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1.  Common variants of a urate-associated gene LRP2 are not associated with gout susceptibility 
Rheumatology International  2013;34:473-476.
A recent genome-wide association study revealed that there is an association between serum uric acid (SUA) levels and rs2544390, a common variant in low-density lipoprotein-related protein 2 (LRP2/Megalin) gene. Two other variants of LRP2, rs2229268 and rs3755166, are also found to have associations with dyslipidemia and Alzheimer’s disease, respectively, which also could have a relationship with SUA in human. Although no studies report that LRP2 transports urate, LRP2 is a multi-ligand receptor and expresses in many tissues including kidney, suggesting a direct and/or indirect relationship with gout. In the present study, we investigated the association between gout and these variants of LRP2 with 741 clinically diagnosed male gout patients and 1,302 controls. As a result, the three common LRP2 variants, rs2544390, rs2229268 and rs3755166, showed no association with gout (P = 0.76, 0.55, and 0.22, respectively). Our study is the first to reveal that an SUA-related gene LRP2 is not involved in gout susceptibility.
doi:10.1007/s00296-013-2924-8
PMCID: PMC3953547  PMID: 24366390
Gouty arthritis; Hyperuricemia; Hyperlipidemia; Urate exporter; Low-density lipoprotein receptor (LDLR); LDLR gene family
2.  Gene-Gene Combination Effect and Interactions among ABCA1, APOA1, SR-B1, and CETP Polymorphisms for Serum High-Density Lipoprotein-Cholesterol in the Japanese Population 
PLoS ONE  2013;8(12):e82046.
Background/Objective
Gene-gene interactions in the reverse cholesterol transport system for high-density lipoprotein-cholesterol (HDL-C) are poorly understood. The present study observed gene-gene combination effect and interactions between single nucleotide polymorphisms (SNPs) in ABCA1, APOA1, SR-B1, and CETP in serum HDL-C from a cross-sectional study in the Japanese population.
Methods
The study population comprised 1,535 men and 1,515 women aged 35–69 years who were enrolled in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. We selected 13 SNPs in the ABCA1, APOA1, CETP, and SR-B1 genes in the reverse cholesterol transport system. The effects of genetic and environmental factors were assessed using general linear and logistic regression models after adjusting for age, sex, and region.
Principal Findings
Alcohol consumption and daily activity were positively associated with HDL-C levels, whereas smoking had a negative relationship. The T allele of CETP, rs3764261, was correlated with higher HDL-C levels and had the highest coefficient (2.93 mg/dL/allele) among the 13 SNPs, which was statistically significant after applying the Bonferroni correction (p<0.001). Gene-gene combination analysis revealed that CETP rs3764261 was associated with high HDL-C levels with any combination of SNPs from ABCA1, APOA1, and SR-B1, although no gene-gene interaction was apparent. An increasing trend for serum HDL-C was also observed with an increasing number of alleles (p<0.001).
Conclusions
The present study identified a multiplier effect from a polymorphism in CETP with ABCA1, APOA1, and SR-B1, as well as a dose-dependence according to the number of alleles present.
doi:10.1371/journal.pone.0082046
PMCID: PMC3869658  PMID: 24376512
3.  A common variant of leucine-rich repeat-containing 16A (LRRC16A) gene is associated with gout susceptibility 
Human Cell  2013;27:1-4.
Gout is a common disease resulting from hyperuricemia which causes acute arthritis. Recently, genome-wide association studies revealed an association between serum uric acid levels and a common variant of leucine-rich repeat-containing 16A (LRRC16A) gene. However, it remains to be clarified whether LRRC16A contributes to the susceptibility to gout. In this study, we investigated the relationship between rs742132 in LRRC16A and gout. A total of 545 Japanese male gout cases and 1,115 male individuals as a control group were genotyped. rs742132 A/A genotype significantly increased the risk of gout, conferring an odds ratio of 1.30 (95 % CI 1.05–1.60; p = 0.015). LRRC16A encodes a protein called capping protein ARP2/3 and myosin-I linker (CARMIL), which serves as an inhibitor of the actin capping protein (CP). CP is an essential element of the actin cytoskeleton, which binds to the barbed end of the actin filament and regulates its polymerization. In the apical membrane of proximal tubular cells in the human kidney, the urate-transporting multimolecular complex (urate transportsome) is proposed to consist of several urate transporters and scaffolding proteins, which interact with the actin cytoskeleton. Thus, if there is a CARMIL dysfunction and regulatory disability in actin polymerization, urate transportsome may be unable to operate appropriately. We have shown for the first time that CARMIL/LRRC16A was associated with gout, which could be due to urate transportsome failure.
Electronic supplementary material
The online version of this article (doi:10.1007/s13577-013-0081-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s13577-013-0081-8
PMCID: PMC3889988  PMID: 24318514
Gouty arthritis; Single nucleotide polymorphism (SNP); Urate transport; PDZ domain-containing 1 (PDZK1); Sodium–proton exchanger regulatory factor 1 (NHERF1)
4.  Polymorphisms in genes encoding antioxidant enzymes (SOD2, CAT, GPx, TXNRD, SEPP1, SEP15 and SELS) and risk of chronic kidney disease in Japanese - cross-sectional data from the J-MICC study 
Chronic kidney disease (CKD) is well known as a strong risk factor for both of end-stage renal disease and cardiovascular disease. To clarify the association of polymorphisms in the genes encoding antioxidant enzymes (SOD2, CAT, GPx, TXNRD, SEPP1, SEP15 and SELS) with the risk of CKD in Japanese, we examined this association using the cross-sectional data of Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. The subjects were 3,285 men and women, aged 35–69 years, selected from J-MICC Study participants for whom genotyping were conducted by multiplex polymerase chain reaction-based Invader assay. The prevalence of CKD was determined for CKD stages 3–5 (eGFR <60 ml/min/1.73 m2). When those with CAT C-262T C/C were defined as reference, those with CAT C-262T C/T demonstrated the OR for CKD of 0.67 (95% CI 0.43–1.06) with the marginally significant trend for decreased odds ratio with increasing numbers of T allele (p = 0.070). There were no significant associations between the other polymorphisms with CKD risk. The present study found a marginally significant trend of the decreased risk of CKD with increasing numbers of T allele of CAT, which may suggest the possibility of personalized risk estimation of this life-limiting disease in the near future.
doi:10.3164/jcbn.13-17
PMCID: PMC3705159  PMID: 23874065
antioxidant enzymes; genetic predisposition to disease; single nucleotide polymorphisms; chronic kidney disease
5.  No association between the frequency of forest walking and blood pressure levels or the prevalence of hypertension in a cross-sectional study of a Japanese population 
Objective
To study the non-temporary effects of successive walks in forested areas (shinrin-yoku) on hypertension prevalence and blood pressure levels.
Methods
Data for the analysis were derived from the baseline survey of the Japan Multi-Institutional Collaborative Cohort (J-MICC) study in the Shizuoka area. Eligible participants were individuals aged 35–69 years who attended a health check-up center during 2006 and 2007. Of the 5,040 individuals who participated in the J-MICC study, Shizuoka, 4,666 were included in this analysis [3,174 men and 1,492 women; age (mean ± standard deviation) 52.1 ± 8.7 years]. The frequency of forest walking was estimated by a self-administrated questionnaire. Hypertension was defined as a systolic blood pressure ≥140 mmHg, a diastolic blood pressure ≥90 mmHg or, based on information provided in the questionnaire, the use of medication for hypertension.
Results
After adjusting for age, body mass index (BMI), smoking status, alcohol consumption, and habitual exercise, the odds ratios of hypertension associated with forest walking once a week or more frequently, relative to less than once a month were 0.98 in men [95% confidence interval (CI) 0.68–1.42] and 1.48 (95% CI 0.80–2.71) in women. There was no significant trend between adjusted blood pressure levels and the frequency of forest walking.
Conclusion
The results of our cross-sectional study in a Japanese population show no association between either blood pressure levels or the prevalence of hypertension and the frequency of forest walking.
doi:10.1007/s12199-010-0197-3
PMCID: PMC3156837  PMID: 21431814
Forest walking; Shinrin-yoku; Hypertension; Cross-sectional study; Japanese population
6.  Pro-/anti-inflammatory cytokine gene polymorphisms and chronic kidney disease: a cross-sectional study 
BMC Nephrology  2012;13:2.
Background
The aim of this study was to explore the associations between common potential functional promoter polymorphisms in pro-/anti-inflammatory cytokine genes and kidney function/chronic kidney disease (CKD) prevalence in a large Japanese population.
Methods
A total of 3,323 subjects aged 35-69 were genotyped for all 10 single nucleotide polymorphisms (SNPs) in the promoter regions of candidate genes with minor allele frequencies of > 0.100 in Japanese populations. The estimated glomerular filtration rate (eGFR) and CKD prevalence (eGFR < 60 ml/min/1.73 m2) of the subjects were compared among the genotypes.
Results
A higher eGFR and lower prevalence of CKD were observed for the homozygous variants of IL4 -33CC (high IL-4 [anti-inflammatory cytokine]-producing genotype) and IL6 -572GG (low IL-6 [pro-inflammatory cytokine]-producing genotype). Subjects with IL4 CC + IL6 GG showed the highest mean eGFR (79.1 ml/min/1.73 m2) and lowest CKD prevalence (0.0%), while subjects carrying IL4 TT + IL6 CC showed the lowest mean eGFR (73.4 ml/min/1.73 m2) and highest CKD prevalence (17.9%).
Conclusions
The functional promoter polymorphisms IL4 T-33C (rs2070874) and IL6 C-572G (rs1800796), which are the only SNPs that affect the IL-4 and IL-6 levels in Japanese subjects, were associated with kidney function and CKD prevalence in a large Japanese population.
doi:10.1186/1471-2369-13-2
PMCID: PMC3297507  PMID: 22230215
7.  Profile of Participants and Genotype Distributions of 108 Polymorphisms in a Cross-Sectional Study of Associations of Genotypes With Lifestyle and Clinical Factors: A Project in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study 
Journal of Epidemiology  2011;21(3):223-235.
Background
Most diseases are thought to arise from interactions between environmental factors and the host genotype. To detect gene–environment interactions in the development of lifestyle-related diseases, and especially cancer, the Japan Multi-institutional Collaborative Cohort (J-MICC) Study was launched in 2005.
Methods
We initiated a cross-sectional study to examine associations of genotypes with lifestyle and clinical factors, as assessed by questionnaires and medical examinations. The 4519 subjects were selected from among participants in the J-MICC Study in 10 areas throughout Japan. In total, 108 polymorphisms were chosen and genotyped using the Invader assay.
Results
The study group comprised 2124 men and 2395 women with a mean age of 55.8 ± 8.9 years (range, 35–69 years) at baseline. Among the 108 polymorphisms examined, 4 were not polymorphic in our study population. Among the remaining 104 polymorphisms, most variations were common (minor allele frequency ≥0.05 for 96 polymorphisms). The allele frequencies in this population were comparable with those in the HapMap-JPT data set for 45 Japanese from Tokyo. Only 5 of 88 polymorphisms showed allele-frequency differences greater than 0.1. Of the 108 polymorphisms, 32 showed a highly significant difference in minor allele frequency among the study areas (P < 0.001).
Conclusions
This comprehensive data collection on lifestyle and clinical factors will be useful for elucidating gene–environment interactions. In addition, it is likely to be an informative reference tool, as free access to genotype data for a large Japanese population is not readily available.
doi:10.2188/jea.JE20100139
PMCID: PMC3899413  PMID: 21467728
allele frequency; cross-sectional studies; gene–environment interactions; Japan Multi-institutional Collaborative Cohort Study; polymorphism

Results 1-7 (7)