Denosumab-induced hypocalcemia in patients with solid tumors and renal dysfunction: a multicenter, retrospective, observational study.

BACKGROUND: Bone metastases are frequently observed in advanced cancer, and bone modifying agents are used to prevent or treat skeletal-related events. Zoledronic acid is contraindicated in patients with severe renal impairment (Ccr < 30 mL/min), but it is not completely known whether denosumab can be used in them. We aimed to determine the association between renal function and hypocalcemia development during denosumab treatment. METHODS: We included patients with solid cancer and bone metastases who started denosumab treatment between April 2017 and March 2019. They were classified into four groups based on creatinine clearance (Ccr; mL/min): normal (Ccr ≥ 80), mild (50 ≤ Ccr ˂80), moderate (30 ≤ Ccr ˂50), and severe (Ccr ˂30). Hypocalcemia was evaluated using the Common Terminology Criteria for Adverse Events (v5.0) based on the albumin-adjusted serum calcium levels; its incidence (stratified by renal function) and risk factors were investigated using a Chi-square test and logistic regression analysis. RESULTS: Of 524 patients (age: 69 ± 11 years; 303 men), 153 had a normal renal function and 222, 117, and 32 had mild, moderate, and severe renal dysfunction. The albumin-adjusted serum calcium level was higher than the measured (total) calcium level in most patients. The incidence of grade ≥ 1 hypocalcemia was 32.0% in the normal group and 37.4%, 29.9%, and 62.5% in the mild, moderate, and severe renal dysfunction groups, respectively. It was, therefore, higher in the severe renal dysfunction groups than in the normal group (P = 0.002). The incidence of grade ≥ 3 hypocalcemia did not differ significantly among the groups. Pre-treatment low serum calcium levels and severe renal dysfunction were risk factors for hypocalcemia. CONCLUSIONS: Evaluating denosumab-induced hypocalcemia required albumin adjustment, and its incidence was high among patients with severe renal dysfunction. Reduced serum calcium levels and severely impaired renal function were associated with an elevated hypocalcemia risk.

Comparison of Analgesic Efficacy and Safety of Low-Dose Transdermal Fentanyl and Oral Oxycodone in Opioid-Naïve Patients with Cancer Pain.

In Japan, a low-dose transdermal fentanyl (TDF; 0.5 mg) has been approved to address pain in opioid-naïve patients with cancer; however, efficacy and safety data are lacking. To determine the efficacy and safety of TDF, patients with opioid-naïve cancer pain prescribed TDF (0.5 mg/d) and oral oxycodone sustained-release formulation (OXY) 10 mg/d were extracted from electronic medical and nursing records. Overall, 40 and 101 subjects were analyzed in the TDF and OXY groups, respectively. Compared with baseline (median [minimum, maximum]) values, changes in the Numerical Rating Scale (NRS) score on days 1, 3, and 7 post-administration were as follows: TDF (0 [-5, 4]) and OXY (-1.0 [-8, 3]); TDF (-1.5 [-6, 3]) and OXY (-2.0 [-8, 4]); and TDF (-2.0[-6, 3]) and OXY (-3.0[-8, 5]), respectively. No significant difference was observed between the groups on days 1 and 3; however, the change in the NRS on day 7 was significantly higher in the OXY group than that in the TDF group. Regarding adverse events, nausea occurred in 12.5 and 13.9% of patients in the TDF and OXY groups, respectively, while 12.5% of TDF- and 10.9% of OXY-treated patients experienced somnolence, revealing similar occurrence in both groups. However, constipation was more common in the OXY group (TDF: 50.0%, OXY: 71.3%). No serious adverse events (e.g., respiratory depression) were observed in either group. Low-dose TDF (0.5 mg), available only in Japan, showed comparable efficacy and safety to OXY (10 mg/d) and can be a first choice for opioid-naïve patients with cancer pain.

Retrospective multicentre study on the effectiveness of first-line direct-acting antivirals against hepatitis C virus genotype-1.

WHAT IS KNOWN AND OBJECTIVE: In Japan, ledipasvir/sofosbuvir, elbasvir/grazoprevir and glecaprevir/pibrentasvir are recommended as first-line treatments for patients with untreated hepatitis C virus genotype 1. Although they have demonstrated a high efficacy in clinical trials, there are no direct comparative studies. Clarification of their effectiveness and safety in real-world clinical practice is required. Therefore, we conducted a retrospective multicentre study on the effectiveness of these direct-acting antivirals in real-world clinical practice. METHODS: We retrospectively evaluated the clinical data of untreated patients with persistent HCV genotype 1 infection who started first-line treatment with ledipasvir/sofosbuvir, elbasvir/grazoprevir or glecaprevir/pibrentasvir between September 2015 and January 2019 at 11 medical institutions in Japan. The primary efficacy endpoint was a sustained virologic response after 12 weeks of treatment. The secondary endpoints included sustained virologic response after 24 weeks of treatment and end of treatment response. The safety endpoint was treatment completion rate. RESULTS AND DISCUSSION: During the study, 420 patients (median age, 70 years; 181 males) received ledipasvir/sofosbuvir, 48 (median age 72, years; 29 males) received elbasvir/grazoprevir and 63 (median age 66, years; 35 males) received glecaprevir/pibrentasvir. For ledipasvir/sofosbuvir, elbasvir/grazoprevir and glecaprevir/pibrentasvir, the sustained virologic response after 12 weeks of treatment was 98.6%, 97.9% and 100%; the sustained virologic response after 24 weeks of treatment was 99.0%, 97.7% and 100%; the end of treatment response was 99.8%, 97.9% and 98.4%; and the treatment completion rate was 98.3%, 91.7% and 100% respectively. WHAT IS NEW AND CONCLUSION: In real-world clinical practice, hepatitis C virus treatment with ledipasvir/sofosbuvir, elbasvir/grazoprevir and glecaprevir/pibrentasvir was effective with safety.

Sedentary time, physical activity, and serum SPARC in a middle-aged population.

The influence of habitual physical activity (PA) on the circulating levels of secreted protein acidic and rich in cysteine (SPARC) remains unclear. The purpose of the current study was to clarify the effects of sedentary time, light-intensity PA (LPA), and moderate- to vigorous-intensity PA (MVPA) on the serum SPARC in a general middle-aged population. The current study is a cross-sectional study of 4,000 men and 6,040 women (40-69 years). Sedentary time, LPA, and MVPA were objectively measured by an accelerometer. The serum SPARC concentration was measured by enzyme-linked immunosorbent assay. Using an isotemporal substitution model, cross-sectional associations of replacing sedentary time with either LPA or MVPA on serum SPARC levels were analysed according to sex. Interactions with subject characteristics, such as the body mass index (BMI), smoking, and alcohol consumption, were also examined. In men, replacing 60 min of sedentary time with 60 min of MVPA was significantly associated with 23 ng/mL lower serum SPARC levels (confidence interval: -43, -2) after adjusting for confounders, including the BMI (P = 0.028). A significant interaction between replacing sedentary behaviour with LPA and the BMI on SPARC was detected in women (P = 0.029), although the stratified associations for each BMI level (<25 or ≥25 kg/m2) did not reach significance. The current study suggests that replacing sedentary time with MVPA is associated with reduced serum SPARC levels in middle-aged men, but not in women. In addition, a potential interaction between LPA and the BMI on SPARC was also found in women.Highlights An isotemporal substitution analysis showed that replacing sedentary behaviour with moderate- to vigorous-intensity physical activity (MVPA) is associated with decreased serum SPARC levels in men.Such an inverse association between replacing sedentary behaviour with MVPA and the SPARC levels was not observed in women.A potential interaction between replacing sedentary behaviour with light-intensity PA and the body mass index on the serum SPARC levels was also found in women.

A retrospective study comparing interventions by oncology and non-oncology pharmacists in outpatient chemotherapy.

BACKGROUND: The differences in the clinical pharmacy services (CPS) provided by oncology and non-oncology pharmacists have not been sufficiently explained. AIM: This study aimed to demonstrate the differences in direct CPS provided by oncology and non-oncology pharmacists for patients and physicians, and to assess the potential impact of these services on medical costs. METHODS: We retrospectively examined CPS provided by oncology and non-oncology pharmacists for outpatients who underwent chemotherapy between January and December 2016. RESULTS: In total, 1177 and 1050 CPS provided by oncology and non-oncology pharmacists, respectively, were investigated. The rates of interventions performed by oncology and non-oncology pharmacists for physicians-determined treatment were 18.5% and 11.3%, respectively (p < .001). The rates of oncology and non-oncology pharmacist interventions accepted by physicians were 84.6 and 78.8%, respectively (p = .12). Level 4 and Level 5 interventions accounted for 64.6% of all oncology pharmacist interventions and 53.0% of all non-oncology pharmacist interventions (p = .03). The rates of improvement in symptoms from adverse drug reactions among patients resulting from interventions by oncology and non-oncology pharmacists were 89.4 and 72.1%, respectively (p = .02). Conservative assessments of medical cost impact showed that a single intervention by an oncology and by a non-oncology pharmacist saved ¥6355 and ¥3604, respectively. CONCLUSION: The results of the present study suggested that CPS by oncology pharmacists enable safer and more effective therapy for patients with cancer and indirectly contribute to reducing health care fees.

Habitual Light-intensity Physical Activity and ASC Methylation in a Middle-aged Population.

Apoptosis-associated, speck-like protein containing a caspase recruitment domain (ASC) plays an important role in inflammatory cytokine synthesis in peripheral blood mononuclear cells (PBMCs), and the expression of ASC is suppressed by increased methylation of its CpG sites. The current study investigated the longitudinal association of replacing sedentary time with light-intensity physical activity (LPA) or moderate to vigorous-intensity physical activity (MVPA) on the ASC methylation in middle-aged people. We investigated 1 238 individuals who participated in baseline and 5-year follow-up surveys of a population-based cohort study. Sedentary, LPA and MVPA time were objectively measured using accelerometers. ASC methylation in PBMCs was measured by pyrosequencing. Using a multiple linear regression and employing an isotemporal substitution model, the longitudinal associations of changes in the sedentary time, LPA and MVPA on the changes in the ASC methylation were analyzed after adjusting for potential confounders. Substituting 60 min per day of LPA for sedentary time was associated with 1.17 times (95% confidence interval 1.07, 1.27) higher ASC methylation levels (mean of 7 CpG sites, P<0.001). However, such effects were not seen for MVPA. These results suggest that substituting LPA for sedentary time may be linked with increased (favorable) ASC methylation as a potential biomarker of systemic inflammation.

Intensity-Specific and Modified Effects of Physical Activity on Serum Adiponectin in a Middle-Aged Population.

CONTEXT: The effects of intensity-specific physical activity (PA) and its interaction with other lifestyle factors on serum adiponectin are currently unclear. OBJECTIVE: To investigate the effects of replacing sedentary time with either light-intensity PA (LPA) or moderate- to vigorous-intensity PA (MVPA) on total and high-molecular-weight (HMW) adiponectin and to examine interactions with smoking, alcohol drinking, coffee consumption, and menopausal status in a general population. DESIGN/SETTING: Cross-sectional study of 4013 men and 6050 women (40 to 69 years of age). MAIN OUTCOME MEASURES: The associations of replacing sedentary time with LPA or MVPA on total and HMW adiponectin were analyzed using an isotemporal substitution model. RESULTS: In men, reallocating 60 minutes of sedentary time to 60 minutes of LPA was associated with 9% and 13% higher total and HMW adiponectin levels even after adjusting for confounders, although such associations were not observed for MVPA. A similar pattern of results was also seen in women. The effect of replacing sedentary time with LPA on adiponectin was clearer in middle/high coffee consumers than in low coffee consumers among women. Although increasing the effect of replacing sedentary time with MVPA on adiponectin was clearer in former/current smokers than in never smokers among men, the replacement effect for MVPA on total adiponectin was clearer in premenopausal women than in postmenopausal women. CONCLUSIONS: Replacing sedentary time with LPA resulted in increased levels of total and HMW adiponectin. The replacement effects for LPA or MVPA were found to be multiply modified by smoking, coffee consumption, and menopausal status.

Associations between Dietary Patterns, ADRß2 Gln27Glu and ADRß3 Trp64Arg with Regard to Serum Triglyceride Levels: J-MICC Study.

Interactions between dietary patterns and 2 ß-adrenergic receptor (ADRß) gene polymorphisms (ADRß2 Gln27Glu and ADRß3 Trp64Arg) were examined with regard to the effects on serum triglyceride levels. The cross-sectional study comprised 1720 men and women (aged 35-69 years) enrolled in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. Genotyping was conducted using a multiplex polymerase chain reaction-based invader assay. We used 46 items from a validated short food frequency questionnaire and examined major dietary patterns by factor analysis. We identified four dietary patterns: healthy, Western, seafood and bread patterns. There was no significant association between any dietary pattern and serum triglyceride levels. After a separate genotype-based analysis, significant interactions between ADRß3 Trp64Arg genotype and the bread pattern (p for interaction = 0.01) were associated with serum triglyceride levels; specifically, after adjusting for confounding factors, Arg allele carriers with the bread pattern had lower serum triglycerides (p for trend = 0.01). However, the Trp/Trp homozygous subjects with the bread pattern showed no association with serum triglycerides (p for trend = 0.55). Interactions between other dietary patterns and ADRß polymorphisms were not significant for serum triglyceride levels. Our findings suggest that ADRß3 polymorphism modifies the effects of the bread pattern on triglyceride levels.

Association between brain-muscle-ARNT-like protein-2 (BMAL2) gene polymorphism and type 2 diabetes mellitus in obese Japanese individuals: A cross-sectional analysis of the Japan Multi-institutional Collaborative Cohort Study.

AIMS: Brain-muscle-Arnt-like protein-1 (BMAL1) and BMAL2 genes are essential components of the circadian clock, and are considered to be involved in glucose homeostasis. We examined whether single nucleotide polymorphisms (SNPs) of BMAL1 and BMAL2 were associated with the prevalence of type 2 diabetes (T2DM) in the general Japanese population. METHODS: We studied 2467 subjects (1232 men and 1235 women, 35-69 years old), including 105 men and 57 women with T2DM, from the participants of the Japan Multi-institutional Collaborative Cohort Study. The association between SNPs in the BMAL1 (rs11022775 and rs2290035) and BMAL2 (rs7958822) genes and T2DM were analyzed by multiple logistic regression after adjustment for potential confounders. Analysis was also performed after stratification by body mass index (≥25 kg/m(2) and <25 kg/m(2)) to investigate an interaction between genotypes and obesity. RESULTS: The A/G and A/A genotypes of BMAL2 rs7958822 showed significantly higher adjusted odds ratios (OR) for T2DM than the G/G genotype among obese men (OR=2.2, 95% confidence intervals [CI] 1.1, 4.6, P for interaction=0.0495) and obese women (OR=2.7, 95% CI 1.1, 6.7, P for interaction=0.199). There were no significant associations between BMAL1 rs11022775 or rs2290035 genotypes and T2DM. CONCLUSIONS: To the best of our knowledge, this is the first study to show the significant association between BMAL2 rs7958822 genotype and T2DM among obese subjects.

Dietary patterns and serum gamma-glutamyl transferase in Japanese men and women.

BACKGROUND: Although specific foods and nutrients have been examined as potential determinants of serum gamma-glutamyl transferase (GGT) concentrations, the relationship between dietary patterns and GGT remains unknown. The present cross-sectional study aimed to determine relationships between dietary patterns and GGT concentrations, and the effects of lifestyle factors on GGT. METHODS: Relationships between dietary patterns and GGT were analyzed in 9803 Japanese individuals (3723 men and 6080 women age 40-69 years) without a history of liver diseases or elevated serum aminotransferase. We examined major dietary patterns by factor analysis of 46 items determined from a validated, short food frequency questionnaire. RESULTS: We defined dietary patterns as healthy, Western, seafood, bread, and dessert. The healthy pattern was inversely related to GGT in men (odds ratio [OR] for highest vs lowest quartile, 0.72; 95% confidence interval [CI], 0.57-0.92; P < 0.01 for trend) and women (OR 0.82; 95% CI, 0.66-1.0; P = 0.05 for trend), whereas the seafood pattern was positively related to GGT in men (OR 1.27; 95% CI, 1.01-1.61; P = 0.03 for trend) and women (OR 1.21; 95% CI, 0.98-1.49; P = 0.05 for trend). Male-specific inverse associations with GGT were found for bread and dessert patterns (OR 0.63; 95% CI, 0.50-0.80 and OR 0.53; 95% CI, 0.41-0.68, respectively; P < 0.01 for both trends). Seafood or bread patterns and alcohol consumption significantly interacted with GGT in men (P = 0.03 and <0.01 for interaction, respectively) and between the dessert pattern and body mass index or smoking habit in women (P = 0.03 and <0.01, respectively, for interaction). CONCLUSIONS: Dietary patterns may be important determinants of GGT, and their possible clinical implications warrant further investigation.

Perceived stress and coping strategies in relation to body mass index: cross-sectional study of 12,045 Japanese men and women.

BACKGROUND: Accumulated evidence suggests a weak positive relationship between psychosocial stress and body mass index (BMI), but little is known about stress coping strategies and BMI. OBJECTIVE: We aimed to examine if perceived stress and coping strategies are related to BMI, with any of their mutual interactions on BMI. METHODS: This cross-sectional study included 5,063 men and 6,982 women aged 40-69 years. A self-administered questionnaire ascertained perceived stress and 5 items of coping strategies (emotion expression, emotional support seeking, positive reappraisal, problem solving, and disengagement). Analyses were performed by gender with adjustment for age, socioeconomic status, and lifestyle factors. RESULTS: No significant associations were detected between perceived stress and BMI in either men (P(trend) = 0.09) or women (P(trend) = 0.58). In men, however, 'disengagement' showed an inverse association with BMI (P(trend) < 0.001), and 'positive reappraisal' and 'problem solving' revealed a positive association with BMI (P(trend) = 0.04 and 0.007, respectively) even after controlling for perceived stress. A possible interaction between perceived stress and 'disengagement' on BMI was found in men (P(interaction) = 0.027); the inverse association between 'disengagement' and BMI was more evident in higher levels of stress (ß = -0.13, P(trend) = 0.21 in low; ß = -0.22, P(trend) = 0.01 in medium; and ß = -0.24, P(trend) = 0.06 in high). In men, 'disengagement' was inversely associated with overweight/obesity (odds ratio 0.79, 95% confidential interval 0.67-0.95), and "positive reappraisal" was positively associated with it (1.25, 1.02-1.54). CONCLUSIONS: Coping strategies may have an important role in developing overweight/obesity, particularly in men.

Associations between hOGG1 Ser326Cys polymorphism and increased body mass index and fasting glucose level in the Japanese general population.

BACKGROUND: Evidence suggests that Ser326Cys, a genetic polymorphism of human 8-oxoguanine glycosylase 1 (hOGG1), is associated with insulin resistance and type 2 diabetes; however, the underlying mechanism is unclear. Recently, an animal study showed a significant association between the hOGG1 genotype and obesity, although evidence for such an association in humans is limited. The purpose of this study was to examine the association between the hOGG1 genotype and body mass index (BMI) and fasting blood glucose (FBG) levels. METHODS: Cross-sectional analysis was conducted using the baseline survey data from a Japan Multi-Institutional Collaborative Cohort Study, which included 1793 participants aged 40-69 years. The hOGG1 polymorphism was detected using a multiplex polymerase chain reaction-based invader assay. Multiple linear regression, analysis of covariance, and logistic regression were used to control for confounding variables. RESULTS: The Cys allele was significantly associated with increased BMI, FBG level, and total cholesterol (TC) level, even after adjustment for gender, age, energy intake, alcohol, smoking, physical activity, and family history of diabetes. An association with BMI was still observed after further adjustment for FBG and TC, but not for the study area (Amami or the mainland). The Cys/Cys genotype was significantly more prevalent in the participants with higher BMI (>27.5 kg/m(2)). However, the impact of genotype decreased and significance disappeared after adjusting for the study area. CONCLUSIONS: The present results suggest that the study area being inside Japan confounds the association between hOGG1 genotype and obesity.

Objectively measured physical activity and inflammatory cytokine levels in middle-aged Japanese people.

OBJECTIVE: Studies using self-reported physical activity (PA) showed that higher PA is associated with lower circulating levels of C-reactive protein; in contrast, studies investigating associations of objective PA and other inflammatory markers are limited. We investigated cross-sectional associations of accelerometer-determined PA with circulating levels of myokine-type inflammatory cytokines in a middle-aged Japanese population. METHOD: A total of 1838 individuals (737 men and 1101 women) aged 40 to 69 years participated in the baseline survey of a population-based cohort study in Saga, Japan (2005-2007). Habitual PA was assessed by a single-axis accelerometer. Serum interleukin (IL)-4, IL-6, IL-8, IL-15, and tumor necrosis factor (TNF)-α were measured by a multiplex enzyme-linked immunosorbent assay. Associations between PA and cytokine levels were assessed by multiple regression analysis and analysis of covariance, with adjustment for potential confounders. RESULTS: Step count and PA level (PAL) were inversely associated with TNF-α and IL-15 even after adjusting for BMI. Similarly, greater PA indices were also independently associated with a lower level of inflammatory cytokine z score as an index of overall inflammation. CONCLUSION: The current results suggest that greater engagement in daily PA may be linked with reduced levels of myokine-type cytokines including IL-15, irrespective of body weight in middle-aged Japanese people.

Gender-specific associations of perceived stress and coping strategies with C-reactive protein in middle-aged and older men and women.

BACKGROUND: Perceived stress and coping strategies may influence the risk of cardiovascular disease through their possible association with inflammation, but data remain controversial for perceived stress or scanty for coping strategies. PURPOSE: We examined the associations of perceived stress and coping strategies with serum high-sensitivity C-reactive protein (CRP) in a Japanese general population. METHODS: This cross-sectional study included 2,971 men and 4,902 women aged 40-69 years who were enrolled between 2005 and 2007. Subjects with possible inflammation-related disease, CRP levels ≥3,000 ng/mL, or currently used analgesics or lipid-lowering drugs were excluded. Analyses were performed by gender with adjustment for lifestyle, socioeconomic, and psychosocial factors. RESULTS: Unexpectedly, elevated perceived stress was significantly associated with lower CRP levels in men (P trend < 0.001) but not in women (P trend = 0.90) after adjustment for age and covariates. Among five items of coping strategies evaluated, "disengagement" showed a significant inverse association with CRP in men only (P trend = 0.027). In addition, a possible interaction between "emotional support seeking" and perceived stress on CRP was detected in men (P interaction = 0.021); "emotional support seeking" was associated with lower CRP at the high stress level only (P trend = 0.028). CONCLUSIONS: Both perceived stress and coping strategies may be associated with systemic inflammation in Japanese men, yet caution must be exercised before accepting the stress-inflammation-disease pathway.

MTHFR, MTR and MTRR polymorphisms and risk of chronic kidney disease in Japanese: cross-sectional data from the J-MICC Study.

PURPOSE: 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 associations of MTHFR, MTR, and MTRR polymorphisms with the risk of CKD in Japanese, we examined this association among Japanese subjects using cross-sectional data. METHODS: The subjects for this analysis were 3,318 participants consecutively selected from the Japan Multi-institutional Collaborative Cohort (J-MICC) Study. The polymorphisms were genotyped by a multiplex polymerase chain reaction-based Invader assay. Age- and sex-adjusted odds ratio (aOR) of CKD with stage 3-5 was calculated for each genotype. RESULTS: When those with MTHFR C677T C/C were defined as references, those with MTHFR C677T C/T and T/T demonstrated the aORs for CKD of 1.14 (95 % CI 0.93-1.40) and 1.39 (1.06-1.82), respectively. Marginally significantly decreased risk of CKD with increasing number of MTR A2756G G allele (p = 0.058) was observed. Stratified analyses by plasma folate low (<7.4 ng/ml) or high (≥7.4 ng/ml) suggested significantly higher OR of CKD for those with MTHFR C677T T/T and low serum folate with the aOR of 2.07 (95 % CI 1.30-3.31) compared with that for those with MTHFR C677T T/T and high serum folate. CONCLUSIONS: The present study found a significant association between the subjects with the T/T genotype of MTHFR C677T polymorphism and the elevated risk of CKD, which may suggest the possibility of the risk evaluation and prevention of this potentially life-threatening disease based on genetic traits in the near future.

Associations of apolipoprotein A5 (APOA5), glucokinase (GCK) and glucokinase regulatory protein (GCKR) polymorphisms and lifestyle factors with the risk of dyslipidemia and dysglycemia in Japanese - a cross-sectional data from the J-MICC Study.

This study examined the associations of the APOA5 T-1131C (rs662799), G553T (Cys185Gly, rs2075291), GCK G-30A (rs1799884), GCKR A/G at intron 16 (rs780094) and T1403C (Leu446Pro, rs1260326) polymorphisms with serum lipid and glucose levels in Japanese, considering lifestyle factors. Study subjects were 2,191 participants (aged 35-69 years, 1,159 males) enrolled in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. Dyslipidemia was defined as fasting serum triglycerides (FTG) ≥ 150 mg/dL and/or HDL-cholesterol (HDL-C) < 40 mg/dL, while dysglycemia was as fasting blood sugar (FBS) ≥ 110 mg/dL. When those with APOA5 -1131 T/T or 553 G/G were defined as references, those with APOA5 -1131 T/C, C/C or 553 G/T, T/T demonstrated significantly elevated risk of dyslipidemia (age- and sex-adjusted odds ratio: 1.77 [95% confidence interval:1.39-2.27], 3.35 [2.41-4.65], 2.23 [1.64-3.02] and 13.78 [3.44-55.18], respectively). Evaluation of FTG, HDL-C or FBS levels according to the genotype revealed that FTG and HDL-C levels were significantly associated with the APOA5 T-1131C and G553T polymorphisms, FTG with the GCKR rs780094 and rs1260326 polymorphisms, and FBS with the GCKR rs780094 and rs1260326 polymorphisms. Moreover, a significant positive interaction between APOA5 553 G/T+T/T genotypes and fat intake ≥ 25% of total energy for the risk of dyslipidemia was observed. Our cross-sectional study confirmed the essential roles of the polymorphisms of the APOA5, GCK and GCKR in the lipid or glucose metabolism disorders, and suggested the importance of fat intake control in the individualized prevention of dyslipidemia.

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.

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.

Optimal cutoff values of waist circumference and the discriminatory performance of other anthropometric indices to detect the clustering of cardiovascular risk factors for metabolic syndrome in Japanese men and women.

OBJECTIVE: To evaluate the pertinent cutoffs of waist circumference (WC) and the discriminatory performance of other anthropometric indices to detect clustering cardiovascular risk factors for metabolic syndrome (MetS) in Japan, where the current WC cutoffs for MetS (85 cm for men and 90 cm for women) remain controversial. METHODS: We analyzed the baseline data from 844 subjects (330 men and 514 women) aged 40-69 years who participated in a cohort study in Saga city, Japan, between November 2005 and December 2007. Receiver operating characteristic (ROC) analyses were performed to find an appropriate cutoff (defined as the point nearest to the upper left corner of the ROC curve) of each anthropometric index for the presence of multiple risk factors among dyslipidemia, hypertension, and hyperglycemia [which was defined as hemoglobin A1c (HbA1c) levels at and above 5.2, 5.5, or 5.8%, values approximately corresponding to fasting plasma glucose levels of 100, 110, and 120 mg/dL, respectively]. RESULTS: The optimal WC cutoff was 88 cm (sensitivity 60%, specificity 70%) for men and 82 cm (sensitivity 78%, specificity 62%) for women; changing the HbA1c cutoff affected the results in women only (~85 cm). For the currently defined WC cutoffs in Japan, specificity was low (53-57%) in men, whereas sensitivity was very low (32-42%) in women. Body mass index, proportion of body fat, waist-to-height ratio, and waist-to-hip ratio showed area under the curve values similar to that of WC. CONCLUSION: The current Japanese criteria of WC for MetS may be low for men and too high and insensitive for women in our study population. Other anthropometric indices such as waist-to-height ratio did not confer an improved discriminatory performance compared with WC.

Association between dietary pattern and serum C-reactive protein in Japanese men and women.

BACKGROUND: Dietary pattern may influence the risks of cardiovascular disease, atherosclerosis, type 2 diabetes, and metabolic syndrome through its effects on inflammation. We evaluated the association between dietary pattern and serum high-sensitivity C-reactive protein (hs-CRP) in a Japanese population. METHODS: In this cross-sectional analysis, we used baseline data from 3905 men and 5640 women (age 40-69 years) who participated in a population-based cohort study between November 2005 and December 2007. Participants with possible inflammation-related diseases, current analgesic use, high hs-CRP levels (≥3000 ng/mL) or extreme dietary energy intake were excluded. We used 46 items from a validated short food frequency questionnaire and examined major dietary patterns by factor analysis. RESULTS: We identified 5 dietary patterns: healthy (high in vegetables and fruit), Western (high in meat and fried foods), seafood (high in shellfish, squid, fish, etc.), bread (high in bread and low in rice), and dessert (high in confections and fruit). After adjustment for age, alcohol use, smoking, physical activity, and body mass index, hs-CRP levels in men were inversely associated with the healthy, bread, and dessert patterns (P-trend: 0.01, 0.06, and <0.01, respectively) and positively associated with the seafood pattern (P-trend = 0.02). In women, hs-CRP levels were inversely associated with the healthy pattern (P-trend = 0.06) and positively associated with the Western pattern (P-trend = 0.06). CONCLUSIONS: The healthy dietary pattern may be associated with suppressed inflammation in Japanese men and women, independently of body mass index and other factors. The sex-specific associations of hs-CRP with other dietary patterns (eg, the seafood pattern) require further study.

Factors influencing participation rate in a baseline survey of a genetic cohort in Japan.

BACKGROUND: Although many studies have examined factors that influence the response to postal questionnaires, few have addressed baseline recruitment for cohort studies involving genetic analyses. The aim of this study was to describe the method used for a baseline survey, the Japan Multi-institutional Collaborative Cohort Study (J-MICC Study), in Saga Prefecture, and to examine the factors that might influence the recruitment of participants in such studies. METHODS: The Saga J-MICC Study is an ongoing population-based prospective cohort study of the genetic and environmental interactions associated with lifestyle-related disease. From 2005 through 2007, a total of 61 447 residents between the ages of 40 and 69 were invited by mail to participate in this study. The survey date and time were arranged by telephone. RESULTS: Among that population, 31 002 (50.5%) responded and 12 078 (19.7%) agreed to participate. A completed questionnaire and blood pressure and anthropometric data were collected from all participants; blood, DNA specimens, and accelerometer measures were obtained from the great majority of them. Female sex and older age were associated with a higher participation rate. In addition, the convenience of the survey location and the sending of a reminder significantly improved the participation rate (odds ratio, 1.3). CONCLUSIONS: Our findings suggest that making the survey location as convenient as possible and sending a reminder can both substantially improve participation rate in population-based studies.