Coffee and tea consumption and dementia risk: The role of sex and vascular comorbidities.

BACKGROUND: Coffee and tea consumption has been linked to dementia. However, it remained unknown how sex and vascular risk factors modify the association. We aimed to investigate the association of coffee and tea consumption with dementia and whether sex and vascular comorbidities modified the association. METHODS: We included 278 elderly patients with Alzheimer's disease (AD) and 102 patients with vascular dementia (VaD) from three hospitals; controls (N = 468) were recruited during the same period. We collected the frequency and amount of coffee and tea consumption and the presence of vascular comorbidities. The multinomial logistic regression model was utilized to evaluate the association of coffee and tea consumption with dementia, stratified by sex and vascular comorbidities. RESULTS: Different combinations and quantities of coffee and tea consumption protected against AD and VaD. Consumption of ≥3 cups of coffee or tea per day was protective against AD [adjusted odds ratio (aOR) = 0.42; 95% confidence interval (CI) = 0.22-0.78)] and VaD (aOR = 0.42; 95% CI = 0.19-0.94). Stratified analyses showed that the protective effects of a higher quantity of coffee and tea against AD were more pronounced among females and individuals with hypertension. Consumption of either coffee or tea was associated with a decreased risk of VaD among diabetic participants (aOR = 0.23; 95% CI = 0.06-0.98). Hyperlipidemia modified the association of coffee or tea consumption on the risk of AD and VaD (both Pinteraction < 0.01). CONCLUSION: The risk of AD and VaD was lower with increased consumption of coffee and tea; the impact differed by sex and vascular comorbidities including hypertension, hyperlipidemia, and diabetes.

DLC1 inhibits colon adenocarcinoma cell migration by promoting secretion of the neurotrophic factor MANF.

DLC1 (deleted in liver cancer-1) is downregulated or deleted in colorectal cancer (CRC) tissues and functions as a potent tumor suppressor, but the underlying molecular mechanism remains elusive. We found that the conditioned medium (CM) collected from DLC1-overexpressed SW1116 cells inhibited the migration of colon adenocarcinoma cells HCT116 and SW1116, but had no effect on proliferation, which suggested DLC1-mediated secretory components containing a specific inhibitor for colon adenocarcinoma cell migration. Analysis by mass spectrometry identified mesencephalic astrocyte-derived neurotrophic factor (MANF) as a candidate. More importantly, exogenous MANF significantly inhibited the migration of colon adenocarcinoma cells HCT116 and SW1116, but did not affect proliferation. Mechanistically, DLC1 reduced the retention of MANF in ER by competing the interaction between MANF and GRP78. Taken together, these data provided new insights into the suppressive effects of DLC1 on CRC, and revealed the potential of MANF in the treatment of CRC.

Hypoxia facilitates the proliferation of colorectal cancer cells by inducing cancer-associated fibroblast-derived IL6.

Colorectal cancer (CRC) is the most common malignancy worldwide, and its underlying molecular mechanisms remain largely unexplored. Accumulating evidences indicate cancer-associated fibroblasts (CAFs), abundant stromal cell population in the tumor microenvironment, play a key role in tumor development. Herein, we have successfully isolated CAFs and paired normal fibroblasts (NFs) from colorectal cancer tissues (n=10). By using a multiplex cytokine profiling assay, we have identified IL-6 as a major cytokine released by CAFs. Co-culturing of CAFs with CRC cell lines HCT116 or SW480 increases IL-6 release, and the secretion by CAFs can be further enhanced under hypoxia. By using the CCK-8 assay, we have found that HCT116 or SW480 cells treated with culture medium from CAFs, IL-6, or hypoxia showed a significant cell growth compared to control cells (p<0.01). Mechanistically, we have found that hypoxia could enhance the effect of the IL-6/STAT3 signaling on CRC cells, in part, through HIF-1a targeting PKM2. In conclusion, our data clearly proposes the interconnected mechanisms for constitutive activation of STAT3 signal by CAFs-derived IL-6 under hypoxia in colorectal cancer. The pharmacological inhibition of STAT3, PKM2, or HIF-1α can significantly reduce the oncogenic effect of IL-6, providing a potential therapeutic target for CRC patients.

MicroRNA-1254 inhibits the migration of colon adenocarcinoma cells by targeting PSMD10.

OBJECTIVE: MicroRNA-1254 (miR-1254) has not been studied in colorectal cancer (CRC) to date. This study aimed to investigate the inhibitory mechanism of miR-1254 in CRC tumorigenesis. METHODS: MiR-1254 expression was examined using real-time polymerase chain reaction in CRC and adjacent non-tumorous tissues. The correlation between miR-1254 expressions and proliferation and migration of cancer cells was determined using the CCK-8 and transwell assays. RNA sequencing was used to identify differentially expressed genes downstream from miR-1254. A luciferase reporter assay was used to confirm the direct interaction between miR-1254 and its predicted target gene, PSMD10. Moreover, PSMD10 was either overexpressed or silenced in colon carcinoma cells overexpressing miR-1254 to determine whether their interaction contributed to CRC migration and epithelial-mesenchymal transition (EMT). RESULTS: Significantly lower miR-1254 expressions were observed in CRC tissues than in adjacent non-tumorous tissues. Exogenous miR-1254 expression suppressed the migration of colon carcinoma cell lines SW1116 and HCT116. RNA sequencing and luciferase assays revealed that miR-1254 directly binded to the 3'-untranslated region of PSMD10, an important regulator of EMT and cell migration. PSMD10 knockdown inhibited EMT and colon cancer cell migration, whereas PSMD10 overexpression reversed the inhibition of EMT and cell migration caused by miR-1254. CONCLUSION: MiR-1254 may act as a tumor suppressor in CRC and may inhibit CRC migration by directly targeting PSMD10 to suppress the EMT process.

Performance Metrics for Selecting Single Nucleotide Polymorphisms in Late-onset Alzheimer's Disease.

Previous genome-wide association studies using P-values to select single nucleotide polymorphisms (SNPs) have suffered from high false-positive and false-negative results. This case-control study recruited 713 late-onset Alzheimer's disease (LOAD) cases and controls aged ≥65 from three teaching hospitals in northern Taiwan from 2007 to 2010. Performance metrics were used to select SNPs in stage 1, which were then genotyped to another dataset (stage 2). Four SNPs (CPXM2 rs2362967, APOC1 rs4420638, ZNF521 rs7230380, and rs12965520) were identified for LOAD by both traditional P-values (without correcting for multiple tests) and performance metrics. After correction for multiple tests, no SNPs were identified by traditional P-values. Simultaneous testing of APOE e4 and APOC1 rs4420638 (the SNP with the best performance in the performance metrics) significantly improved the low sensitivity of APOE e4 from 0.50 to 0.78. A point-based genetic model including these 2 SNPs and important covariates was constructed. Compared with elders with low-risks score (0-6), elders belonging to moderate-risk (score = 7-11) and high-risk (score = 12-18) groups showed a significantly increased risk of LOAD (adjusted odds ratio = 7.80 and 46.93, respectively; Ptrend < 0.0001). Performance metrics allow for identification of markers with moderate effect and are useful for creating genetic tests with clinical and public health implications.

CHRNA7 Polymorphisms and Dementia Risk: Interactions with Apolipoprotein ε4 and Cigarette Smoking.

α7 nicotinic acetylcholine receptor (α7nAChR, encoded by CHRNA7) is involved in dementia pathogenesis through cholinergic neurotransmission, neuroprotection and interactions with amyloid-ß. Smoking promotes atherosclerosis and increases dementia risk, but nicotine exerts neuroprotective effect via α7nAChR in preclinical studies. No studies explored the gene-gene, gene-environment interactions between CHRNA7 polymorphism, apolipoprotein E (APOE) ε4 status and smoking on dementia risk. This case-control study recruited 254 late-onset Alzheimer's disease (LOAD) and 115 vascular dementia (VaD) cases (age ≥65) from the neurology clinics of three teaching hospitals in Taiwan during 2007-2010. Controls (N = 435) were recruited from health checkup programs and volunteers during the same period. Nine CHRNA7 haplotype-tagging single nucleotide polymorphisms representative for Taiwanese were genotyped. Among APOE ε4 non-carriers, CHRNA7 rs7179008 variant carriers had significantly decreased LOAD risk after correction for multiple tests (GG + AG vs. AA: adjusted odds ratio = 0.29, 95% confidence interval = 0.13-0.64, P = 0.002). Similar findings were observed for carriers of GT haplotype in CHRNA7 block4. A significant interaction was found between rs7179008, GT haplotype in block4 and APOE ε4 on LOAD risk. rs7179008 variant also reduced the detrimental effect of smoking on LOAD risk. No significant association was found between CHRNA7 and VaD. These findings help to understand dementia pathogenesis.

Genetic polymorphisms of lipid metabolism gene SAR1 homolog B and the risk of Alzheimer's disease and vascular dementia.

BACKGROUND/PURPOSE: Lipid metabolism is involved in beta amyloid generation, which has been related with the progression of Alzheimer's disease (AD). No study has explored the association between polymorphisms of SAR1 homolog B (SAR1B) and the risk of dementia previously. METHODS: This is a case-control study. A total of 279 AD and 117 vascular dementia (VaD) patients were recruited from neurology clinics at three teaching hospitals in Taiwan from 2007 to 2010. Controls (n = 466) were recruited from the elderly health checkup program and volunteers in the hospital during the same time interval. Three common (frequency ≥ 5%) haplotype-tagging single nucleotide polymorphisms were selected from the lipid metabolism gene SAR1B to assess its association with AD and VaD. RESULTS: Homozygous variants of rs11948613 were associated with a decreased AD risk (CC vs. TT: adjusted odds ratio = 0.39, 95% confidence interval = 0.15-0.98) with a population attributable risk of 26.7%. This association decreased further in apolipoprotein E ε4 (ApoE ε4) noncarriers (adjusted odds ratio = 0.28, 95% confidence interval = 0.09-0.91). No association was found for VaD. Two common haplotypes (with a cumulative frequency of 95.7% in controls) were identified for SAR1B, and no association was found for AD or VaD. Simultaneous screening using rs11948613 and ApoE ε4 significantly improved the sensitivity of ApoE ε4 alone (from 0.40 to 0.75). CONCLUSION: SAR1B polymorphisms were associated with AD risk; results were not significant after correction for multiple tests. Simultaneous screening using SAR1B rs11948613 and ApoE ε4 status offered a better sensitivity for AD screening.

Sequence variants of the aging gene CISD2 and the risk for Alzheimer's disease.

BACKGROUND/PURPOSE: The CISD2 gene has been related to life span control and mitochondrial dysfunction in animals. In addition, inhibition of mitochondrial enzymes due to an accumulation of beta-amyloid peptide has been related to Alzheimer's disease (AD). This study aimed to explore the association between sequence variants of the CISD2 gene and risk for AD, which has not been explored previously. METHODS: This was a case-control study involving a total of 276 patients with AD who were recruited from three teaching hospitals in Taiwan from 2007 to 2010; 460 controls were recruited from elderly individuals attending for health check-ups and volunteers in the hospital during the same period of time. All participants were aged 60 years or older. Two haplotype-tagging single nucleotide polymorphisms (htSNPs), rs223330 and rs223331, were selected from the CISD2 gene to test the association between their polymorphisms and the risk for dementia, and how ApoE ɛ4 status, sex, hypertension, and type 2 diabetes mellitus might modify this association. RESULTS: rs223330 variant carriage was not associated with risk for AD [TT versus CC: adjusted odds ratio (AOR) = 0.98, 95% confidence interval (CI) = 0.59-1.62; TC versus CC: AOR = 0.72, 95% CI = 0.47-1.11]. Similar findings were observed for rs223331 (AA versus TT: AOR = 1.12; AT versus TT: AOR = 0.99). In addition, hypertension significantly modified the association between rs223331 and risk for AD (p = 0.005).Three common haplotypes (with a frequency of 99.8%) were observed for CISD2. Common CISD2 haplotypes were not associated with the risk for AD. CONCLUSION: Our findings suggested that CISD2 htSNPs are not associated with AD risk.

Role of B7-H4 siRNA in Proliferation, Migration, and Invasion of LOVO Colorectal Carcinoma Cell Line.

OBJECTIVES: Colorectal cancer is one of the most common malignancies. Recent studies investigated that B7-H4 is highly expressed in various cancers. We aimed at exploring the effect of B7-H4 siRNA on proliferation, invasion, and migration of LOVO cells which expressed B7-H4 notably. DESIGN AND METHODS: Colon adenocarcinoma dataset was downloaded from The Cancer Genome Atlas. 35 colorectal cancer patients admitted to Shanghai Tongren Hospital were enrolled in this study. Cell proliferation and cell cycle distribution were identified by CCK8 and flow cytometry, respectively. Transwell assay was performed to detect the invasion and migration of LOVO cells. CXCL12/CXCR4 expression and JAK2/STAT3 phosphorylation were determined by real-time PCR and western blot. RESULTS: B7-H4 expressed is elevated in colorectal cancer tissues than in the adjacent normal tissues. B7-H4 siRNA effectively inhibited the proliferation at 24 h and 48 h, arrested cell cycle at G0/G1, and suppressed cell invasion and migration. Gene set enrichment analysis showed that CXCL12/CXCR4 and JAK/STAT were correlative with the B7-H4 expression. Additionally, CXCL12/CXCR4 expression and JAK2/STAT3 phosphorylation were reduced. CONCLUSIONS: B7-H4 siRNA can effectively inhibit proliferation, invasion, and migration of LOVO cells by targeting CXCL12/CXCR4 and JAK2/STAT3 signaling, which can serve as a new target for colorectal carcinoma treatment.

Religious affiliation and the risk of dementia in Taiwanese elderly.

INTRODUCTION: Religious affiliations vary across ethnic groups because of different cultural backgrounds. Some studies have explored the association between religious affiliation and cognitive decline. Only a small portion of patients with cognitive decline progress to dementia. However, the association between religious affiliation and dementia risk remains unclear. METHODS: In this case-control study, we recruited 280 patients with Alzheimer's disease (AD) and 138 with vascular dementia (VaD) (both aged ≥60 years) from three teaching hospitals in northern Taiwan between 2007 and 2010. Age-matched healthy controls (n=466) were recruited from an elderly health checkup program and from volunteers visiting the hospital during the same period. Three religious affiliations-Taoism, Buddhism, and Christianity-were evaluated. The study also assessed the effect of important factors such as gender or leisure activities on the association of religious affiliation with dementia risk. RESULTS: Participants with Christianity affiliation showed decreased AD risk (adjusted odds ratio [AOR]=0.46, 95% confidence interval [CI]=0.25-0.87) compared with those without any religious affiliation. Moreover, this effect was stronger in women (AOR=0.38, 95% CI=0.15-0.92) and in participants who exercised regularly (>3 times/week; AOR=0.33, 95% CI=0.14-0.77). No significant association was observed among participants with Taoism and Buddhism affiliations. Affiliation to none of the religions was associated with VaD risk. CONCLUSIONS: Thus, Chinese participants having Christianity affiliation showed decreased AD risk. Moreover, the protective effect was more evident in women and in participants who exercised regularly.

Association between air pollutants and dementia risk in the elderly.

BACKGROUND: The aging rate in Taiwan is the second highest in the world. As the population ages quickly, the prevalence of dementia increases rapidly. There are some studies that have explored the association between air pollution and cognitive decline, but the association between air pollution and dementia has not been directly evaluated. METHODS: This was a case-control study comprising 249 Alzheimer's disease (AD) patients, 125 vascular dementia (VaD) patients, and 497 controls from three teaching hospitals in northern Taiwan from 2007 to 2010. Data of particulate matter <10 µm in diameter (PM10) and ozone were obtained from the Taiwan Environmental Protection Administration for 12 and 14 years, respectively. Blood samples were collected to determine the apolipoprotein E (APOE) ɛ4 haplotype. Bayesian maximum entropy was used to estimate the individual exposure level of air pollutants, which was then tertiled for analysis. Conditional logistic regression models were used to estimate adjusted odds ratios (AORs) and 95% confidence intervals between the association of PM10 and ozone exposure with AD and VaD risk. RESULTS: The highest tertile of PM10 (≥49.23 µg/m(3)) or ozone (≥21.56 ppb) exposure was associated with increased AD risk (highest vs. lowest tertile of PM10: AOR = 4.17; highest vs. lowest tertile of ozone: AOR = 2.00). Similar finding was observed for VaD. The association with AD and VaD risk remained for the highest tertile PM10 exposure after stratification by APOE ɛ4 status and gender. CONCLUSIONS: Long-term exposure to the highest tertile of PM10 or ozone was significantly associated with an increased risk of AD and VaD.

Leisure activities, apolipoprotein E e4 status, and the risk of dementia.

BACKGROUND/PURPOSE: Leisure activities have been associated with a decreased risk of dementia. However, to date, no study has explored how apolipoprotein E (ApoE) e4 status or vascular risk factors modified the association between leisure activities and dementia risks. METHODS: This case-control study recruited patients (age ≥ 60 years) with Alzheimer's disease (AD; n = 292) and vascular dementia (VaD; n = 144) and healthy controls (n = 506) from three teaching hospitals in Taiwan between 2007 and 2010. Information on patient's leisure activities were obtained through a questionnaire. Conditional logistic regression models were used to assess the association of leisure activities and ApoE e4 status with the risk of dementia. RESULTS: High-frequency physical activity was associated with a decreased risk of AD [adjusted odds ratio (AOR) = 0.45], and the results become more evident among ApoE e4 carriers with AD (AOR = 0.30) and VaD (AOR = 0.26). Similar findings were observed for cognitive (AOR = 0.42) and social activities (AOR = 0.55) for AD. High-frequency physical, cognitive, and social activities were associated with a decreased risk of VaD (AOR = 0.29-0.60). Physical and social activities significantly interacted with each other on the risk of VaD (pinteraction = 0.04). CONCLUSION: Physical activity consistently protects against AD and VaD. Significant interactions were identified across different types of leisure activities in lowering dementia risk.

CHRNA7 polymorphisms and response to cholinesterase inhibitors in Alzheimer's disease.

BACKGROUND: CHRNA7 encodes the α7 nicotinic acetylcholine receptor subunit, which is important to Alzheimer's disease (AD) pathogenesis and cholinergic neurotransmission. Previously, CHRNA7 polymorphisms have not been related to cholinesterase inhibitors (ChEI) response. METHODS: Mild to moderate AD patients received ChEIs were recruited from the neurology clinics of three teaching hospitals from 2007 to 2010 (n = 204). Nine haplotype-tagging single nucleotide polymorphisms of CHRNA7 were genotyped. Cognitive responders were those showing improvement in the Mini-Mental State Examination score ≥ 2 between baseline and 6 months after ChEI treatment. RESULTS: AD women carrying rs8024987 variants [GG+GC vs. CC: adjusted odds ratio (AOR) = 3.62, 95% confidence interval (CI) = 1.47-8.89] and GG haplotype in block1 (AOR = 3.34, 95% CI = 1.38-8.06) had significantly better response to ChEIs (false discovery rate <0.05). These variant carriers using galantamine were 11 times more likely to be responders than female non-carriers using donepezil or rivastigmine. CONCLUSION: For the first time, this study found a significant association between CHRNA7 polymorphisms and better ChEI response. If confirmed by further studies, CHRNA7 polymorphisms may aid in predicting ChEI response and refining treatment choice.

Sequence variants of toll like receptor 4 and late-onset Alzheimer's disease.

BACKGROUND: Toll like receptor 4 (TLR4) has been related to inflammation and beta-amyloid deposition in Alzheimer's disease (AD) brain. No study has explored the association between haplotype-tagging single nucleotide polymorphisms (htSNPs) of TLR4 and AD risk previously and ApoE e4 status alone showed low sensitivity in identifying late-onset AD (LOAD) patients. METHODS: A total of 269 LOAD patients were recruited from three hospitals in northern Taiwan (2007-2010). Controls (n = 449) were recruited from elderly health checkup and volunteers of the hospital during the same period of time. Five common (frequency≥5%) TLR4 htSNPs were selected to assess the association between TLR4 polymorphisms and the risk of LOAD in the Chinese ethnic population. RESULTS: Homozygosity of TLR4 rs1927907 was significantly associated with an increased risk of LOAD [TT vs. CC: adjusted odds ratio (AOR) = 2.45, 95% confidence interval (CI) = 1.30-4.64]. After stratification, the association increased further in ApoE e4 non-carriers (AOR = 3.07) and in hypertensive patients (AOR = 3.60). Haplotype GACGG was associated with a decreased risk of LOAD (1 vs. 0 copies: AOR = 0.59, 95% CI = 0.36-0.96; 2 vs. 0 copies: AOR = 0.31, 95% CI = 0.14-0.67) in ApoE e4 non-carriers. ApoE e4 status significantly modified this association (p(interaction) = 0.01). These associations remained significant after correction for multiple tests. CONCLUSIONS: Sequence variants of TLR4 were associated with an increased risk of LOAD, especially in ApoE e4 non-carriers and in hypertensive patients. The combination of TLR4 rs1927907 and ApoE e4 significantly increased the screening sensitivity in identifying LOAD patients from 0.4 to 0.7.

Sequence variants of interleukin 6 (IL-6) are significantly associated with a decreased risk of late-onset Alzheimer's disease.

BACKGROUND: Interleukin 6 (IL-6) has been related to beta-amyloid aggregation and the appearance of hyperphosphorylated tau in Alzheimer's disease (AD) brain. However, previous studies relating IL-6 genetic polymorphisms to AD included few and unrepresentative single nucleotide polymorphisms (SNPs) and the results were inconsistent. METHODS: This is a case-control study. A total of 266 patients with AD, aged≧65, were recruited from three hospitals in Taiwan (2007-2010). Controls (n = 444) were recruited from routine health checkups and volunteers of the hospital during the same period of time. Three common IL-6 haplotype-tagging SNPs were selected to assess the association between IL-6 polymorphisms and the risk of late-onset AD (LOAD). RESULTS: Variant carriers of IL-6 rs1800796 and rs1524107 were significantly associated with a reduced risk of LOAD [(GG + GC vs. CC): adjusted odds ratio (AOR) = 0.64 and (CC + CT vs. TT): AOR = 0.60, respectively]. Haplotype CAT was associated with a decreased risk of LOAD (0 and 1 copy vs. 2 copies: AOR = 0.65, 95% CI = 0.44-0.95). These associations remained significant in ApoE e4 non-carriers only. Hypertension significantly modified the association between rs2069837 polymorphisms and the risk of LOAD (pinteraction = 0.03). CONCLUSIONS: IL-6 polymorphisms are associated with reduced risk of LOAD, especially in ApoE e4 non-carriers. This study identified genetic markers for predicting LOAD in ApoE e4 non-carriers.

Genetic polymorphisms of nerve growth factor receptor (NGFR) and the risk of Alzheimer's disease.

BACKGROUND: Loss of basal forebrain cholinergic neurons is attributable to the proapoptotic signaling induced by nerve growth factor receptor (NGFR) and may link to Alzheimer's disease (AD) risk. Only one study has investigated the association between NGFR polymorphisms and the risk of AD in an Italian population. Type 2 diabetes mellitus (DM) may modify this association based on previous animal and epidemiologic studies. METHODS: This was a case-control study in a Chinese population. A total of 264 AD patients were recruited from three teaching hospitals between 2007 to 2010; 389 controls were recruited from elderly health checkup and volunteers of the hospital during the same period of time. Five common (frequency≥5%) haplotype-tagging single nucleotide polymorphisms (htSNPs) were selected from NGFR to test the association between NGFR htSNPs and the risk of AD. RESULTS: Variant NGFR rs734194 was significantly associated with a decreased risk of AD [GG vs. TT copies: adjusted odds ratio (OR) = 0.43, 95% confidence interval (CI) = 0.20-0.95]. Seven common haplotypes were identified. Minor haplotype GCGCG was significantly associated with a decreased risk of AD (2 vs. 0 copies: adjusted OR = 0.39, 95% CI = 0.17-0.91). Type 2 DM significantly modified the association between rs2072446, rs741072, and haplotype GCTTG and GTTCG on the risk of AD among ApoE ε4 non-carriers (P(interaction) < 0.05). CONCLUSION: Inherited polymorphisms of NGFR were associated with the risk of AD; results were not significant after correction for multiple tests. This association was further modified by the status of type 2 DM.

Genetic polymorphisms of a novel vascular susceptibility gene, Ninjurin2 (NINJ2), are associated with a decreased risk of Alzheimer's disease.

BACKGROUND: Accumulated evidences have shown that vascular risk factors, e.g., hypertension, diabetes mellitus and hyperlipidemia, may be related to the risk of dementia. This study investigated the association between genetic polymorphisms of a vascular susceptibility gene, Ninjurin2 (NINJ2), and the risk of dementia, which has not been explored previously. METHODS: A total of 275 Alzheimer's disease (AD) patients and 119 vascular dementia (VaD) patients aged 50 or older were recruited from three teaching hospitals from 2007 to 2010. Healthy controls (n = 423) with the same age of cases were recruited from the health checkup and volunteers worked at the hospital during the same time period. Five common (frequency >5%) haplotype-tagging single nucleotide polymorphisms (htSNPs) in NINJ2 were genotyped to test for the association between sequence variants of NINJ2 and dementia risk, and how vascular risk factors modify this association. RESULTS: Homozygosity of two NINJ2 SNPs was significantly associated with a decreased risk of AD [rs11833579: adjusted odds ratio (AOR) = 0.43; 95% confidence interval (CI)= 0.23-0.80; rs12425791: AOR= 0.33, 95% CI= 0.12-0.96]. Five common haplotypes (cumulative frequency= 97%) were identified. The global test for the association between NINJ2 haplotypes and AD was significant (p = 0.03). Haplotype CAGGA was significantly associated with a decreased risk of AD (AOR= 0.32, 95% CI= 0.11-0.94). No associations were observed for VaD. CONCLUSION: Inherited polymorphisms of the vascular susceptibility gene NINJ2 were associated with AD risk.

Glycated albumin is independently associated with estimated glomerular filtration rate in nondiabetic patients with chronic kidney disease.

BACKGROUND: Glycated albumin (GA) may contribute to diabetic nephropathy, but the clinical significance of GA in patients with chronic kidney disease (CKD) is unknown. METHODS: Patients were classified with the NKF/DOQI classification system as mild (stage I, II), moderate (stage III), or advanced CKD (stage IV). Those undergoing dialysis or with CKD stage V were excluded. GA was measured using the Lucica TM GA-L assay kit. The relationship between GA and renal dysfunction was analyzed in patients with or without diabetes. RESULTS: A total of 187 subjects were enrolled. GA values in those with normal, mild, moderate and advanced CKD were 18.4 ± 1.4%, 18.4 ± 3.1%, 19.0 ± 3.8%, 20.4 ± 6.4%, respectively, in diabetic patients (N=67, p=0.5), and were 14.1 ± 1.9%, 14.2 ± 2.2%, 15.9 ± 1.9%, 15.0 ± 1.7%, respectively, in nondiabetic patients (N=120, p=0.004). GA value was negatively correlated to eGFR in nondiabetic patients (r=-0.35, p<0.001) but not in diabetic patients (r=-0.11, p=0.39). In the adjusted model, GA is independently correlated to eGFR only in nondiabetic subjects. CONCLUSIONS: Increased GA concentrations are independently associated with renal dysfunction in nondiabetic patients with CKD.

Comparison of insulin sensitivity, glucose sensitivity, and first phase insulin secretion in patients treated with repaglinide or gliclazide.

The traditional sulfonylureas with long half-lives have sustained stimulatory effects on insulin secretion compared to the short-acting insulin secretagogue. In this study, we used the frequently sampled intravenous glucose tolerance test (FSIGT) to evaluate the insulin sensitivity (IS), glucose sensitivity (SG), and acute insulin response after glucose load (AIRg) after 4 months treatment with either gliclazide or repaglinide. The design of study was randomizedcrossover. We enrolled 20 patients with new-onset type 2 diabetes (mean age, 49.3 years). Totally three FSIGTs were performed, one before and one after each of the two treatment periods as aforementioned. No significant differences in fasting plasma glucose, insulin, body mass index, blood pressure, glycated hemoglobin, or lipids were noted between the two treatments. After the repaglinide treatment, higher AIRg, lower IS, and lower SG were noted, but they did not reach statistical significance. The disposal index (DI) was also not significantly different between the two treatments. In conclusion, since non-significantly higher DI, AIRg, lower IS and SG were noted after repaglinide treatment, it might be a better treatment for diabetes, relative to gliclazide.