Prediction of the neurological outcomes post-cardiac arrest: A prospective validation of the CAST and rCAST.

INTRODUCTION: The neurologic prognosis of out-of-hospital cardiac arrest (OHCA) patients in whom return of spontaneous circulation (ROSC) is achieved remains poor. The aim of this study was to externally and prospectively validate two scoring systems developed by us: the CAST score, a scoring system to predict the neurological prognosis of OHCA patients undergoing targeted temperature management (TTM), and a simplified version of the same score developed for improved ease of use in clinical settings, the revised CAST (rCAST) score. METHODS: This study was a prospective, multicenter, observational study conducted using the SOS KANTO 2017 registry, an OHCA registry involving hospitals in the Kanto region (including Tokyo) of Japan. The primary outcome was favorable neurological outcome (defined as Cerebral Performance Category score of 1 or 2) at 30 days and the secondary outcomes were favorable neurological outcome at 90 days and survival at 30 and 90 days. The predictive accuracies of the original CAST (oCAST) and rCAST scores were evaluated by using area under the receiver operating characteristic curve (AUC). RESULTS: Of 9909 OHCA patients, 565 showed ROSC and received TTM. Of these, we analyzed the data of 259 patients in this study. The areas under the receiver operating characteristic curve (AUCs) of the oCAST and rCAST scores for predicting a favorable neurological outcome at 30 days were 0.86 and 0.87, respectively, and those for predicting a favorable neurological outcome at 90 days were 0.87 and 0.88, respectively. The rCAST showed a higher predictive accuracy for the neurological outcome as compared with the NULL-PLEASE score. The patients with a favorable neurological outcome who had been classified into the high severity group based on the rCAST tended to have hypothermia at hospital arrival and to not show any signs of loss of gray-white matter differentiation on brain CT. Neurological function at 90 days was correlated with the rCAST (r = 0.63, p < 0.001). CONCLUSIONS: rCAST showed high predictive accuracy for the neurological prognosis of OHCA patients managed by TTM, comparable to that of the oCAST score. The scores on the rCAST were strongly correlated with the neurological functions at 90 days, implying that the rCAST is a useful scale for assessing the severity of brain injury after cardiac arrest.

Extended-spectrum antibiotics for community-acquired pneumonia with a low risk for drug-resistant pathogens.

OBJECTIVES: The potential hazards of extended-spectrum antibiotic therapy for patients with community-acquired pneumonia (CAP) with low risk for drug-resistant pathogens (DRPs) remain unclear; however, risk assessment for DRPs is essential to determine the initial antibiotics to be administered. The study objective was to assess the effect of unnecessary extended-spectrum therapy on the mortality of such patients. METHODS: A post hoc analysis was conducted after a prospective multicenter observational study for CAP. Multivariable logistic regression analysis was performed to assess the effect of extended-spectrum therapy on 30-day mortality. Three sensitivity analyses, including propensity score analysis to confirm the robustness of findings, were also performed. RESULTS: Among 750 patients with CAP, 416 with CAP with a low risk for DRPs were analyzed; of these, 257 underwent standard therapy and 159 underwent extended-spectrum therapy. The 30-day mortality was 3.9% and 13.8% in the standard and extended-spectrum therapy groups, respectively. Primary analysis revealed that extended-spectrum therapy was associated with increased 30-day mortality compared with standard therapy (adjusted odds ratio 2.82; 95% confidence interval 1.20-6.66). The results of the sensitivity analyses were consistent with those of the primary analysis. CONCLUSION: Physicians should assess the risk for DRPs when determining the empirical antibiotic therapy and should refrain from administering unnecessary extended-spectrum antibiotics for patients with CAP with a low risk for DRPs.

Epicardial adipose tissue volume is associated with abdominal aortic aneurysm expansion.

BACKGROUND: The epicardial adipose tissue volume (EATV) is associated with cardiovascular diseases such as coronary artery disease. However, no information is available regarding the relationship between the EATV and abdominal aortic aneurysm (AAA) expansion. In the present study, we evaluated the association between the EATV and AAA growth and sought to identify the predictors of AAA expansion. METHODS: Between June 2009 and December 2019, 906 patients had undergone endovascular or open repair of AAAs at our institution. Patients with previous cardiac surgery, previous ascending thoracic aortic surgery, a ruptured AAA, an infected AAA, an inflammatory AAA, a saccular aneurysm, a solitary iliac aneurysm, or reintervention after treatment of the AAA were excluded. A total of 237 patients with at least two preoperative computed tomography (CT) scans performed >180 days apart were included in the present study. The EATV within the pericardium was retrospectively quantified from the preoperative non-contrast-enhanced CT images using a three-dimensional workstation. The EATV index was defined as the EATV divided by the body surface area. The AAA expansion rate was defined as an increase in the AAA diameter annually, and the patients were divided into the slow-expansion group (expansion rate, <5 mm/y) and the fast-expansion group (expansion rate, ≥5 mm/y). The correlation between the expansion rate and the EATV index was analyzed, and the cutoff value for the EATV index was determined using a receiver operating characteristics curve. Multivariate analysis was used to assess the predictors of the AAA expansion rate. RESULTS: The expansion rate of AAA correlated positively with the EATV index (R = 0.237; P < .001). The initial aneurysm diameter (P < .001) and EATV index (P = .009) differed significantly between the two groups. The cutoff for the EATV index was 60.3 cm3/m2 (area under the curve, 0.658; 95% confidence interval [CI], 0.568-0.749; sensitivity, 1.000; specificity, 0.309). Multivariate analysis revealed that the initial aneurysm diameter and an EATV index of >60.3 cm3/m2 were significantly associated with the AAA expansion rate. CONCLUSIONS: The results of the present study have demonstrated that the EATV index is associated with AAA expansion.

The rCAST score is useful for estimating the neurological prognosis in pediatric patients with post-cardiac arrest syndrome before ICU admission: External validation study using a nationwide prospective registry.

INTRODUCTION: The objective of this cohort study was to investigate whether the revised post-Cardiac Arrest Syndrome for Therapeutic hypothermia score (rCAST), which we previously developed as a prognostic score for adult patients with post-cardiac arrest syndrome (PCAS), is also applicable to pediatric patients. METHODS: Pediatric PCAS patients were included from an out-of-hospital cardiac arrest (OHCA) registry of the Japanese Association for Acute Medicine (JAAM). We validated the predictive accuracy of the rCAST for the neurological outcomes at 30 and 90 days. We also evaluated the probability of a good neurological outcome in each of the three specified severity categories based on the rCAST (low severity: ≤5.5; moderate severity: 6.0-14.0; high severity: ≥14.5). RESULTS: Among the 737 pediatric patients with OHCA, the data of 179 pediatric PCAS patients in whom return of spontaneous circulation was achieved were analyzed. The areas under the curve (AUC) of the rCAST for predicting the neurological outcomes at 30 days and 90 days were 0.95 (95% CI: 0.90-0.99) and 0.96 (0.91-1.00), respectively. The proportions of patients with a good neurological outcome at 30 days were 100% (12/12) in the low severity group, 36.1% (13/36) in the moderate severity group, and 2.3% (3/131) in the high severity group. CONCLUSIONS: The AUC of the rCAST for pediatric PCAS patients was found to be greater than 0.9 in the external validation, which corresponds to excellent predictive accuracy. There was no patient with good neurological outcome among the patients with more than 17.0 points (extremely high severity group).

Postoperative stroke and neurological outcomes in the early phase after revascularization surgeries for moyamoya disease: an age-stratified comparative analysis.

Stroke and neurological outcomes in the early phase following revascularization for moyamoya disease (MMD) may depend on the patient's age. In this study, an age-stratified comparative analysis was performed to clarify this issue. We reviewed 105 MMD patients who underwent 179 revascularization surgeries. The demographic characteristics were collected in four age groups (≤ 5 and 6-17 years for pediatric patients and 18-49 and ≥ 50 years for adults). Additionally, we assessed the incidence of subsequent stroke and deterioration of modified Rankin Scale (mRS) score. Then, we evaluated predictors of postoperative stroke and mRS deterioration using logistic regression. The mean patient age was 26.2 ± 18.5 years. No significant difference in the incidence of postoperative stroke was observed between age groups; however, the incidence tended to be increased among patients aged ≤ 5 years (17.9%) and patients aged ≥ 50 years (16.7%). Deterioration of mRS scores was significantly associated with ages ≤ 5 years (17.9%) and ≥ 50 years (11.1%). Logistic regression showed that posterior cerebral artery involvement (odds ratio [OR], 4.6) and postoperative transient neurological events (TNEs) (OR, 5.93) were risk factors for postoperative stroke. Age ≤ 5 years (OR, 9.73), postoperative TNEs (OR, 7.38), and postoperative stroke (OR, 49) were identified as predictors of unfavorable neurological outcomes. The novel feature of this comparative analysis by age group is that membership in the early-childhood MMD patient group (under 5 years old) was an independent risk factor for unfavorable short-term neurological outcomes and was mainly associated with the incidence of postoperative severe cerebral infarction.

Variable Selection for Nonparametric Learning with Power Series Kernels.

In this letter, we propose a variable selection method for general nonparametric kernel-based estimation. The proposed method consists of two-stage estimation: (1) construct a consistent estimator of the target function, and (2) approximate the estimator using a few variables by ℓ1-type penalized estimation. We see that the proposed method can be applied to various kernel nonparametric estimation such as kernel ridge regression, kernel-based density, and density-ratio estimation. We prove that the proposed method has the property of variable selection consistency when the power series kernel is used. Here, the power series kernel is a certain class of kernels containing polynomial and exponential kernels. This result is regarded as an extension of the variable selection consistency for the nonnegative garrote (NNG), a special case of the adaptive Lasso, to the kernel-based estimators. Several experiments, including simulation studies and real data applications, show the effectiveness of the proposed method.

Accuracy of the first interpretation of early brain CT images for predicting the prognosis of post-cardiac arrest syndrome patients at the emergency department.

BACKGROUND: Early brain CT is one of the most useful tools for estimating the prognosis in patients with post-cardiac arrest syndrome (PCAS) at the emergency department (ED). The aim of this study was to evaluate the prognosis-prediction accuracy of the emergency physicians' interpretation of the findings on early brain CT in PCAS patients treated by targeted temperature management (TTM). METHODS: This was a double-center, retrospective, observational study. Eligible subjects were cardiac arrest patients admitted to the intensive care unit (ICU) for TTM between April 2011 and March 2017. We performed the McNemar test to compare the predictive accuracies of the interpretation by emergency physicians and radiologists and calculated the kappa statistic for determining the concordance rate between the interpretations by these two groups. RESULTS: Of the 122 eligible patients, 106 met the inclusion criteria for this study. The predictive accuracies (sensitivity, specificity) of the interpretations by the emergency physicians and radiologists were (0.34, 1.00) and (0.41, 0.93), respectively, with no significant difference in either the sensitivity or specificity as assessed by the McNemar test. The kappa statistic calculated to determine the concordance between the two interpretations was 0.66 (0.48-0.83), which showed a good conformity. CONCLUSIONS: The emergency physicians' interpretation of the early brain CT findings in PCAS patients treated by TTM was as reliable as that of radiologists, in terms of prediction of the prognosis.

Empirical Bayes Estimation of Semi-parametric Hierarchical Mixture Models for Unbiased Characterization of Polygenic Disease Architectures.

Genome-wide association studies (GWAS) suggest that the genetic architecture of complex diseases consists of unexpectedly numerous variants with small effect sizes. However, the polygenic architectures of many diseases have not been well characterized due to lack of simple and fast methods for unbiased estimation of the underlying proportion of disease-associated variants and their effect-size distribution. Applying empirical Bayes estimation of semi-parametric hierarchical mixture models to GWAS summary statistics, we confirmed that schizophrenia was extremely polygenic [~40% of independent genome-wide SNPs are risk variants, most within odds ratio (OR = 1.03)], whereas rheumatoid arthritis was less polygenic (~4 to 8% risk variants, significant portion reaching OR = 1.05 to 1.1). For rheumatoid arthritis, stratified estimations revealed that expression quantitative loci in blood explained large genetic variance, and low- and high-frequency derived alleles were prone to be risk and protective, respectively, suggesting a predominance of deleterious-risk and advantageous-protective mutations. Despite genetic correlation, effect-size distributions for schizophrenia and bipolar disorder differed across allele frequency. These analyses distinguished disease polygenic architectures and provided clues for etiological differences in complex diseases.

Effect of Administration of Ramelteon, a Melatonin Receptor Agonist, on the Duration of Stay in the ICU: A Single-Center Randomized Placebo-Controlled Trial.

OBJECTIVES: Occurrence of delirium in the ICU is associated with a longer stay in the ICU. To examine whether the use of ramelteon, a melatonin agonist, can prevent delirium and shorten the duration of ICU stay of critically ill patients. DESIGN: A single-center, triple-blinded, randomized placebo-controlled trial. SETTING: ICU of an academic hospital. PATIENTS: Eligible patients were ICU patients who could take medicines orally or through a nasogastric tube during the first 48 hours of admission. INTERVENTIONS: The intervention group received ramelteon (8 mg/d), and the control group received placebo (1 g/d of lactose powder) at 20:00 hours every day until discharge from the ICU. MEASUREMENTS AND MAIN RESULTS: A total of 88 subjects were randomized to the ramelteon group (45 subjects) or the placebo group (43 subjects). As the primary endpoint, there was a trend toward decrease in the duration of ICU stay (4.56 d) in the ramelteon group compared with the placebo group (5.86 d) (p = 0.082 and p = 0.028 before and after adjustments). As the secondary endpoints, statistically significant decreases in the occurrence rate (24.4% vs 46.5%; p = 0.044) and duration (0.78 vs 1.40 d; p = 0.048) of delirium were observed in the ramelteon group. The nonintubated patients of the ramelteon group showed statistically significantly fewer awakenings per night and a higher proportion of nights without awakenings. CONCLUSIONS: Ramelteon tended to decrease the duration of ICU stay as well as decreased the occurrence rate and duration of delirium statistically significantly.

Multi-subgroup gene screening using semi-parametric hierarchical mixture models and the optimal discovery procedure: Application to a randomized clinical trial in multiple myeloma.

This article proposes an efficient approach to screening genes associated with a phenotypic variable of interest in genomic studies with subgroups. In order to capture and detect various association profiles across subgroups, we flexibly estimate the underlying effect size distribution across subgroups using a semi-parametric hierarchical mixture model for subgroup-specific summary statistics from independent subgroups. We then perform gene ranking and selection using an optimal discovery procedure based on the fitted model with control of false discovery rate. Efficiency of the proposed approach, compared with that based on standard regression models with covariates representing subgroups, is demonstrated through application to a randomized clinical trial with microarray gene expression data in multiple myeloma, and through a simulation experiment.

A novel scoring system for predicting the neurologic prognosis prior to the initiation of induced hypothermia in cases of post-cardiac arrest syndrome: the CAST score.

BACKGROUND: The aim of this study was to develop a scoring system for identifying the post-cardiac arrest syndrome (PCAS) patients with a good potential for recovery prior to the initiation of induced therapeutic hypothermia. METHODS: A multi-center, retrospective, observational study was performed. Data of a total of 151 consecutive adults who underwent induced hypothermia after cardiac arrest (77 learning cases from two hospitals and 74 validation cases from two other hospitals) were analyzed. RESULTS: In the learning set, 8 factors (initial rhythm, witnessed status and time until return of spontaneous circulation, pH, serum lactate, motor score according to the Glasgow Coma Scale (GCS), gray matter attenuation to white matter attenuation ratio (GWR), serum albumin, and hemoglobin) were found to be strongly correlated with the neurological outcomes. A tentative scoring system was created from the learning data using these factors, and the predictive accuracy (sensitivity and specificity) was evaluated in terms of both internal validation (0.85 and 0.84) and external validation (cutoff 50%: 0.95 and 0.90, 30%: 0.87 and 0.98, 15%: 0.67 and 1.00). Finally, using all the data, we established a post-Cardiac Arrest Syndrome for induced Therapeutic hypothermia (CAST) score to predict the neurologic prognosis prior to initiation of induced hypothermia. CONCLUSIONS: The CAST score was developed to predict the neurological outcomes of PCAS patients treated by induced hypothermia. The likelihood of good recovery at 30 days was extremely low in PCAS patients with a CAST score of ≤15%. Prospective validation of the score is needed in the future.

Association of renal function with clinical parameters and conditions in a longitudinal population-based epidemiological study.

The aim of the present study was to examine the association of renal function with clinical parameters and conditions in the general population. Study subjects comprised 6,027 community-dwelling individuals who were recruited to the Inabe Health and Longevity Study: A longitudinal genetic epidemiological study of atherosclerotic, cardiovascular and metabolic diseases. The cutoff value, which was used to divide the subjects into those with normal and those with low estimated glomerular filtration rate (eGFR), was 60 ml/min/1.73 m2. Bonferroni's correction was applied to establish the statistical significance of the association. Longitudinal analysis using the generalized linear mixed-effect model, following adjustments for age and gender, revealed that the eGFR was significantly associated (P<0.0017) with serum levels of triglycerides, low-density lipoprotein cholesterol, uric acid, blood glycosylated hemoglobin content, fasting plasma glucose and body mass index. These parameters decreased curvilinearly with increases in eGFR. Furthermore, eGFR correlated positively with serum levels of high-density lipoprotein (HDL) cholesterol. Longitudinal analysis using the generalized estimating equation following adjustment for age and gender indicated a significant association (P<0.0024) between eGFR and prevalence of hypertension, type 2 diabetes mellitus, hypo-HDL cholesterolemia, hyperuricemia and obesity. Thus, low eGFR results in detrimental effects on various clinical parameters and conditions, resulting in increased risk of hypertension, dyslipidemia, type 2 diabetes mellitus, hyperuricemia and obesity.

Obesity-related changes in clinical parameters and conditions in a longitudinal population-based epidemiological study.

OBJECTIVES: The purpose of the present study was to examine the association of body mass index (BMI) or obesity with various clinical parameters and conditions in a longitudinal population-based epidemiological study in Japan. METHODS: Study subjects comprised 6027 community-dwelling individuals who were recruited to the Inabe Health and Longevity Study, a longitudinal genetic epidemiological study of atherosclerotic, cardiovascular, and metabolic diseases. Obesity was defined as BMI ≥25kg/m2. RESULTS: Longitudinal analysis with the generalised linear mixed-effect model after adjustment for age showed that for men, BMI was significantly (P<0.0008) related to systolic, diastolic, and mean blood pressure and serum concentrations of high-density lipoprotein (HDL)-cholesterol and low-density lipoprotein (LDL)-cholesterol. For women, BMI was also significantly related to serum concentrations of triglycerides, HDL-cholesterol, and LDL-cholesterol. Longitudinal analysis with the generalised estimating equation with adjustment for age showed that in men, BMI was significantly (P<0.0012) associated with the prevalence of hypertension, type 2 diabetes mellitus, hypertriglyceridemia, hypo-HDL-cholesterolemia, decreased estimated glomerular filtration rate, and hyperuricemia. In women, BMI was also significantly associated with the prevalence of hypertension, type 2 diabetes mellitus, hypertriglyceridemia, and hyperuricemia. CONCLUSION: Obesity has detrimental effects on various clinical parameters and conditions, resulting in increased risk of hypertension, dyslipidemia, type 2 diabetes mellitus, hyperuricemia, and chronic kidney disease.

Association of genetic variants of the α-kinase 1 gene with type 2 diabetes mellitus in a longitudinal population-based genetic epidemiological study.

Previously, our studies identified nine genes and the chromosomal region 3q28 as susceptibility loci for myocardial infarction, ischemic stroke or chronic kidney disease in individuals by genome-wide or candidate gene association studies. The present study examined the possible association of 13 polymorphisms at these 10 loci with the prevalence of type 2 diabetes mellitus (DM) in community-dwelling individuals. Study subjects comprised 6,027 individuals (797 subjects with type 2 DM and 5,230 controls) who were recruited to the Inabe Health and Longevity Study, a longitudinal genetic epidemiological study of atherosclerotic, cardiovascular and metabolic diseases. The subjects were recruited from individuals who visited for an annual health checkup and they were followed up each year (mean follow-up, 5 years). Longitudinal analysis with a generalized estimating equation and with adjustment for age, gender and body mass index (BMI) revealed that rs2116519 (C→T) of FAM78B (P=0.0188), as well as rs2074379 (G→A, P=0.0121) and rs2074388 (A→G, P=0.0053) of ALPK1 were significantly (P<0.05) associated with the prevalence of type 2 DM. Longitudinal analysis with a generalized linear mixed-effect model and with adjustment for age, gender and BMI among all the individuals revealed that rs2116519, rs2074379 and rs2074388 were significantly associated with fasting plasma glucose level (P=0.0352, 0.0017 and 0.0010, respectively) and to blood glycosylated hemoglobin (hemoglobin A1c) content (P=0.0065, 0.0090 and 0.0079, respectively). Similar analysis among individuals not taking antidiabetic medication revealed that rs2074379 and rs2074388 were associated with the fasting plasma glucose level (P=0.0073 and 0.0042, respectively) and blood hemoglobin A1c content (P=0.0142 and 0.0126, respectively), whereas rs2116519 was associated with blood hemoglobin A1c content only (P=0.0470). ALPK1 may thus be a susceptibility gene for type 2 DM.

Association of genetic variants with coronary artery disease and ischemic stroke in a longitudinal population-based genetic epidemiological study.

Our previous studies identified nine genes and chromosomal region 3q28 as susceptibility loci for myocardial infarction, ischemic stroke or chronic kidney disease by genome-wide or candidate gene association studies. As coronary artery disease (CAD) and ischemic stroke may share genetic architecture, certain genetic variants may confer susceptibility to the two diseases. The present study examined the association of 13 polymorphisms at these 10 loci with the prevalence of CAD or ischemic stroke in community-dwelling individuals, with the aim of identifying genetic variants that confer susceptibility to the two conditions. Study subjects (170 with CAD, 117 with ischemic stroke and 5,718 controls) were recruited to the Inabe Health and Longevity Study, a longitudinal genetic epidemiological study of atherosclerotic, cardiovascular and metabolic diseases. The subjects were recruited from individuals who visited for an annual health checkup and they were followed up each year (mean follow-up period, 5 years). Longitudinal analysis with a generalized estimating equation, and with adjustment for age, gender, body mass index, smoking status, the prevalence of hypertension, diabetes mellitus and dyslipidemia and the serum concentration of creatinine, revealed that rs2074380 (G→A) and rs2074381 (A→G) of the α-kinase 1 (ALPK1) gene and rs8089 (T→G) of the thrombospondin 2 (THBS2) gene were significantly (P<2×10-16) associated with the prevalence of CAD, with the AA genotype of rs2074380 and GG genotypes of rs2074381 and rs8089 being protective against this condition. Similar analysis revealed that rs9846911 (A→G) at chromosome 3q28, rs2074381 of ALPK1, rs8089 of THBS2 and rs6046 (G→A) of the coagulation factor VII gene were significantly (P<2×10-16) associated with the prevalence of ischemic stroke, with the GG genotypes of rs9846911, rs2074381 and rs8089 and the AA genotype of rs6046 being protective against this condition. ALPK1 and THBS2 may thus be susceptibility loci for CAD and ischemic stroke.

Association of genetic variants with hypertension in a longitudinal population-based genetic epidemiological study.

We previously identified 9 genes and chromosomal region 3q28 as susceptibility loci for Japanese patients with myocardial infarction, ischemic stroke, or chronic kidney disease by genome-wide or candidate gene association studies. In the present study, we investigated the possible association of 13 single nucleotide polymorphisms (SNPs) at these 10 loci with the prevalence of hypertension or their association with blood pressure (BP) in community-dwelling individuals in Japan. The study subjects comprised 6,027 individuals (2,250 subjects with essential hypertension, 3,777 controls) who were recruited into the Inabe Health and Longevity Study, a longitudinal genetic epidemiological study on atherosclerotic, cardiovascular and metabolic diseases. The subjects were recruited from individuals who visited the Health Care Center of Inabe General Hospital for an annual health checkup, and they are followed up each year (mean follow­up period, 5 years). Longitudinal analysis with a generalized estimating equation and with adjustment for age, gender, body mass index and smoking status revealed that rs2116519 of family with sequence similarity 78, member B (FAM78B; P=0.0266), rs6929846 of butyrophilin, subfamily 2, member A1 (BTN2A1; P=0.0013), rs146021107 of pancreatic and duodenal homeobox 1 (PDX1; P=0.0031) and rs1671021 of lethal giant larvae homolog 2 (Drosophila) (LLGL2; P=0.0372) were significantly (P<0.05) associated with the prevalence of hypertension. Longitudinal analysis with a generalized linear mixed-effect model and with adjustment for age, gender, body mass index and smoking status among individuals not taking anti-hypertensive medication revealed that rs6929846 of BTN2A1 was significantly associated with systolic (P=0.0017), diastolic (P=0.0008) and mean (P=0.0005) BP, and that rs2116519 of FAM78B, rs146021107 of PDX1 and rs1671021 of LLGL2 were significantly associated with diastolic (P=0.0495), systolic (P=0.0132), and both diastolic (P=0.0468) and mean (0.0471) BP, respectively. BTN2A1 may thus be a susceptibility gene for hypertension.

Association of genetic variants with dyslipidemia and chronic kidney disease in a longitudinal population-based genetic epidemiological study.

We previously identified 9 genes and chromosomal region 3q28 as susceptibility loci for myocardial infarction, ischemic stroke, or chronic kidney disease (CKD) in Japanese individuals by genome-wide or candidate gene association studies. In the present study, we examined the association of 13 polymorphisms at these 10 loci with the prevalence of hypertriglyceridemia, hyper-low-density lipoprotein (LDL) cholesterolemia, hypo-high-density lipoprotein (HDL) cholesterolemia, or CKD in community-dwelling Japanese individuals. The study subjects comprised 6,027 individuals who were recruited to the Inabe Health and Longevity Study, a longitudinal genetic epidemiological study of atherosclerotic, cardiovascular and metabolic diseases. The subjects were recruited from individuals who visited the Health Care Center at Inabe General Hospital for an annual health checkup, and they were followed up each year (mean follow­up period, 5 years). Longitudinal analysis with a generalized estimating equation and with adjustment for covariates revealed that rs6929846 of butyrophilin, subfamily 2, member A1 gene (BTN2A1) was significantly associated with the prevalence of hypertriglyceridemia (P=0.0001), hyper-LDL cholesterolemia (P=0.0004), and CKD (P=0.0007); rs2569512 of interleukin enhancer binding factor 3 (ILF3) was associated with hyper-LDL cholesterolemia (P=0.0029); and rs2074379 (P=0.0019) and rs2074388 (P=0.0029) of alpha-kinase 1 (ALPK1) were associated with CKD. Longitudinal analysis with a generalized linear mixed-effect model and with adjustment for covariates among all individuals revealed that rs6929846 of BTN2A1 was significantly associated with the serum concentrations of triglycerides (P=0.0011), LDL cholesterol (P=3.3 x 10(-5)), and creatinine (P=0.0006), as well as with the estimated glomerular filtration rate (eGFR) (P=0.0004); rs2569512 of ILF3 was shown to be associated with the serum concentration of LDL cholesterol (P=0.0221); and rs2074379 (P=0.0302) and rs2074388 (P=0.0336) of ALPK1 were shown to be associated with the serum concentration of creatinine. Similar analysis among individuals not taking any anti­dyslipidemic medication revealed that rs6929846 of BTN2A1 was significantly associated with the serum concentrations of triglycerides (P=8.3 x 10­5) and LDL cholesterol (P=0.0004), and that rs2569512 of ILF3 was associated with the serum concentration of LDL cholesterol (P=0.0010). BTN2A1 may thus be a susceptibility gene for hypertriglyceridemia, hyper­LDL cholesterolemia and CKD in Japanese individuals.