothrombotic cerebral infarction, metabolic syndrome and type 2 diabetes. Here, we assessed the hypothesis that mtSNPs may confer a risk for atherosclerosis, the most important intermediate phenotype of ischemic cardiovascular events. METHODS: The subjects were 1,536 consecutive autopsy cases (827 men and 709 women). The average age at death was 80 years. The severity of coronary atherosclerosis was semi-quantitatively examined on cut sections. We examined 149 mtSNPs using the PCR-Luminex method, with a success rate of 97%. Phylogenetic tree analysis yielded 36 haplogroups. Multiple logistic regression analysis was performed after adjustments for sex, age, and conventional cardiovascular risk factors. RESULTS: Among the 45 mtSNPs with minor genotype frequencies >0.05, 6 mtSNPs were associated with coronary atherosclerosis. Among 10 haplogroups with frequencies >0.04, haplogroups A and M7a were significantly associated with coronary atherosclerosis, with odds ratios (95% confidence intervals) of 1.80 (1.09-2.97; p=0.023) and 1.92 (1.23-3.01; p=0.004), respectively. Haplogroup D4a, which was previously reported to be associated with extreme longevity in a Japanese population, was associated with pathological myocardial infarction in men with an odds ratio of 2.05 (1.01-4.14; p=0.046). CONCLUSIONS: The mitochondrial haplogroups A and M7a confer a significant risk for coronary atherosclerosis in the Japanese. The mitochondrial haplogroup may contribute some genetic risk for coronary heart disease.

Mitochondrial haplogroups associated with lifestyle-related diseases and longevity in the Japanese population.

Recently published results on the association between metabolic syndrome, type 2 diabetes, myocardial infarction or atherothrombotic cerebral infarction and Japanese major haplogroups based on the comprehensive analysis of mitochondrial genome polymorphisms (mtSNP) in the coding region of human mitochondrial DNA (mtDNA), and longevity-related haplogroups are described in the present review. Our aim was to provide information that would allow us to predict the genetic risk for lifestyle-related diseases and thereby contribute to the primary prevention of these conditions. The mitochondrial genome variation is so large that a given haplogroup might consist of various subhaplogroups carrying unique and presumably functional mtSNP. The frequency of each subhaplogroup is sometimes only a few percent. Therefore, large-scale association study is necessary for elucidating the impact of each subhaplogroup on the susceptibility to various common diseases.

Effect of fresh apple extract on glycated protein/iron chelate-induced toxicity in human umbilical vein endothelial cells in vitro.

Consumption of fruits and vegetables has been associated with a low incidence of cardiovascular and other chronic diseases. The present study was aimed at evaluating the protective effects of fresh apple extract (AE) on human umbilical vein endothelial cells (HUVEC) exposed to cytotoxic glycated protein (GFBS)/iron (FeCl(3)) chelate. The experimental design comprised 10 groups with 5 flasks in each group. Group I was treated with 15% foetal bovine serum (FBS). Groups II, III and IV were treated with GFBS (70 microM), FBS + FeCl(3) (20 microM), and GFBS + FeCl(3), respectively. The other six groups were as follows: Group V, GFBS + AE (100 microg); Group VI, FBS + FeCl(3) + AE (100 microg); Group VII, GFBS + FeCl(3) + AE (100 microg); Group VIII, GFBS + AE (250 microg); Group IX, FBS + FeCl(3) + AE (250 microg); and Group X, GFBS + FeCl(3) + AE (250 microg). After 24 h incubation, cells were collected from all the experimental groups and assessed for lipid peroxidation (LPO) and activities of the antioxidant enzymes cytochrome c reductase and glutathione S-transferase (GST). HUVEC incubated with glycated protein (GFBS) either alone or combined with iron chelate showed a significant (p < 0.001) elevation of LPO accompanied by depletion of superoxide dismutase, catalase, glutathione peroxidase (GPx) and glutathione reductase (GR), in addition to increased microsomal cytochrome c reductase and decreased GST activities. Treatment of GFBS- or GFBS + FeCl(3)-exposed HUVEC with AE at 100 or 250 microg significantly decreased the level of LPO and returned the levels of antioxidants cytochrome c reductase and GST to near normal in a dose-dependent manner. The extracts recovered viability of HUVEC damaged by GFBS-iron treatment in a concentration-dependent manner. These findings suggest a protective effect of AE on HUVEC against glycated protein/iron chelate-induced toxicity, which suggests that AE could exert a beneficial effect by preventing diabetic angiopathies.

Macrophages that survive hyperoxia exposure have higher superoxide dismutase activities in their mitochondria.

Prolonged exposure to hyperoxia, which is routinely used in patients with severe respiratory failure, leads to the generation of excessive reactive oxygen species, resulting in lung injury. In the present study, we focused on macrophages and their survival, superoxide dismutase (SOD) activity in mitochondria (Mn-SOD activity), and mitochondrial DNA (mtDNA) mutation after exposure to hyperoxia. Macrophages were cultured under two different conditions: normoxia and intermittent hyperoxia. The number of cells exposed to intermittent hyperoxia for 3 weeks significantly decreased, compared with the number of cells exposed to normoxia. The Mn-SOD activity of the cells that survived intermittent hyperoxia exposure was significantly higher than that of the cells exposed to normoxia. Direct sequencing and a PCR-RFLP assay did not provide any evidence of mutation in the cells that survived intermittent hyperoxia exposure. In conclusion, an increase in the antioxidative activity of mitochondria is important for the survival of macrophages exposed to hyperoxia, and the increased activity level possibly enhances protective effects against mtDNA mutations in surviving cells.

Extensive and rapid screening for major mitochondrial DNA point mutations in patients with hereditary hearing loss.

Sensorineural hearing loss (HL) is one of the most frequent clinical features in patients with mitochondrial diseases caused by mitochondrial DNA (mtDNA) mutations, and hearing is impaired in over half of all cases with mitochondrial disorders. This study analyzed 373 patients with suspected hereditary HL using an extensive and rapid suspension-array screening system for 29 major mtDNA mutations, including the m.1555A>G homoplasmic mutation in the MT-RNR1 gene, which causes non-syndromic sensorineural HL and aminoglycoside-induced HL, and the m.3243A>G heteroplasmic mutation in the MT-TL1 gene. This method is rapid and suitable for large-scale screening because universal 96-well plates are available for use, and because an analysis of each plate can be completed within 1 h. This system detected five different mtDNA mutations in 24 of the 373 (6.4%) patients. The m.1555A>G and m.3243A>G mutations were detected in 11 (2.9%) and 9 (2.7%) patients, respectively. In addition, three mutations, that is, m.8348A>G in the MT-TK gene, m.11778G>A in the MT-ND4 gene and 15498G>A in the MT-CYB gene were detected in one patient for each. This screening system is useful for the genetic diagnosis and epidemiological study of both syndromic and non-syndromic HL.

Extensive screening system using suspension array technology to detect mitochondrial DNA point mutations.

We established an extensive and rapid system using suspension array to detect 61 representative mitochondrial DNA (mtDNA) heteroplasmic or homoplasmic point mutations (29 for Series A and 32 for Series B) in 22 genes: 1 each in MT-RNR1, -TV, -ND1, -TQ, -TW, -TC, and -TH genes; 2 each in MT-TN, -TG, -ND4, -TL2, -TE, and -CYB genes; 3 each in MT-ATP6, -ND3, and -ND5 genes; 4 each in MT-CO1 and -TK genes; 5 each in MT-TI, -TS1, and -ND6 genes; and 10 in the MT-TL1 gene. We carefully selected 5'-biotinylated primers and pooled primers for use in two sets of multiplex-PCR amplifications. To detect both mutant and wild-type mtDNA, even when polymorphisms were present near the target mutation sites, we designed specific oligonucleotide probes. By using the mtDNA point mutation detection system of Series A (29 mutations) and Series B (32 mutations), we screened a total of 3103 mutant sites in 107 DNA samples for Series A and 13,101 mutant sites in 397 DNA samples for Series B. We succeeded in determining 99.4% (Series A) and 99.6% (Series B) of the targeted mutant sites by use of the system. The 22 samples with the m.3243A>G heteroplasmic mutation revealed positive signals with both mutant- and wild-type-specific probes in this detection system with a detection limit of approximately 2%. This genetic screening platform is useful to reach a definitive diagnosis for mitochondrial diseases.

Cytoprotective role of astaxanthin against glycated protein/iron chelate-induced toxicity in human umbilical vein endothelial cells.

Astaxanthin (ASX), a red carotenoid pigment with no pro-vitamin A activity, is a biological antioxidant that occurs naturally in a wide variety of plants, algae and seafoods. This study investigated whether ASX could inhibit glycated protein/iron chelate-induced toxicity in human umbilical-vein endothelial cells (HUVEC) by interfering with ROS generation in these cells. Glycated fetal bovine serum (GFBS) was prepared by incubating fetal bovine serum (FBS) with high-concentration glucose. Stimulation of cultured HUVECs with 50 mm 1 mL of GFBS significantly enhanced lipid peroxidation and decreased antioxidant enzyme activities and levels of phase II enzymes. However, preincubation of the cultures with ASX resulted in a marked decrease in the level of lipid peroxide (LPO) and an increase in the levels of antioxidant enzymes in an ASX concentration-dependent manner. These results demonstrate that ASX could inhibit LPO formation and enhance the antioxidant enzyme status in GFBS/iron chelate-exposed endothelial cells by suppressing ROS generation, thereby limiting the effects of the AGE-RAGE interaction. The results indicate that ASX could have a beneficial role against glycated protein/iron chelate-induced toxicity by preventing lipid and protein oxidation and increasing the activity of antioxidant enzymes.

Pyruvate therapy for Leigh syndrome due to cytochrome c oxidase deficiency.

BACKGROUND: Recently we proposed the therapeutic potential of pyruvate therapy for mitochondrial diseases. Leigh syndrome is a progressive neurodegenerative disorder ascribed to either mitochondrial or nuclear DNA mutations. METHODS: In an attempt to circumvent the mitochondrial dysfunction, we orally applied sodium pyruvate and analyzed its effect on an 11-year-old female with Leigh syndrome due to cytochrome c oxidase deficiency accompanied by cardiomyopathy. The patient was administered sodium pyruvate at a maintenance dose of 0.5 g/kg/day and followed up for 1 year. RESULTS: The exercise intolerance was remarkably improved so that she became capable of running. Echocardiography indicated improvements both in the left ventricle ejection fraction and in the fractional shortening. Electrocardiography demonstrated amelioration of the inverted T waves. When the pyruvate administration was interrupted because of a gastrointestinal infection, the serum lactate level became elevated and the serum pyruvate level, decreased, suggesting that the pyruvate administration was effective in decreasing the lactate-to-pyruvate ratio. CONCLUSIONS: These data indicate that pyruvate therapy was effective in improving exercise intolerance at least in a patient with cytochrome c oxidase deficiency. GENERAL SIGNIFICANCE: Administration of sodium pyruvate may prove effective for other patients with cytochrome c oxidase deficiency due to mitochondrial or nuclear DNA mutations.

Analysis of mitochondrial DNA variants in Japanese patients with schizophrenia.

To test the hypothesis that mitochondrial DNA (mtDNA) variants contribute to the susceptibility to schizophrenia, we sequenced the entire mtDNAs from 93 Japanese schizophrenic patients. Three non-synonymous homoplasmic variants in subunit six of the ATP synthase (MT-ATP6) gene that were detected only in patients but not in controls were suggested to be slightly deleterious, because (1) their original amino acid residues (AA) were highly conserved and (2) the physicochemical differences between the original and altered AA were relatively high. In addition, we detected three novel heteroplasmic variants that were potentially pathogenic. Although functional analysis is needed, rare variants in the mtDNA may convey susceptibility to schizophrenia.

[Mitochondrial genome and longevity].

In humans, mitochondrial DNA (mtDNA) is a 16,569-bp double-stranded circular molecule, encoding 37 genes, and is exclusively transmitted from the mother. According to the recent findings from many studies of mitochondrial diseases caused by nuclear gene mutations, the accumulation of somatic mtDNA mutations in tissues has been expected to contribute toward age-associated mitochondrial dysfunction and a life span.

Association of genetic variants with chronic kidney disease in individuals with different lipid profiles.

The purpose of the present study was to identify genetic variants that confer susceptibility to chronic kidney disease (CKD) in individuals with low or high serum concentrations of triglycerides (TG), high-density lipoprotein (HDL)-cholesterol, or low-density lipoprotein (LDL)-cholesterol, thereby contributing to the personalized prevention of CKD in such individuals. The study population comprised 5944 Japanese individuals, including 1706 subjects with CKD [estimated glomerular filtration rate (eGFR)<60 ml/min/1.73 m2] and 4238 controls (eGFR>or=60 ml/min/1.73 m2). The genotypes for 296 polymorphisms of 202 candidate genes were determined. The Chi-square test, multivariable logistic regression analysis with adjustment for covariates, and a stepwise forward selection procedure revealed that seven different polymorphisms were significantly (P<0.005) associated with the prevalence of CKD in individuals with low or high serum concentrations of TG or HDL- or LDL-cholesterol: the Aright curved arrow G (Glu23Lys) polymorphism of KCNJ11 and the 125592Cright curved arrow A (Thr431Asn) polymorphism of ROCK2 in individuals with low serum TG; the 734Cright curved arrow T (Thr254Ile) polymorphism of ACAT2 and the Cright curved arrow G (Gln27Glu) polymorphism of ADRB2 in individuals with high serum TG; the -1607/1Gright curved arrow 2G polymorphism of MMP1 in individuals with low serum HDL-cholesterol; the Gright curved arrow A (Val158Met) polymorphism of COMT in individuals with low serum LDL-cholesterol; the 584Gright curved arrow A (Gln192Arg) polymorphism of PON1 in individuals with high serum LDL-cholesterol. No polymorphism was associated with CKD in individuals with high serum HDL-cholesterol. These results suggest that polymorphisms associated with CKD may differ among individuals with different lipid profiles. Stratification of subjects according to lipid profiles may thus be important for personalized prevention of CKD based on genetic information.