Hsin-Bang Leu

Diabetes Mellitus and the Risk of Alzheimer’s Disease: A Nationwide Population-Based Study

Objectives Possible association between diabetes mellitus (DM) and Alzheimer’s disease (AD) has been controversial. This study used a nationwide population-based dataset to investigate the relationship between DM and subsequent AD incidence. Methods Data were collected from Taiwan’s National Health Insurance Research Database, which released a cohort dataset of 1,000,000 randomly sampled people and confirmed it to be representative of the Taiwanese population. We identified 71,433 patients newly diagnosed with diabetes (age 58.74±14.02 years) since January 1997. Using propensity score, we matched them with 71,311 non-diabetic subjects by time of enrollment, age, gender, hypertension, hyperlipidemia, and previous stroke history. All the patients were followed up to December 31, 2007. The endpoint of the study was occurrence of AD. Results Over a maximum 11 years of follow-up, diabetic patients experienced a higher incidence of AD than non-diabetic subjects (0.48% vs. 0.37%, p<0.001). After Cox proportional hazard regression model analysis, DM (hazard ratio [HR], 1.76; 95% confidence interval [CI], 1.50–2.07, p<0.001), age (HR, 1.11; 95% CI, 1.10–1.12, p<0.001), female gender (HR, 1.24; 95% CI, 1.06–1.46, p = 0.008), hypertension (HR, 1.30; 95% CI, 1.07–1.59, p = 0.01), previous stroke history (HR, 1.79; 95% CI, 1.28–2.50, p<0.001), and urbanization status (metropolis, HR, 1.32; 95% CI, 1.07–1.63, p = 0.009) were independently associated with the increased risk of AD. Neither monotherapy nor combination therapy with oral antidiabetic medications were associated with the risk of AD after adjusting for underlying risk factors and the duration of DM since diagnosis. However, combination therapy with insulin was found to be associated with greater risk of AD (HR, 2.17; 95% CI, 1.04–4.52, p = 0.039). Conclusion Newly diagnosed DM was associated with increased risk of AD. Use of hypoglycemic agents did not ameliorate the risk.

A Genome-Wide Association Study Reveals a Quantitative Trait Locus of Adiponectin on CDH13 That Predicts Cardiometabolic Outcomes

OBJECTIVE The plasma adiponectin level, a potential upstream and internal facet of metabolic and cardiovascular diseases, has a reasonably high heritability. Whether other novel genes influence the variation in adiponectin level and the roles of these genetic variants on subsequent clinical outcomes has not been thoroughly investigated. Therefore, we aimed not only to identify genetic variants modulating plasma adiponectin levels but also to investigate whether these variants are associated with adiponectin-related metabolic traits and cardiovascular diseases. RESEARCH DESIGN AND METHODS We conducted a genome-wide association study (GWAS) to identify quantitative trait loci (QTL) associated with high molecular weight forms of adiponectin levels by genotyping 382 young-onset hypertensive (YOH) subjects with Illumina HumanHap550 SNP chips. The culpable single nucleotide polymorphism (SNP) variants responsible for lowered adiponectin were then confirmed in another 559 YOH subjects, and the association of these SNP variants with the risk of metabolic syndrome (MS), type 2 diabetes mellitus (T2DM), and ischemic stroke was examined in an independent community–based prospective cohort, the CardioVascular Disease risk FACtors Two-township Study (CVDFACTS, n = 3,350). RESULTS The SNP (rs4783244) most significantly associated with adiponectin levels was located in intron 1 of the T-cadherin (CDH13) gene in the first stage (P = 7.57 × 10−9). We replicated and confirmed the association between rs4783244 and plasma adiponectin levels in an additional 559 YOH subjects (P = 5.70 × 10−17). This SNP was further associated with the risk of MS (odds ratio [OR] = 1.42, P = 0.027), T2DM in men (OR = 3.25, P = 0.026), and ischemic stroke (OR = 2.13, P = 0.002) in the CVDFACTS. CONCLUSIONS These findings indicated the role of T-cadherin in modulating adiponectin levels and the involvement of CDH13 or adiponectin in the development of cardiometabolic diseases.

A genome-wide association study identifies new loci for ACE activity: potential implications for response to ACE inhibitor

Because angiotensin-converting enzyme (ACE) activity is implicated widely in biological systems, we aimed to identify its novel quantitative trait loci for the purposes of understanding ACE activity regulation and pharmacogenetics relating to ACE inhibitor (ACEI). We performed a two-stage genome-wide association study: (1) from 400 young-onset hypertension (YOH) subjects and (2) a confirmation study with an additional 623 YOH subjects. In the first stage, eight single nucleotide polymorphisms (SNPs) of the ACE structural gene and one SNP of ABO genes were significantly associated with ACE activity. SNP rs4343 in exon17 near the well-known insertion/deletion polymorphism had the strongest association. We confirmed in the second stage that three SNPs: rs4343 in ACE gene (P=3.0 × 10−25), rs495828 (P=3.5 × 10−8) and rs8176746 (P=9.3 × 10−5) in ABO gene were significantly associated with ACE activity. We further replicated the association between ABO genotype/blood types and ACE activity in an independent YOH family study (428 hypertension pedigrees), and showed a potential differential blood pressure response to ACEI in subjects with varied numbers of ACE-activity-raising alleles. These findings may broaden our understanding of the mechanisms controlling ACE activity and advance our pharmacogenetic knowledge on ACEI.

Incidence of bleeding from gastroduodenal ulcers in patients with end-stage renal disease receiving hemodialysis

Background: Few large population-based studies have compared the incidence of bleeding of gastroduodenal ulcers between patients with and without end-stage renal disease. We investigated the association between ulcer bleeding and end-stage renal disease in patients receiving hemodialysis, and we sought to identify risk factors for ulcer bleeding. Methods: We performed a nationwide seven-year population study using data from the National Health Insurance Research Database in Taiwan. We identified 36 474 patients with end-stage renal disease who were receiving hemodialysis, 6320 patients with chronic kidney disease and 36 034 controls matched for age, sex and medication use. We performed log-rank testing to analyze differences in survival time without ulcer bleeding among the three groups. We performed Cox proportional hazard regressions to evaluate the risk factors for ulcer bleeding among the three groups and to identify risk factors in patients receiving hemodialysis. Results: Patients receiving hemodialysis and those with chronic kidney disease had a significantly higher incidence of ulcer bleeding than controls had (p < 0.001). Hemodialysis (hazard ratio [HR] 5.24, 95% confidence interval [CI] 4.67–5.86) and chronic kidney disease (HR 1.95, 95% CI 1.62–2.35) were independently associated with an increased risk of ulcer bleeding. Diabetes mellitus, coronary artery disease, cirrhosis and use of nonsteroidal anti-inflammatory drugs were risk factors for ulcer bleeding in patients with end-stage renal disease who were receiving hemodialysis Interpretation: Patients with end-stage renal disease who are receiving hemodialysis had a high risk of ulcer bleeding. Diabetes mellitus, coronary artery disease, cirrhosis and the use of nonsteroidal anti-inflammatory drugs were important risk factors for ulcer bleeding in these patients.

Angiotensin II Receptor Blockers and Risk of Cancer in Patients With Systemic Hypertension

Recently, concerns have been raised that angiotensin II receptor blockers (ARBs) may be associated with an increased risk for cancer development. However, the relation between ARBs and cancer is still unclear. Therefore, a nationwide population-based study was conducted to investigate the possible influence of ARBs on the occurrence of new cancers in patients with hypertension by using the Taiwan National Health Insurance database. A total of 109,002 patients with newly diagnosed hypertension were identified from a cohort database of 1 million individuals from January 1, 1998, to December 31, 2006. Among them, 40,124 (36.8%) had received ARBs for hypertension. The end point was the development of any type of cancer before the end of 2007. During an average of 5.7 ± 2.6 years of follow-up, a total of 9,067 cases of new cancer occurrence were observed. The log-rank test showed that the occurrence rate of newly diagnosed cancers in the subjects receiving ARBs was significantly lower than those receiving treatment without ARBs (ARBs vs controls 3,082 vs 5,985, p <0.001). After adjusting for age, gender, co-morbidities, and medications for hypertension control, ARB use was found to be independently associated with a decreased risk for cancer occurrence (hazard ratio 0.66, 95% confidence interval 0.63 to 0.68, p <0.001). In conclusion, long-term use of ARBs is associated with a lower incidence of cancer occurrence, thereby suggesting that ARBs may prevent cancer development.

Statin use in patients with asthma: a nationwide population-based study.

Eur J Clin Invest 2011; 41 (5): 507–512

Genome-Wide Association Study of Young-Onset Hypertension in the Han Chinese Population of Taiwan

Young-onset hypertension has a stronger genetic component than late-onset counterpart; thus, the identification of genes related to its susceptibility is a critical issue for the prevention and management of this disease. We carried out a two-stage association scan to map young-onset hypertension susceptibility genes. The first-stage analysis, a genome-wide association study, analyzed 175 matched case-control pairs; the second-stage analysis, a confirmatory association study, verified the results at the first stage based on a total of 1,008 patients and 1,008 controls. Single-locus association tests, multilocus association tests and pair-wise gene-gene interaction tests were performed to identify young-onset hypertension susceptibility genes. After considering stringent adjustments of multiple testing, gene annotation and single-nucleotide polymorphism (SNP) quality, four SNPs from two SNP triplets with strong association signals (−log10(p)>7) and 13 SNPs from 8 interactive SNP pairs with strong interactive signals (−log10(p)>8) were carefully re-examined. The confirmatory study verified the association for a SNP quartet 219 kb and 495 kb downstream of LOC344371 (a hypothetical gene) and RASGRP3 on chromosome 2p22.3, respectively. The latter has been implicated in the abnormal vascular responsiveness to endothelin-1 and angiotensin II in diabetic-hypertensive rats. Intrinsic synergy involving IMPG1 on chromosome 6q14.2-q15 was also verified. IMPG1 encodes interphotoreceptor matrix proteoglycan 1 which has cation binding capacity. The genes are novel hypertension targets identified in this first genome-wide hypertension association study of the Han Chinese population.

Risk of Adverse Outcomes in Taiwan Associated With Concomitant Use of Clopidogrel and Proton Pump Inhibitors in Patients Who Received Percutaneous Coronary Intervention

Recent studies have suggested that proton pump inhibitors (PPIs) might reduce the inhibitory effect of clopidogrel on platelet aggregation, possibly through inhibition of the hepatic cytochrome P450 2C19 (CYP2C19) isoenzyme. The prevalence of CYP2C19 loss-of-function alleles is much greater among East Asians than among other populations. Thus, potential drug interactions might be more apparent. Therefore, we conducted a nationwide, population-based study using the Taiwan National Health Insurance database. We identified 3,278 patients (mean age 65.9 +/- 11.9 years, 71.9% men) with coronary artery disease who had taken clopidogrel after percutaneous coronary intervention from the 1 million sampling cohort data set since January 1, 2002. Of the 3,278 patients, 572 had received concomitant PPIs for underlying gastrointestinal disease and 2,706 had not used PPIs. To the end of 2007, 1,410 patients had been rehospitalized, 970 patients had undergone revascularization, and 499 patients had died. According to the Kaplan-Meier analysis, the incidence of rehospitalization (p = 0.001) and mortality (p <0.001) was significantly greater for the patients with concomitant PPI use than for those without concomitant PPI use. However, the incidence of revascularization was similar in the 2 groups. Multivariate analyses showed that concomitant PPI use was associated with an increased risk of rehospitalization (hazard ratio 1.23, 95% confidence interval 1.07 to 1.41, p = 0.003) and mortality (hazard ratio 1.65, 95% confidence interval 1.35 to 2.01, p <0.001). In conclusion, the concomitant use of clopidogrel and PPIs should be done with care to avoid adverse outcome in East Asians patients who have undergone percutaneous coronary intervention.

Plasma matrix metalloproteinase-3 level is an independent prognostic factor in stable coronary artery disease

Background  Recent evidence suggests the important role of matrix metalloproteinases (MMPs) in the progression of atherosclerosis and development of clinical events. We assessed the prognostic value of different plasma MMPs in patients with stable coronary artery disease (CAD).

Nonpeptic Ulcer, Nonvariceal Gastrointestinal Bleeding in Hemodialysis Patients

OBJECTIVES Hemodialysis patients carry a higher risk of peptic ulcer bleeding. Whether hemodialysis patients also have a higher occurrence of nonpeptic ulcer, nonvariceal gastrointestinal bleeding needs further evaluation. METHODS Using Taiwans National Health Insurance research database, the occurrence of nonpeptic ulcer, nonvariceal gastrointestinal bleeding was compared among the hemodialysis patients, chronic kidney disease patients, and controls using log-rank test. Risk factors were identified by Cox regression analysis. RESULTS A total of 20,830 patients were enrolled, including 8210 hemodialysis and 4190 chronic kidney disease patients and 8430 age- and sex-matched controls in a 2:1:2 ratio. In the 7-year follow-up period, hemodialysis patients had a significantly higher cumulative hazard of nonpeptic ulcer, nonvariceal gastrointestinal bleeding than chronic kidney disease patients and controls (P <.001, by log-rank test). The hazard also was significantly higher in the chronic kidney disease patients than in controls. Cox regression analysis revealed that older age, the comorbidities of diabetes mellitus, cirrhosis, and chronic obstructive pulmonary disease, history of uncomplicated peptic ulcer disease, chronic kidney disease (hazard ratio 5.17), hemodialysis (hazard ratio 9.43), and use of selective serotonin reuptake inhibitors were independent risk factors for nonpeptic ulcer, nonvariceal gastrointestinal bleeding in all study patients. Old age, diabetes mellitus, cirrhosis, chronic obstructive pulmonary disease, history of uncomplicated peptic ulcer disease, and use of selective serotonin reuptake inhibitors were independent risk factors in hemodialysis patients. CONCLUSIONS There is a higher risk of developing nonpeptic ulcer, nonvariceal gastrointestinal bleeding in hemodialysis patients after adjustments for age, sex, underlying comorbidities, and ulcerogenic medication. The risk has increased since patients had chronic kidney disease.