Genome- and transcriptome-wide splicing associations with alcohol use disorder.

Genetic mechanisms of alternative mRNA splicing have been shown in the brain for a variety of neuropsychiatric traits, but not substance use disorders. Our study utilized RNA-sequencing data on alcohol use disorder (AUD) in four brain regions (n = 56; ages 40-73; 100% 'Caucasian'; PFC, NAc, BLA and CEA) and genome-wide association data on AUD (n = 435,563, ages 22-90; 100% European-American). Polygenic scores of AUD were associated with AUD-related alternative mRNA splicing in the brain. We identified 714 differentially spliced genes between AUD vs controls, which included both putative addiction genes and novel gene targets. We found 6463 splicing quantitative trait loci (sQTLs) that linked to the AUD differentially spliced genes. sQTLs were enriched in loose chromatin genomic regions and downstream gene targets. Additionally, the heritability of AUD was enriched for DNA variants in and around differentially spliced genes associated with AUD. Our study also performed splicing transcriptome-wide association studies (TWASs) of AUD and other drug use traits that unveiled specific genes for follow-up and splicing correlations across SUDs. Finally, we showed that differentially spliced genes between AUD vs control were also associated with primate models of chronic alcohol consumption in similar brain regions. Our study found substantial genetic contributions of alternative mRNA splicing in AUD.

Opioid Use Disorder and Alternative mRNA Splicing in Reward Circuitry.

Opiate/opioid use disorder (OUD) is a chronic relapsing brain disorder that has increased in prevalence in the last two decades in the United States. Understanding the molecular correlates of OUD may provide key insights into the pathophysiology of this syndrome. Using publicly available RNA-sequencing data, our study investigated the possible role of alternative mRNA splicing in human brain tissue (dorsal-lateral prefrontal cortex (dlPFC), nucleus accumbens (NAc), and midbrain) of 90 individuals with OUD or matched controls. We found a total of 788 differentially spliced genes across brain regions. Alternative mRNA splicing demonstrated mostly tissue-specific effects, but a functionally characterized splicing change in the clathrin and AP-2-binding (CLAP) domain of the Bridging Integrator 1 (BIN1) gene was significantly linked to OUD across all brain regions. We investigated two hypotheses that may underlie differential splicing in OUD. First, we tested whether spliceosome genes were disrupted in the brains of individuals with OUD. Pathway enrichment analyses indicated spliceosome perturbations in OUD across brain regions. Second, we tested whether alternative mRNA splicing regions were linked to genetic predisposition. Using a genome-wide association study (GWAS) of OUD, we found no evidence that DNA variants within or surrounding differentially spliced genes were implicated in the heritability of OUD. Altogether, our study contributes to the understanding of OUD pathophysiology by providing evidence of a possible role of alternative mRNA splicing in OUD.

A Review of Associations between Externalizing Behaviors and Prenatal Cannabis Exposure: Limitations & Future Directions.

In utero cannabis exposure can disrupt fetal development and increase risk for various behavioral disruptions, including hyperactivity, inattention, delinquent behaviors, and later substance abuse, among others. This review summarizes the findings from contemporary investigations linking prenatal cannabis exposure to the development of psychopathology and identifies the limitations within the literature, which constrain our interpretations and generalizability. These limitations include a lack of genetic/familial control for confounding and limited data examining real world products, the full range of cannabinoids, and motives for use specifically in pregnant women. Taken together, our review reveals the need to continue to improve upon study designs in order to allow researchers to accurately draw conclusions about the development of behavioral consequences of prenatal cannabis exposure. Findings from such studies would inform policy and practices regarding cannabis use during pregnancy and move the field toward developing a comprehensive teratogenic profile of cannabis similar to what is characterized in the prenatal alcohol and tobacco literature.

Mitochondrial complex I inhibitors suppress tumor growth through concomitant acidification of the intra- and extracellular environment.

The disruption of the tumor microenvironment (TME) is a promising anti-cancer strategy, but its effective targeting for solid tumors remains unknown. Here, we investigated the anti-cancer activity of the mitochondrial complex I inhibitor intervenolin (ITV), which modulates the TME independent of energy depletion. By modulating lactate metabolism, ITV induced the concomitant acidification of the intra- and extracellular environment, which synergistically suppressed S6K1 activity in cancer cells through protein phosphatase-2A-mediated dephosphorylation via G-protein-coupled receptor(s). Other complex I inhibitors including metformin and rotenone were also found to exert the same effect through an energy depletion-independent manner as ITV. In mouse and patient-derived xenograft models, ITV was found to suppress tumor growth and its mode of action was further confirmed. The TME is usually acidic owing to glycolytic cancer cell metabolism, and this condition is more susceptible to complex I inhibitors. Thus, we have demonstrated a potential treatment strategy for solid tumors.

Novel allelic mutations in murine Serca2 induce differential development of squamous cell tumors.

Dominant mutations in the Serca2 gene, which encodes sarco(endo)plasmic reticulum calcium-ATPase, predispose mice to gastrointestinal epithelial carcinoma [1-4] and humans to Darier disease (DD) [14-17]. In this study, we generated mice harboring N-ethyl-N-nitrosourea (ENU)-induced allelic mutations in Serca2: three missense mutations and one nonsense mutation. Mice harboring these Serca2 mutations developed tumors that were categorized as either early onset squamous cell tumors (SCT), with development similar to null-type knockout mice [2,4] (aggressive form; M682, M814), or late onset tumors (mild form; M1049, M1162). Molecular analysis showed no aberration in Serca2 mRNA or protein expression levels in normal esophageal cells of any of the four mutant heterozygotes. There was no loss of heterozygosity at the Serca2 locus in the squamous cell carcinomas in any of the four lines. The effect of each mutation on Ca(2+)-ATPase activity was predicted using atomic-structure models and accumulated mutated protein studies, suggesting that putative complete loss of Serca2 enzymatic activity may lead to early tumor onset, whereas mutations in which Serca2 retains residual enzymatic activity result in late onset. We propose that impaired Serca2 gene product activity has a long-term effect on squamous cell carcinogenesis from onset to the final carcinoma stage through an as-yet unrecognized but common regulatory pathway.

Novel mouse model for Gardner syndrome generated by a large-scale N-ethyl-N-nitrosourea mutagenesis program.

Mutant mouse models are indispensable tools for clarifying the functions of genes and elucidating the underlying pathogenic mechanisms of human diseases. We carried out large-scale mutagenesis using the chemical mutagen N-ethyl-N-nitrosourea. One specific aim of our mutagenesis project was to generate novel cancer models. We screened 7012 animals for dominant traits using a necropsy test and thereby established 17 mutant lines predisposed to cancer. Here, we report on a novel cancer model line that developed osteoma, trichogenic tumor, and breast cancer. Using fine mapping and genomic sequencing, we identified a point mutation in the adenomatous polyposis coli (Apc) gene. The Apc1576 mutants bear a nonsense mutation at codon 1576 in the Apc gene. Although most Apc mutant mice established thus far have multifocal intestinal tumors, mice that are heterozygous for the Apc1576 mutation do not develop intestinal tumors; instead, they develop multifocal breast cancers and trichogenic tumors. Notably, the osteomas that develop in the Apc1576 mutant mice recapitulate the lesion observed in Gardner syndrome, a clinical variant of familial adenomatous polyposis. Our Apc1576 mutant mice will be valuable not only for understanding the function of the Apc gene in detail but also as models of human Gardner syndrome.

Albuminuria is an independent predictor of all-cause and cardiovascular mortality in the Japanese population: the Takahata study.

BACKGROUND: Albuminuria is a known risk factor for cardiovascular events and premature deaths. However, the association between urinary albumin excretion and mortality is unknown in the Japanese population. To clarify this, we conducted a community-based longitudinal study. METHODS: This study included 3,445 registered Japanese subjects (mean age 62.6 years), with a 7-year follow-up. Albuminuria was defined as a urine albumin-creatinine ratio (ACR) ≥30 mg/g in the morning spot urine. RESULTS: Subjects with albuminuria (n = 514, 14.9 %) were older and showed a higher prevalence of hypertension, obesity, and diabetes and lower values of estimated glomerular filtration rate (eGFR) than those without albuminuria (n = 2931, 85.1 %). During the follow-up, 138 subjects died. A Kaplan-Meier analysis showed that all-cause mortality significantly increased along with the increase in urine albumin excretion (log-rank test, P < 0.001). The subjects with albuminuria showed a significantly higher mortality rate than those without albuminuria (7.4 vs. 3.4 %; log-rank test, P < 0.001). A Cox proportional hazard model analysis after adjusting for possible confounders showed that albuminuria was an independent risk factor for all-cause and cardiovascular mortality (hazard ratio [HR] 1.69, 95 % confidence interval [CI] 1.12-2.56 and HR 2.27, 95 % CI 1.10-4.70, respectively) but not for noncardiovascular mortality. These associations were preserved after excluding subjects with high ACR (≥300 mg/g). CONCLUSIONS: Albuminuria was a risk factor for all-cause and cardiovascular mortality in the Japanese population. To detect subjects with a high risk for premature death, measuring urinary albumin excretion might be useful.

Rapid decline in renal function after acute myocardial infarction.

AIM: To investigate the long term effects of cardiac events on renal function, a prospective study of patients with acute myocardial infarction was conducted. METHODS: A total of 137 patients with acute myocardial infarction were followed for 1 year. The change of estimated glomerular filtration rate (eGFR) in cardiac patients was compared with that in background-matched controls, and the factors associated with eGFR changes were analyzed. RESULTS: The eGFR decrease was much larger after myocardial infarction, from 73.7 ± 1.9 ml/min/1.73 m2 (mean ± SEM) at baseline to 64.7 ± 1.7 at 1 year, (p < 0.001), compared with that of controls (from 72.8 ± 1.2 to 72.1 ± 1.3, p = 0.305). Multiple regression analysis showed that eGFR change was associated negatively with age, baseline eGFR, proteinuria, and positively with the administration of angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, but not the severity of cardiac damage and comorbidities. Longitudinal analysis 1 year before and 2 years after myocardial infarction showed that eGFR decrease was larger during baseline and 6 months after the event (-7.0 ± 1.0). CONCLUSIONS: Renal decline was rapid after myocardial infarction and was affected by clinical characteristics of patients. Careful follow-up of renal function is recommended to prevent the progression of renal and cardiac disease.

The association between serum uric acid and renal damage in a community-based population: the Takahata study.

BACKGROUND: Hyperuricemia is a risk factor for end-stage renal disease. This study examined the association between serum uric acid and renal damage in a community-based population. METHODS: In this study 3126 subjects without renal insufficiency were recruited at baseline and were followed for one year. The urinary albumin-creatinine ratio (UACR) and ß2-microglobulin-creatinine ratio (UBCR) in morning spot urine samples were used as indices of either glomerular (UACR) or tubular (UBCR) damage. RESULTS: The mean value of serum uric acid (mg/dL) was 5.8 ± 1.3 (SD) in men and 4.5 ± 1.1 in women. In cross-sectional analysis the increased serum uric acid levels were accompanied by higher UACR values in both men and women (P < 0.01). In contrast, UBCR values were reduced when uric acid levels increased in both men and women (P < 0.01). Multivariate analysis revealed that albuminuria (UACR ≥ 30 mg/g) was significantly associated with increased uric acid (≥7 mg/dL for men, ≥6 mg/dL for women). High UBCR (≥300 µg/g) was negatively associated with uric acid in men, but not in women, after adjustment for possible confounders. In longitudinal analysis in 1388 subjects multiple linear regression analysis showed that uric acid at baseline was an independent factor for one-year increase of UACR [coefficient 4.80 (95 % confidence interval 0.40-9.33) (mg/g) per 1 mg/dL increase in uric acid, P = 0.033]. CONCLUSION: This study showed that serum uric acid concentration was positively associated with UACR, suggesting that uric acid may be related to glomerular damage in a community-based population.

Comparison of Mortality between Japanese Peritoneal Dialysis and Hemodialysis Patients: A 5-Year Multicenter Follow-Up Study.

To examine the relationship between dialysis modality and prognosis in Japanese patients, we conducted a prospective multicenter observational study. We recruited 83 background-matched peritoneal dialysis (PD) and 83 hemodialysis (HD) patients (average age, 64.9 years; men, 53.6%; diabetic patients, 22.9%; median duration of dialysis, 48 months in all patients) and followed them for 5 years. During the follow-up period, 27 PD patients (16 cardiovascular and 11 non-cardiovascular deaths) and 27 HD patients died (14 cardiovascular and 13 non-cardiovascular deaths). There were 8 PD patients switched to HD, and 6 PD patients received renal transplantation. Kaplan-Meier analysis revealed that the crude survival rate was not significantly different at the end of 5 years (PD 67.5% versus 67.5%, log-rank P = 0.719). The difference in cardiovascular and non-cardiovascular mortalities between PD and HD was not statistically significant. Multivariate Cox analysis showed that the independent predictors for death were age and serum albumin levels, but not the dialysis modality. This study showed that the overall mortality was not significantly different between PD and HD patients, which suggests that dialysis modality might not be an independent factor for survival in Japanese patients.

Blood pressure control in a Japanese population with chronic kidney disease: a baseline survey of a nationwide cohort.

BACKGROUND: Hypertension is a key risk factor for adverse renal outcomes in chronic kidney disease (CKD), and strict blood pressure control is recommended to halt its progression. This study assessed blood pressure control in the Japanese CKD population. METHODS: We used a nationwide database of 250,130 subjects (aged 20-88), including 45,845 CKD subjects (18.3%), participated in an annual health check, "The Specific Health Check and Guidance in Japan," and examined the relationship between CKD status and blood pressure. Blood pressures were measured in sitting position by trained staff, and target blood pressure for CKD subjects was defined as systolic (SBP)/diastolic blood pressure (DBP) <130/80 mm Hg. RESULTS: In total population, CKD subjects had a higher prevalence of hypertension (58.0% vs. 41.8%, P < 0.001) and a higher proportion with antihypertensive medication (42.4% vs. 26.7%, P < 0.001), compared with non-CKD subjects. The proportion of subjects achieving target blood pressure was significantly lower among total CKD subjects than among total non-CKD subjects (34.6% vs. 43.8%, P ≤ 0.001). Among CKD subjects, these proportions were especially low in those with stage 4-5 (24.3-27.5%), those on antihypertensive medication (21.6%) and those with proteinuria ≥2± (21.3%). Logistic regression analysis showed that independent factors for high-blood pressure in CKD subjects were age, male gender, alcohol consumption, nonsmoking, diabetes, dyslipidemia, obesity, proteinuria, and antihypertensive medication. CONCLUSIONS: Blood pressure control was inadequate in the majority of Japanese CKD subjects, despite antihypertensive treatment. More aggressive efforts to achieve target blood pressures among CKD subjects are recommended.

Significance of past history of renal failure for the detection of high-risk individuals for cardiovascular and end-stage renal disease: analysis of data from a nationwide health checkup.

BACKGROUND: Clinical information regarding risk factors may be helpful in the detection of various diseases. This cross-sectional study examined the characteristics of subjects with past history of renal failure, and assessed whether this information would be useful for the efficient detection of high-risk individuals for chronic kidney disease (CKD) and cardiovascular disease (CVD) at health checkup. METHODS: This study utilized data from a nationwide health checkup, "The Specific Health Check and Guidance in Japan," and data for 250,130 adult subjects were analyzed. Subjects with self-reported history of renal failure and receiving dialysis therapy were defined as having a history of renal failure. RESULTS: Among total participants, there were 1,400 (0.6%) with a history of renal failure. The prevalence of a history of renal failure was higher in subjects with CKD than in those without CKD (1.5 vs. 0.3%, P < 0.001) and increased with progression of the stage of CKD (0.9-43.5%). Subjects with a history of renal failure had a reduced estimated glomerular filtration rate (44.6 ± 20.3 ml/min/1.73 m(2)) and a higher prevalence of CKD (50.5%) and CVD (31.9%), compared with subjects with hypertension, diabetes or metabolic syndrome. Multivariate logistic regression analysis showed an independent association between a history of CVD and renal failure (odds ratio 3.68, 95% confidence interval 3.26-4.15), after adjustment for confounding factors. CONCLUSIONS: A history of renal failure was strongly associated with advanced CKD and CVD. Information regarding history of renal failure could be utilized to efficiently detect high-risk individuals at health checkup.

Polymorphism of proinflammatory cytokine genes and albuminuria in the Japanese general population: the Takahata study.

BACKGROUND: A cluster of proinflammatory cytokines plays an important role in the development of various renal diseases, and the expression of these cytokines is genetically modified. To examine the association between polymorphisms of proinflammatory cytokine genes and albuminuria, a cross-sectional study was conducted in the general population. METHODS: Single nucleotide polymorphisms (SNPs) in six proinflammatory cytokine genes, including interleukin (IL)-1ß, IL-6, IL-8, tumor necrosis factor (TNF)-α, CC chemokine ligand 1 (CCL1) and monocyte chemoattractant protein-1 (MCP-1), were genotyped in 2927 Japanese subjects. Urine albumin-creatinine ratio (UACR) was measured in morning spot urine samples. RESULTS: Albuminuria (UACR ≥ 30 mg/g) was significantly associated with the A/A + A/G genotype at rs2069852 in the IL-6 gene (P = 0.01) and the A/A genotype at rs228269 in the CCL1 gene (P = 0.002). Multivariate analysis with adjustment for traditional risk factors showed that these genotypes independently predicted albuminuria [odds ratio (OR) 1.782, 95% confidence interval (CI) 1.171-2.712, P = 0.007 for the A/A + A/G genotype at rs2069852 in IL-6, and OR 1.432, 95% CI 1.128-1.770, P = 0.003 for the A/A genotype at rs228269 in CCL1]. The prevalence of albuminuria and the UACR were increased along with the increase of risk genotypes. CONCLUSIONS: This study revealed that SNPs in the IL-6 and CCL1 genes were associated with albuminuria, and the combination of these genotypes had an additive effect on the prevalence and severity of albuminuria. This indicates that genetic factors influencing inflammatory responses may affect the development of renal injury in the Japanese general population.

The association between renal tubular damage and rapid renal deterioration in the Japanese population: the Takahata study.

BACKGROUND: Injury to renal tubules plays an important role in the development of various renal diseases; however, the prevalence and significance of renal tubular damage in the general population are unclear. To clarify this point, we conducted a community-based study, using urinary ß(2)-microglobulin as a marker of tubular damage. METHODS: The subjects studied were 3,444 Japanese over the age of 40 years. The urinary ß(2)-microglobulin-creatinine ratio (UBCR) was assessed in morning spot urine samples. RESULTS: In this population, the distribution of the UBCR among these subjects was skewed towards higher values and a high UBCR (≥300 µg/g) was identified in 438 (12.7%) subjects. However, overlap with macroalbuminuria and renal insufficiency [estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2)] was observed in only 25 (5.7%) and 58 (13.2%) of these subjects, respectively. Multivariate analysis indicated that a high UBCR was positively associated with aging, hypertension, macroalbuminuria and increased urinary sodium excretion. A 5-year longitudinal analysis in 899 subjects indicated a greater decline in eGFR in parallel with the increase in baseline UBCR. After adjustment for possible confounders, a high UBCR was an independent risk factor for rapid decline in eGFR [<-10 mL/min/1.73 m(2); odds ratio 1.79 (95% confidence interval 1.07-2.99), P = 0.026]. CONCLUSION: This study showed that renal tubular damage was common and was an independent risk factor for renal deterioration in the Japanese population. More attention should be paid to occult renal tubular damage in order to prevent end-stage renal disease.

The novel and independent association between single-point SNP of NPHP4 gene and renal function in non-diabetic Japanese population: the Takahata study.

Nephronophthisis (NPHP) 4 gene coding nephrocystin-4 is involved in the development of renal tubules and its congenital mutations cause juvenile end-stage renal disease, NPHP. To investigate the association between single-point single-nucleotide polymorphism (SNP) of NPHP4 gene and renal function, we conducted a cross-sectional study in Japanese population. The subjects of this study were non-diabetic general population consisting of 2604 individuals >40 years in Takahata town, Japan. We genotyped 11 SNPs within NPHP4 gene that displayed frequent minor allele frequencies (>0.1) in Japanese general population. Among 11 SNPs in NPHP4 gene, only rs1287637 that induces amino acid substitution (A (Gln)/T (Leu)), located in the acceptor site of exon 21, showed a significant association with estimated glomerular filtration rate (eGFR; T/T: 81.3±15.6 (n=1886), A/T: 82.0±15.5 (n=652) and A/A: 87.4±21.4 ml min(-1) per 1.73m(2) (n=66); mean±s.d., P=0.006). This SNP was not in linkage disequilibrium with the surrounding SNPs. The multivariate analysis adjusted with possible confounders showed that the A/T+T/T genotype of rs1287637 was independently associated with reduced renal function (eGFR <90 ml min(-1) per 1.73m(2); odds ratio (OR) 1.75, 95% confidence interval (CI) 1.05-2.94, P=0.033). These results indicate the novel and independent association between single-point SNP rs1287637 in NPHP4 gene and renal function in non-diabetic Japanese population.

High variability of albuminuria in nondiabetic population: the Takahata Study.

BACKGROUND: Albuminuria is a risk factor for renal and cardiovascular events and shows a quick change reflecting vascular status. The aim of this study is to examine the frequency and related factors of the short-term change of albuminuria in nondiabetic Japanese population. METHODS: The study subjects were 1,378 individuals (mean age 63.9 years) who attended community-based health checkup in 2004 and 2005 in Takahata town. Albuminuria was evaluated by urine albumin creatinine ratio in morning urine and was categorized into four stages (low normal, high normal, and micro- and macroalbuminuria). RESULTS: At baseline, the prevalence of subjects with low normal, high normal, and micro- and macroalbuminuria was 62.3, 17.3, 18.7, and 1.7%, respectively. During 1 year, progression and remission of albuminuria stages were observed in 23.1 and 14.5% of total subjects, respectively. Both progression and remission of albuminuria were frequently detected at every stage, especially in high normal albuminuria (29% in progression and 39% in remission, respectively). On multivariate analysis, the changes of albuminuria were associated with older age, blood pressures, total protein, estimated glomerular filtration rate (GFR), and urine sodium excretion at baseline, start of antidiabetic drugs, changes in body weight (+/-1 kg), hemoglobin (+/-1 g/dl), and urine sodium excretion (+/-50 mEq/day). CONCLUSION: This study revealed that albuminuria showed high variability associated with age and small changes in modifiable risk factors during 1 year. In the treatment and risk analysis of subjects with albuminuria, the effect of these factors should be considered.

Genetic polymorphisms of paraoxonase-1 are associated with chronic kidney disease in Japanese women.

Paraoxonase-1 (PON1) is an HDL cholesterol-associated antioxidant enzyme, and some of its polymorphisms are linked with systemic oxidative stress and cardiovascular events. In this study, we genotyped seven single nucleotide polymorphisms (SNPs) within the PON1 gene and determined their association with chronic kidney disease in 2,968 individuals from the general Japanese population. We found that a missense SNP (rs662) with a G-to-A substitution leading to an amino acid substitution (G[Arg]/A[Gln]), was significantly associated with albuminuria and estimated glomerular filtration rate (eGFR), especially in women. The A/A genotype in women had the highest prevalence of albuminuria and the lowest values of adjusted eGFR. In contrast, such relationships were not detected in men. Multivariate regression analysis found that the A/A genotype was an independent and significant factor for albuminuria and renal insufficiency (eGFR less than 60 ml/min/1.73 m(2)). The serum PON1 activity was lowest in subjects with the A/A genotype. In biopsy specimens, immunohistochemical analysis found increased PON1 expression on the endothelial surface of sclerotic renal arterioles and glomerular capillaries in patients with hypertension or diabetes. Our study shows that this PON1 G-to-A substitution may be a key player in a common pathway to chronic kidney and cardiovascular diseases in women.

In a non-diabetic Japanese population, the combination of macroalbuminuria and increased urine beta 2-microglobulin predicts a decline of renal function: the Takahata study.

BACKGROUND: Glomerular and tubular damage are important factors in the development of renal insufficiency. However, the interaction of these factors is largely unknown in the non-diabetic Japanese population. To clarify the relationship between renal insufficiency and both glomerular and tubular damage, we conducted a community-based study using albuminuria and urine beta 2-microglobulin as markers of glomerular and tubular damages, respectively. METHODS: Subjects of this study were 2816 non-diabetic individuals >40 years old in Takahata, Japan. The urine albumin-creatinine ratio (UACR) and urine beta 2-microglobulin-creatinine ratio (UBCR) were assessed from single spot urine. The glomerular filtration rate (eGFR) was estimated using the abbreviated MDRD equation with a Japanese coefficient. RESULTS: The prevalence of albuminuria (UACR >20 mg/ g in men and >30 mg/g in women), increased UBCR (>300 microg/g) and renal insufficiency (eGFR <60 mL/ min/1.73 m(2)) were 21.0%, 12.5% and 21.7%, respectively, and there was only a small overlap between the three. The mean eGFR was significantly lower in subjects with macroalbuminuria (UACR >200 mg/g in men and >300 mg/g in women) and increased UBCR. No urinary abnormalities were observed in 71.7% of the 611 subjects with renal insufficiency, and were more common in young, women and the non-hypertensive population. The 1-year decline of eGFR was greatest in subjects with an overlap of macroalbuminuria and increased UBCR. CONCLUSIONS: This study indicated that only a small part of renal insufficiency accompanied increased urine albumin or beta 2-microglobulin in the non-diabetic Japanese population. The combination of macroalbuminuria and increased urine beta 2-microglobulin might predict faster renal deterioration.

Factors correlated with plasma renin activity in general Japanese population.

BACKGROUND: The renin-angiotensin-aldosterone system plays a pivotal role in regulation of blood pressure and electrolyte homeostasis and is a target in the treatment of hypertension and renal diseases. However, the factors correlated with plasma renin activity (PRA) are unclarified in general Japanese population. To examine this point, we conducted a community-based cross-sectional study. METHODS: Subjects of this study were 2,056 individuals (mean age, 61 years; 934 men; 1,122 women) over 40-year-old without antihypertensive medication in Takahata town, Japan. PRA was measured by radioimmunoassay. Estimated 24-h urine sodium (e24hUNa) and potassium excretion were calculated from morning spot urine. RESULTS: The median value of PRA was higher in men compared to women (1.1 ng/ml/h vs. 0.7 ng/ml/h, P < 0.001). The increased PRA (>2.0 ng/ml/h) were detected in 248 men (26.3%) and 142 women (12.7%). One-factor analysis of variance showed that PRA was correlated with blood pressure, uric acid, hemoglobin, total protein, total cholesterol, low-density lipoprotein cholesterol, serum adiponectin and e24hUNa in men. In women, PRA was correlated with age, blood pressure, total protein, high-density lipoprotein cholesterol (HDL-C), serum insulin, e24hUNa and obesity. Multivariate logistic regression analysis showed that high PRA (>2.0 ng/ml/h) was independently associated with low blood pressures, low e24UNa and high serum total protein both in men and women, smoking only in men and high HDL-C only in women, respectively. CONCLUSIONS: This study revealed that PRA was higher in men than women and was associated negatively with blood pressures and urine sodium excretion, and positively with total protein, smoking and HDL-C in Japanese population.

Relationship between antinuclear antibody and microalbuminuria in the general population: the Takahata study.

BACKGROUND: Microalbuminuria, a marker of vascular damage, is associated with increased risk of progressive renal deterioration, cardiovascular disease and mortality. However, the relationship between antinuclear antibody (ANA) and microalbuminuria in the general population is unknown. Thus, we conducted a cross-sectional study to examine the relationship between ANA and microalbuminuria. METHODS: The subjects of this community-based study were individuals over 40 years old in Takahata, Japan. The urine albumin-creatinine ratio (UACR) was calculated from a single-spot urine specimen collected in the morning. ANA was examined by enzyme immunoassay (EIA). RESULTS: Among the 2,875 subjects (mean age 63 years; men 1,276; women 1,599), positive ANA (ANA index >or=20.0) was detected in 16.9% of the total population (men 12.9%, women 20.3%) and the prevalence of positive ANA increased with age. The prevalence of microalbuminuria (UACR 30-300 mg/g), but not macroalbuminuria (UACR > 300 mg/g), was significantly higher in the positive ANA group than the negative ANA group (24.1% vs. 16.0%, respectively, P < 0.001). Along with the increase of the ANA index, the prevalence of microalbuminuria and UACR levels were increased. Multivariate logistic regression analyses showed that ANA was significantly associated with microalbuminuria (odds ratio [OR] 1.63 and 95% confidence interval [95%CI] 1.27-2.10). These associations were significant in women, but not men, when examined separately. CONCLUSIONS: These results indicate that the presence of ANA is associated with microalbuminuria in the general population, especially women.