Interactive Effects of a Combination of the HDAC3 and HDAC9 Genes with Diabetes Mellitus on the Risk of Ischemic Stroke

Author(s):  
Hung-Yi Chiou ◽  
Chyi-Huey Bai ◽  
Li-Ming Lien ◽  
Chaur-Jong Hu ◽  
Jiann-Shing Jeng ◽  
...  

Abstract Background and Aim Previous studies indicated that the HDAC3 and HDAC9 genes play critical roles in atherosclerosis and ischemic stroke (IS). The purpose of this study was to investigate the association of combined single-nucleotide polymorphisms in the HDAC3 and HDAC9 genes with the susceptibility to IS. Methods A case–control study was conducted including 863 IS patients and 863 age- and gender-matched healthy participants. A polygenic score was developed to estimate the contribution of a combination of the HDAC3 and HDAC9 genes to the risk of IS. The interactive effects of traditional risk factors of stroke and the polygenic score on the risk of IS were explored. Additionally, the association between the polygenic score and the progression of atherosclerosis, a potential risk factor of IS, was examined in our healthy controls. Results Subjects with a higher polygenic score had an increased risk of IS (odds ratio: 1.83; 95% confidence interval: 1.38–2.43) after adjusting for covariates compared with individuals with a lower polygenic score. An interactive effect of diabetes mellitus and the polygenic score on the risk of IS was observed. A significant positive correlation between the polygenic score and a change in the plaque score (standardized β = 0.42, p = 0.0235) in healthy controls with diabetes mellitus was found. Conclusion Our results suggested that the combination of the HDAC3 and HDAC9 genes with a history of diabetes mellitus could exacerbate the deterioration of atherosclerosis, thereby increasing the risk of IS. Further studies are warranted to explore our results in other populations.

2021 ◽  
pp. 112067212110026
Author(s):  
Pablo Gili ◽  
Leyre Lloreda Martín ◽  
José-Carlos Martín-Rodrigo ◽  
Naon Kim-Yeon ◽  
Laura Modamio-Gardeta ◽  
...  

Purpose: To identify the association between single-nucleotide polymorphisms (SNPs) in CFH, ARMS2, HTRA1, CFB, C2, and C3 genes and exudative age-related macular degeneration (AMD) in a Spanish population. Methods: In 187 exudative AMD patients and 196 healthy controls (61% women, mean age 75 years), 12 SNPs as risk factors for AMD in CFH (rs1410996, rs1061170, r380390), ARMS2 (rs10490924, rs10490923), HTRA1 (rs11200638), CFB (rs641153), C2 (rs547154, rs9332739), and C3 (rs147859257, rs2230199, rs1047286) genes were analyzed. Results: The G allele was the most frequent in CFH gene (rs1410996) with a 7-fold increased risk of AMD (OR 7.69, 95% CI 3.17–18.69), whereas carriers of C allele in CFH (rs1061170) showed a 3-fold increased risk for AMD (OR 3.22, 95% CI 1.93–5.40). In CFH (rs380390), the presence of G allele increased the risk for AMD by 2-fold (OR 2.52, 95% CI 1.47–4.30). In ARMS2 (rs10490924), the T-allele was associated with an almost 5-fold increased risk (OR 5.49, 95% CI 3.23–9.31). The A allele in HTRA1 (rs11200638) was more prevalent in AMD versus controls (OR 6.44, 95% CI 3.62–11.47). In C2 gene (rs9332739) the presence of C increased risk for AMD by 3-fold (OR 3.10, 95% CI 1.06–9.06). Conclusion: SNPs in CFH, ARMS2, HTRA1, and C2 genes were associated in our study with an increased risk for exudative AMD in Spanish patients.


2021 ◽  
pp. 174749302110062
Author(s):  
Bin Yan ◽  
Jian Yang ◽  
Li Qian ◽  
Fengjie Gao ◽  
Ling Bai ◽  
...  

Background: Observational studies have found an association between visceral adiposity and stroke. Aims: The purpose of this study was to investigate the role and genetic effect of visceral adipose tissue (VAT) accumulation on stroke and its subtypes. Methods: In this two-sample Mendelian randomization (MR) study, genetic variants (221 single nucleotide polymorphisms; P<5×10-8) using as instrumental variables for MR analysis was obtained from a genome-wide association study (GWAS) of VAT. The outcome datasets for stroke and its subtypes were obtained from the MEGASTROKE consortium (up to 67,162 cases and 453,702 controls). MR standard analysis (inverse variance weighted method) was conducted to investigate the effect of genetic liability to visceral adiposity on stroke and its subtypes. Sensitivity analysis (MR-Egger, weighted median, MR-PRESSO) were also utilized to assess horizontal pleiotropy and remove outliers. Multi-variable MR analysis was employed to adjust potential confounders. Results: In the standard MR analysis, genetically determined visceral adiposity (per 1 SD) was significantly associated with a higher risk of stroke (odds ratio [OR] 1.30; 95% confidence interval [CI] 1.21-1.41, P=1.48×10-11), ischemic stroke (OR 1.30; 95% CI 1.20-1.41, P=4.01×10-10), and large artery stroke (OR 1.49; 95% CI 1.22-1.83, P=1.16×10-4). The significant association was also found in sensitivity analysis and multi-variable MR analysis. Conclusions: Genetic liability to visceral adiposity was significantly associated with an increased risk of stroke, ischemic stroke, and large artery stroke. The effect of genetic susceptibility to visceral adiposity on the stroke warrants further investigation.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xiaoman Zhou ◽  
Yunjun Zhang ◽  
Yutian Zhang ◽  
Quanni Li ◽  
Mei Lin ◽  
...  

Abstract Objective Chronic obstructive pulmonary disease (COPD) is a complicated multi-factor, multi-gene disease. Here, we aimed to assess the association of genetic polymorphisms in LINC01414/ LINC00824 and interactions with COPD susceptibility. Methods Three single nucleotide polymorphisms (SNPs) in LINC01414/LINC00824 was genotyped by Agena MassARRAY platform among 315 COPD patients and 314 controls. Logistic analysis adjusted by age and gender were applied to estimate the genetic contribution of selected SNPs to COPD susceptibility. Results LINC01414 rs699467 (OR = 0.73, 95% CI 0.56–0.94, p = 0.015) and LINC00824 rs7815944 (OR = 0.56, 95% CI 0.31–0.99, p = 0.046) might be protective factors for COPD occurrence, while LINC01414 rs298207 (OR = 2.88, 95% CI 1.31–6.31, p = 0.008) risk-allele was related to the increased risk of COPD in the whole population. Rs7815944 was associated with the reduced risk of COPD in the subjects aged > 70 years (OR = 0.29, p = 0.005). Rs6994670 (OR = 0.57, p = 0.007) contribute to a reduced COPD risk, while rs298207 (OR = 7.94, p = 0.009) was related to a higher susceptibility to COPD at age ≤ 70 years. Rs298207 (OR = 2.54, p = 0.043) and rs7815944 (OR = 0.43, p = 0.028) variants was associated COPD risk among males. Rs7815944 (OR = 0.16, p = 0.031) was related to the reduced susceptibility of COPD in former smokers. Moreover, the association between rs298207 genotype and COPD patients with dyspnea was found (OR = 0.50, p = 0.016), and rs7815944 was related to COPD patients with wheezing (OR = 0.22, p = 0.008). Conclusion Our finding provided further insights into LINC01414/LINC00824 polymorphisms at risk of COPD occurrence and accumulated evidence for the genetic susceptibility of COPD.


2021 ◽  
Vol 4 (1) ◽  
pp. 51-60
Author(s):  
Sunita Karki ◽  
Anjan Rai ◽  
Manish Pradhan

Introduction Acrochordons or skin tags are common benign cutaneous tumors that occur especially over the neck and major flexures. A possible association between diabetes mellitus and dyslipidemia is observed in numerous past studies with varying results. We aim to find out the association of diabetes mellitus with acrochordons Methods: One hundred patients were enrolled in our study. Among them, 50 (27 males and 23 females) with skin tags were selected as cases and 50 with other dermatologic diseases after matching age and gender were taken as controls. Blood glucose levels including both fasting and postprandial glucose levels were determined for both cases and controls and compared. Results: There was a higher frequency of Diabetes Mellitus and impaired glucose tolerance in patients with skin tags in comparison to controls (p<0.001). Moreover, there were higher odds of acquiring skin tags in patient with abnormal blood glucose levels. Conclusions: There is an increased risk of developing DM in patients with skin tags. It is highly recommended that suspicion for Diabetes Mellitus is to be done in patients with skin tags for early screening and diagnosis of Diabetes.


PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e8521
Author(s):  
Yingli Fu ◽  
Na Zhou ◽  
Wei Bai ◽  
Yaoyao Sun ◽  
Xin Chen ◽  
...  

Background Schizophrenia (SCZ) is a severely complex psychiatric disorder in which ~80% can be explained by genetic factors. Single nucleotide polymorphisms (SNPs) in calcium channel genes are potential genetic risk factors for a spectrum of psychiatric disorders including SCZ. This study evaluated the association between SNPs in the voltage-gated calcium channel auxiliary subunit alpha2delta 2 gene (CACNA2D2) and SCZ in the Han Chinese population of Northeast China. Methods A total of 761 SCZ patients and 775 healthy controls were involved in this case-control study. Three SNPs (rs3806706, rs45536634 and rs12496815) of CACNA2D2 were genotyped by the MALDI-TOF-MS technology. Genotype distribution and allele frequency differences between cases and controls were tested by Chi-square (χ2) in males and females respectively using SPSS 24.0 software. Linkage disequilibrium and haplotype analyses were conducted using Haploview4.2. The false discovery rate correction was utilized to control for Type I error by R3.2.3. Results There was a significant difference in allele frequencies (χ2 = 9.545, Padj = 0.006) and genotype distributions (χ2 = 9.275, Padj = 0.006) of rs45536634 between female SCZ patients and female healthy controls after adjusting for multiple comparisons. Minor allele A (OR = 1.871, 95% CI [1.251–2.798]) and genotype GA + AA (OR = 1.931, 95% CI [1.259–2.963]) were associated with an increased risk of SCZ. Subjects with haplotype AG consisting of rs45536634 and rs12496815 alleles had a higher risk of SCZ (OR = 1.91, 95% CI [1.26–2.90]) compared those with other haplotypes. Conclusions This study provides evidence that CACNA2D2 polymorphisms may influence the susceptibility to SCZ in Han Chinese women.


Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Gautam R Shroff ◽  
Craig A Solid ◽  
Charles A Herzog

Background: Patients with diabetes mellitus (DM) and non valvular atrial fibrillation (AF) are at increased risk of ischemic stroke; but evidence regarding ischemic stroke and warfarin use in the literature is limited. We evaluated temporal trends in ischemic stroke and warfarin use among the US Medicare population with and without DM. Methods: One-year cohorts of patients with Medicare as primary payer, 1992-2010, were created using the Medicare 5% sample. ICD-9-CM codes were used to identify AF, ischemic and hemorrhagic stroke and comorbidities; ≤3 consecutive prothrombin-time claims were used to identify warfarin use. Results: Demographic characteristics between 1992 (n=40255) and 2010 (n=80314) respectively were (proportions): age 65-74 years (37%, 32%); age ≤ 85 years (20%, 25%); white (94%, 93%); hypertension (46%, 80%); DM (20%, 32%), chronic kidney disease (5%, 18%). Ischemic stroke rates among Medicare AF patients with DM decreased by 71% (1992, 2010) from 65 to 19 /1000 patient-years; warfarin utilization increased from 28% to 62% respectively (Figure 1A). Among Medicare AF patients without DM, ischemic stroke rates decreased by 68% from 44 to 14/ 1000 patient-years; warfarin use increased 26% to 59% respectively (Figure 1B). About 38% Medicare AF pts with DM did not receive anticoagulation in 2010. Conclusion: Medicare patients with and without DM had a similar reduction in ischemic stroke rates; and similar increase in warfarin utilization over the study period. A significant proportion of Medicare pts with DM did not receive anticoagulation with warfarin for AF in 2010; this population deserves future attention.


2019 ◽  
Vol 39 (6) ◽  
Author(s):  
Maimaiti Rexidamu ◽  
Hongmei Li ◽  
Haiyan Jin ◽  
Jiankang Huang

Abstract Objective: Accumulating evidence suggests that Trimethylamine-N-oxide (TMAO), a gut microbial metabolite, is implicated in the pathogenesis of many cardiovascular diseases. The aim of the present study was to investigate the serum levels of TMAO in Chinese patients with ischemic stroke. Method: In the present study, 255 consecutive patients with first-ever acute ischemic stroke and 255 age and gender-matched healthy volunteers were included for testing serum TMAO. Stroke severity was determined by the NIH Stroke Scale (NIHSS). The stroke severity was dichotomized as minor (NIHSS ≤ 5) and moderate-to-high clinical severity (NIHSS > 6). Results: The serum levels of TMAO in stroke ranged from 0.5 to 18.3 μM, with a median value of 5.8 (interquartile range (IQR), 3.3–10.0) μM, which was higher than in those controls (3.9; IQR, 2.6–6.1 μM). The median level of TMAO in those patients was significantly lower than in those moderate-to-high stroke patients (4.1 μM [IQR, 2.8–6.2] vs. 9.1 μM [5.1–11.0]; P<0.001). In univariate and multivariable models, the unadjusted risk of moderate-to-high stroke was increased by 31% (odds ratio (OR) = 1.31 [95% confidence interval (CI): 1.21–1.42], P<0.001) and 22% (OR = 1.22; 95% CI = 1.08–1.32; P<0.001), when TMAO was increased each by 1 μM. Based on the receiver operating characteristic (ROC) curve, the optimal cut-off value of serum level of TMAO as an indicator for screening of moderate-to-high stroke was estimated to be 6.6 μM, which yielded a sensitivity of 69.3 % and a specificity of 79.0%, with the area under the curve at 0.750 (95% CI, 0.687–0.812). Conclusions: Higher TMAO levels were associated with increased risk of first ischemic stroke and worse neurological deficit in Chinese patients.


2017 ◽  
Vol 45 (6) ◽  
pp. 2042-2052 ◽  
Author(s):  
Yanzhe Wang ◽  
Fang Liu ◽  
Lei Li ◽  
Shumin Deng ◽  
Zhiyi He

Objective Given its effects on lipid metabolism, the apolipoprotein A1-C3-A5 ( APOA1-C3-A5) gene cluster is thought to play an important role in ischemic stroke pathogenesis. Here, we evaluated whether the APOA1-C3-A5 cluster is associated with ischemic stroke in the northern Chinese Han population. Methods This case–control study analyzed 812 patients with ischemic stroke and 844 healthy controls with regard to four APOA1-C3-A5 cluster promoter single nucleotide polymorphisms (SNPs), rs670, rs2854116, rs2854117, and rs662799, using the SNaPshot Multiplex sequencing assay. Potential associations among ischemic stroke, genotyping, and allele frequencies were assessed. Results APOA1 rs670 CT/TT genotypes, APOA5 rs662799 AG/GG genotypes, and the APOC3 rs2854116 CC genotype were associated with an increased risk of ischemic stroke according to multivariate logistic analysis after adjusting for confounding factors. A significantly increased risk for ischemic stroke was also identified among high-risk haplotypes (C-C-T-A and T-T-C-A) for rs670–rs2854116–rs2854117–rs662799. Conclusion This study showed that rs670, rs2854116, and rs662799 SNPs of the APOA1-C3-A5 cluster are associated with ischemic stroke in the northern Chinese Han population.


Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2590-2590
Author(s):  
Maria C. Pintao ◽  
Dayse M. Lourenço ◽  
Francisco H.A. Maffei ◽  
Vania M. Morelli ◽  
Amelia G. Araujo ◽  
...  

Abstract Venous thrombosis (VT) is considered to be a multifactorial disorder in which several genetic and acquired risk factors interact dynamically. Coagulation factor XIII (FXIII) is an enzyme that participates in the final steps of the coagulation cascade. A number of gene variations have been described in both FXIII A and B subunits. FXIIIA Val34Leu, Tyr204Phe and Pro564Leu polymorphisms have been associated to increased specific activity of FXIII, and FXIIIA Val34Leu has been claimed to be protective against VT in several studies. In the FXIII B subunit, two common polymorphisms (His95Arg and G30899A) have been also reported, but its association with VT is uncertain. In addition, possible interactive effects between these polymorphisms and between these polymorphisms and the two most prevalent mutations associated with VT, factor V Leiden (FVL) and factor II (FII) G20210A mutations, have not been explored. In the present study, we determined the prevalence of the five above-mentioned FXIII polymorphisms in 418 consecutive patients with an objective diagnosis of VT and in 418 age-, gender- and race-matched controls in the BRATROS (Brazilian Thrombosis Study) case-control investigation. Genotyping for Val34Leu, Pro564Leu, His95Arg and G30899A was performed by PCR amplification followed by MseI, BstUI, NsiI and BspHI restriction digestion analysis, respectively. Genotyping for Tyr204Phe was performed by single-strand conformation polymorphism (SSCP) analysis followed by DNA sequencing of samples showing mobility shifts. Odds ratios (OR) as a measure of relative risks of VT, and 95% confidence intervals (CI95), were calculated. Stratified analyses were performed to search for interactions between the FXIII polymorphisms and between the FXIII polymorphisms, FVL and FII G20210A. Overall OR for VT linked to Val34Leu was 0,78 (CI95: 0,59–1,03); OR for heterozygotes (HT) was 0,85 (CI95: 0,64–1,13) and for homozygotes (HM) the OR was 0,33 (CI95: 0,15–0,71). Overall OR linked to G30899A was 1,06 (CI95: 0,81–1,39); OR for HT was 0,96 (CI95: 0,72–1,28) and for HM the OR was 1,58 (IC95: 1,00–2,49). No impacts over the risk of VT were observed, related to the other three polymorphisms investigated. When stratified analyses were performed to search for interactions, a trend towards increased risk of VT was detected when the Val34 allele was co-inherited with the Arg95 allele (OR 1,45; CI95: 0,97–2,18), and a trend towards decreased thrombotic risk was verified when the Leu34 and Leu564 alleles were co-inherited (OR 0,63; CI95: 0,40–1,00). Furthermore, increased risk for VT was observed when the mutant A30899 allele was co-inherited with FII G20210A, pointing to a notable interaction effect (OR 18,29; CI95: 2,41–138,87). The data confirm that homozygosity for FXIII Val34Leu is protective against the occurrence of VT in our population. In addition, the findings point to a previously unknown increased risk of VT related to homozygosity for FXIIIB G30899A of the order of 58%. Lastly, an impressive interactive effect (18-fold increased risk of VT) between FXIIIB G30899A and FII G20210A is reported for the first time. Taken together, the findings from the present investigation strengthen the clinical significance of FXIII in vascular thrombosis and reinforce the concept of VT as a multigenic disease.


2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 173-173
Author(s):  
E. Ludwig ◽  
S. H. Olson ◽  
R. C. Kurtz ◽  
J. Simon ◽  
M. F. Brennan ◽  
...  

173 Background: The epidemiology of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas is poorly defined. Methods: An epidemiologic questionnaire was administered to patients (pts) with IPMN (n=79), pancreatic adenocarcinoma (PC) (n=689) and healthy controls (n=307). Results were adjusted for age, gender and BMI. IPMN was defined either by surgical pathology (n=62) or characteristic endoscopic ultrasound appearance and cyst fluid CEA>200 ng/ml (n=17). Results: In unadjusted analysis IPMN pts were more likely to be ≥ 70 years of age (OR 5.40 [2.88, 10.46]) when compared with PC pts (OR 2.82) and controls. After adjustment for age, gender and BMI, current tobacco smoking was associated with PC (OR 3.06 [1.78, 5.23]) but not IPMN. Pts with IPMN more often had diabetes mellitus for >3 years compared with controls (OR 3.25 [1.45, 7.00], while pts with PC (OR 1.52 (0.86, 2.67]) did not. IPMN pts were more likely to have a history of hypercholesterolemia compared with controls (OR 1.77 [1.05-2.98]); this was not seen for PC pts (OR 1.16 [0.87-1.55]). A first degree relative with PC was not associated with increased risk for IPMN (OR 0.84 [0.27, 2.62]) or PC (OR 1.48 [0.82, 2.67]). Compared to PC, pts with IPMN were more likely to have a history of an unrelated cancer (OR 1.84 [1.08, 3.14]). Conclusions: Risk factors for IPMN and PC may differ. Compared to PC and control pts, IPMN patients were older; more often had diabetes mellitus and hypercholesterolemia; and did not currently smoke. IPMN was more often associated with a prior history of cancer than PC. No significant financial relationships to disclose.


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