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1.
An Expanded Genome-Wide Association Study of Fructosamine Levels Identifies RCN3 as a Replicating Locus and Implicates FCGRT as the Effector Transcript.
Riveros-Mckay, F, Roberts, D, Di Angelantonio, E, Yu, B, Soranzo, N, Danesh, J, Selvin, E, Butterworth, AS, Barroso, I
Diabetes. 2022;(2):359-364
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Abstract
Fructosamine is a measure of short-term glycemic control, which has been suggested as a useful complement to glycated hemoglobin (HbA1c) for the diagnosis and monitoring of diabetes. To date, a single genome-wide association study (GWAS) including 8,951 U.S. White and 2,712 U.S. Black individuals without a diabetes diagnosis has been published. Results in Whites and Blacks yielded different association loci, near RCN3 and CNTN5, respectively. In this study, we performed a GWAS on 20,731 European-ancestry blood donors and meta-analyzed our results with previous data from U.S. White participants from the Atherosclerosis Risk in Communities (ARIC) study (Nmeta = 29,685). We identified a novel association near GCK (rs3757840, βmeta = 0.0062; minor allele frequency [MAF] = 0.49; Pmeta = 3.66 × 10-8) and confirmed the association near RCN3 (rs113886122, βmeta = 0.0134; MAF = 0.17; Pmeta = 5.71 × 10-18). Colocalization analysis with whole-blood expression quantitative trait loci data suggested FCGRT as the effector transcript at the RCN3 locus. We further showed that fructosamine has low heritability (h2 = 7.7%), has no significant genetic correlation with HbA1c and other glycemic traits in individuals without a diabetes diagnosis (P > 0.05), but has evidence of shared genetic etiology with some anthropometric traits (Bonferroni-corrected P < 0.0012). Our results broaden knowledge of the genetic architecture of fructosamine and prioritize FCGRT for downstream functional studies at the established RCN3 locus.
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Deciphering the Role of Filamin B Calponin-Homology Domain in Causing the Larsen Syndrome, Boomerang Dysplasia, and Atelosteogenesis Type I Spectrum Disorders via a Computational Approach.
S, UK, Sankar, S, Younes, S, D, TK, Ahmad, MN, Okashah, SS, Kamaraj, B, Al-Subaie, AM, C, GPD, Zayed, H
Molecules (Basel, Switzerland). 2020;(23)
Abstract
Filamins (FLN) are a family of actin-binding proteins involved in regulating the cytoskeleton and signaling phenomenon by developing a network with F-actin and FLN-binding partners. The FLN family comprises three conserved isoforms in mammals: FLNA, FLNB, and FLNC. FLNB is a multidomain monomer protein with domains containing an actin-binding N-terminal domain (ABD 1-242), encompassing two calponin-homology domains (assigned CH1 and CH2). Primary variants in FLNB mostly occur in the domain (CH2) and surrounding the hinge-1 region. The four autosomal dominant disorders that are associated with FLNB variants are Larsen syndrome, atelosteogenesis type I (AOI), atelosteogenesis type III (AOIII), and boomerang dysplasia (BD). Despite the intense clustering of FLNB variants contributing to the LS-AO-BD disorders, the genotype-phenotype correlation is still enigmatic. In silico prediction tools and molecular dynamics simulation (MDS) approaches have offered the potential for variant classification and pathogenicity predictions. We retrieved 285 FLNB missense variants from the UniProt, ClinVar, and HGMD databases in the current study. Of these, five and 39 variants were located in the CH1 and CH2 domains, respectively. These variants were subjected to various pathogenicity and stability prediction tools, evolutionary and conservation analyses, and biophysical and physicochemical properties analyses. Molecular dynamics simulation (MDS) was performed on the three candidate variants in the CH2 domain (W148R, F161C, and L171R) that were predicted to be the most pathogenic. The MDS analysis results showed that these three variants are highly compact compared to the native protein, suggesting that they could affect the protein on the structural and functional levels. The computational approach demonstrates the differences between the FLNB mutants and the wild type in a structural and functional context. Our findings expand our knowledge on the genotype-phenotype correlation in FLNB-related LS-AO-BD disorders on the molecular level, which may pave the way for optimizing drug therapy by integrating precision medicine.
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Genome-wide meta-analysis identifies novel gender specific loci associated with thyroid antibodies level in Croatians.
Matana, A, Popović, M, Boutin, T, Torlak, V, Brdar, D, Gunjača, I, Kolčić, I, Boraska Perica, V, Punda, A, Polašek, O, et al
Genomics. 2019;(4):737-743
Abstract
Autoimmune thyroid diseases (AITD) are multifactorial endocrine diseases most frequently accompanied by Tg and TPO autoantibodies. Both antibodies have a higher prevalence in females and act under a strong genetic influence. To identify novel variants underlying thyroid antibody levels, we performed GWAS meta-analysis on the plasma levels of TgAb and TPOAb in three Croatian cohorts, as well as gender specific GWAS and a bivariate analysis. No significant association was detected with the level of TgAb and TPOAb in the meta-analysis of GWAS or bivariate results for all individuals. The bivariate analysis in females only revealed a genome-wide significant association for the locus near GRIN3A (rs4457391, P = 7.76 × 10-9). The same locus had borderline association with TPOAb levels in females (rs1935377, P = 8.58 × 10-8). In conclusion, we identified a novel gender specific locus associated with TgAb and TPOAb levels. Our findings provide a novel insight into genetic and gender differences associated with thyroid antibodies.
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Prognostic and clinicopathological significance of S100A14 expression in cancer patients: A meta-analysis.
Hu, L, Kong, F, Pan, Y
Medicine. 2019;(28):e16356
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Abstract
BACKGROUND The prognostic significance of S100A14 for survival of cancer patients remains controversial. Therefore, we conducted this meta-analysis to explore the association between S100A14 expression and cancer prognosis. METHOD Eligible studies were identified by searching the online databases Pubmed and EMBASE up to August 2018. Odds ratios (ORs) with 95% confidence intervals (CIs) severed as the summarized statistics for clinicopathological assessments and hazard ratios (HRs) with 95% CIs were calculated to clarify the correlation between S100A14 expression and prognosis of different cancers. RESULTS A total of 11 studies with 1651 cancer patients were enrolled. The results indicated that S100A14 expression was not significantly associated with overall survival (OS) in total various cancers (HR = 1.54, 95% CI:0.89-2.67, P = .121). Further subgroup analysis stratified by tumor type showed that elevated S100A14 expression was associated with poor OS in breast cancer (HR = 3.66, 95% CI: 1.75-7.62, P < .001) and in ovarian cancer patients (HR = 3.78, 95%CI: 1.63-8.73, P = .002). Interestingly, high S100A14 expression was correlated with poor tumor differentiation (OR = 2.51, 95% CI: 1.52-4.13, P < .001). However, there were no significant correlations between S100A14 expression and other clinicopathologic characteristics. Begg funnel plot and Egger test showed that no publication bias was detected. CONCLUSIONS Our meta-analysis suggests that S100A14 overexpression might be a predictive biomarker for poor prognosis in patients with breast cancer and ovarian cancer. Large-scale studies are required to confirm these results.
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Circulating Nesfatin-1 Levels and Type 2 Diabetes: A Systematic Review and Meta-Analysis.
Zhai, T, Li, SZ, Fan, XT, Tian, Z, Lu, XQ, Dong, J
Journal of diabetes research. 2017;:7687098
Abstract
The role of nesfatin-1 in glucose homeostasis has been investigated previously. However, although numerous studies have examined the relationships between circulating nesfatin-1 levels and type 2 diabetes, the conclusions are contradictory. We aimed to probe the relationship between circulating nesfatin-1 levels and type 2 diabetes by meta-analysis. Seven studies including 328 type 2 diabetes patients and 294 control subjects were included. Although there was no obvious difference in circulating nesfatin-1 levels between patients with type 2 diabetes and the control group (MD = -0.04; 95% CI = -0.32 to -0.23), subgroup analysis showed higher nesfatin-1 levels in newly diagnosed type 2 diabetes patients (MD = 0.59; 95% CI = 0.45 to 0.74) and significantly lower nesfatin-1 levels in type 2 diabetes patients receiving antidiabetic treatment (MD = -0.26; 95% CI = -0.33 to -0.20). In conclusion, the analysis supports a relationship between circulating nesfatin-1 levels and type 2 diabetes, where newly diagnosed type 2 diabetes was associated with an elevated Nesfatin-1 level, and type 2 diabetes patients receiving antidiabetic treatment showed lower circulating nesfatin-1 levels.
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SPARCL1, a Novel Prognostic Predictive Factor for GI Malignancies: a Meta-Analysis.
Hu, H, Cai, W, Zheng, S, Ge, W
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. 2017;(4):1485-1496
Abstract
BACKGROUND/AIMS: Secreted protein acidic and rich in cysteines-like 1 (SPARCL1) is abnormally expressed in gastrointestinal (GI) malignancies. However, the correlation between SPARCL1 expression and the prognosis of patients remains unknown. Therefore, we performed a meta-analysis to investigate the potential value of SPARCL1 as a prognostic predictive marker for GI malignancies. METHODS The PubMed, Embase, EBSCO, CNKI, and Wanfang databases were systematically searched for studies examining SPARCL1 and clinicopathological features, including the prognoses of patients. Hazard ratios (HRs) and odds ratios (ORs) from individual studies were calculated and pooled using a random-effects or fix-effects model. Heterogeneity and publication bias analyses were performed. RESULTS Data from 8 studies, including a total of 2,356 patients, were summarized. The expression of SPARCL1 suggested a better prognosis (HR=0.57, 95% CI: 0.445-0.698, P=0.000) and was associated with clinicopathological features of GI malignancies, including distant metastasis (OR=0.44, 95% CI: 0.23-0.85, P=0.014), lymph node metastasis (OR=0.56, 95% CI: 0.39-0.81, P=0.002) and tumor differentiation (OR=2.21, 95% CI: 1.82-2.69, P=0.000). Subgroup analyses based on cancer type revealed that the expression of SPARCL1 had no effect on lymph node metastasis in colorectal cancer, and it did not influence tumor differentiation in gastric cancer. Egger's test showed no evidence of publication bias (all P>0.05). CONCLUSION SPARCL1 could be a novel prognostic predictive factor for GI malignancies. The expression of SPARCL1 could influence the clinicopathological features of GI malignancies. Further large-scale studies are essential to confirm SPARCL1's prognostic predictive value, and more fundamental experimental studies are needed to illustrate the mechanisms.
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Association of Matrix Gla protein gene (rs1800801, rs1800802, rs4236) polymorphism with vascular calcification and atherosclerotic disease: a meta-analysis.
Sheng, K, Zhang, P, Lin, W, Cheng, J, Li, J, Chen, J
Scientific reports. 2017;(1):8713
Abstract
Association between the MGP gene rs1800801, rs1800802, rs4236 polymorphisms and vascular calcification and atherosclerotic disease was inconsistent. To clarify precise association, we performed this meta-analysis. Medline, Embase and China Knowledge Resource Integrated Database were systematically searched through December 2016. A total of 23 case-control studies, consisting of 5280 cases and 5773 controls, were included. The overall results suggested that the -7A polymorphism was associated with an increased risk for vascular calcification and atherosclerotic disease in the recessive model (OR = 1.50, 95% CI 1.01-2.24, P = 0.045). Subgroup analyses of Caucasians showed significant associations in the allelic model, recessive model, and homozygote model: allelic model (OR = 1.19, 95% CI 1.06-1.34, P = 0.004), recessive model (OR = 1.60, 95% CI 1.26-2.03, P < 0.001), homozygote model (OR = 1.83, 95% CI 1.18-2.81, P = 0.006). Subgroup analysis of the Asian population did not demonstrate any significant associations in any of the genetic models. No significant association was found in any genetic model amongst the rs1800802 and rs4236 polymorphisms. The findings of this meta-analysis indicate that the MGP gene rs1800801 polymorphism is significantly associated with vascular calcification and atherosclerotic disease, especially in the Caucasian population.
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Diagnostic value of S100P for pancreatic cancer: a meta-analysis.
Hu, H, Zhang, Q, Huang, C, Shen, Y, Chen, X, Shi, X, Tang, W
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 2014;(10):9479-85
Abstract
Pancreatic cancer (PC) is a fatal disease with a high mortality and poor prognosis. PC is the fourth leading cause of cancer death in America, and 80 % of PCs are diagnosed at an unresectable stage. Effective early detection assays are crucial since a successful operation at early stage is the best strategy for this disease. S100 calcium-binding protein P (S100P) has been reported as a predictive diagnostic index for PC and involves in the development of PC. However, the diagnostic accuracy of S100P in detecting PC has never been systematically assessed. The aim of the present study was to evaluate the diagnostic performance of S100P for PC. All relevant original articles about S100P in the diagnosis of PC published up to December 2013 were retrieved. The methodological quality of each study was assessed by QUADAS. The overall diagnostic sensitivity, specificity, diagnostic odds ratio (DOR), with 95 % confidence interval (CI), and area under the receiver operating characteristic curve (AUC) were pooled to evaluate the diagnostic value of S100P for PC using the Meta-DiSc1.4 statistical software. Eight studies met our criteria in the present meta-analysis. The pooled sensitivity, specificity, and DOR calculated by the bivariate random effects model were 0.87 (95 % CI 0.83-0.90), 0.88 (95 % CI 0.82-0.93), and 38.32 (95 % CI 11.22-130.87), respectively. The summary receiver operating characteristic (SROC) curve was located near the desirable left corner and the AUC was 0.9272. The current evidence suggests that S100P plays an important role in the diagnosis of PC with a high sensitivity and specificity. S100P may be regarded as a promising diagnostic marker to PC screening.
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Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies.
Nolte, IM, Wallace, C, Newhouse, SJ, Waggott, D, Fu, J, Soranzo, N, Gwilliam, R, Deloukas, P, Savelieva, I, Zheng, D, et al
PloS one. 2009;(7):e6138
Abstract
To identify loci affecting the electrocardiographic QT interval, a measure of cardiac repolarisation associated with risk of ventricular arrhythmias and sudden cardiac death, we conducted a meta-analysis of three genome-wide association studies (GWAS) including 3,558 subjects from the TwinsUK and BRIGHT cohorts in the UK and the DCCT/EDIC cohort from North America. Five loci were significantly associated with QT interval at P<1x10(-6). To validate these findings we performed an in silico comparison with data from two QT consortia: QTSCD (n = 15,842) and QTGEN (n = 13,685). Analysis confirmed the association between common variants near NOS1AP (P = 1.4x10(-83)) and the phospholamban (PLN) gene (P = 1.9x10(-29)). The most associated SNP near NOS1AP (rs12143842) explains 0.82% variance; the SNP near PLN (rs11153730) explains 0.74% variance of QT interval duration. We found no evidence for interaction between these two SNPs (P = 0.99). PLN is a key regulator of cardiac diastolic function and is involved in regulating intracellular calcium cycling, it has only recently been identified as a susceptibility locus for QT interval. These data offer further mechanistic insights into genetic influence on the QT interval which may predispose to life threatening arrhythmias and sudden cardiac death.
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Linkage disequilibrium screening for multiple sclerosis implicates JAG1 and POU2AF1 as susceptibility genes in Europeans.
, , Ban, M, Booth, D, Heard, R, Stewart, G, Goris, A, Vandenbroeck, K, Dubois, B, Laaksonen, M, Ilonen, J, et al
Journal of neuroimmunology. 2006;(1-2):108-16
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Abstract
By combining all the data available from the Genetic Analysis of Multiple sclerosis in EuropeanS (GAMES) project, we have been able to identify 17 microsatellite markers showing consistent evidence for apparent association. As might be expected five of these markers map within the Major Histocompatibility Complex (MHC) and are in LD with HLA-DRB1. Individual genotyping of the 12 non-MHC markers confirmed association for three of them--D11S1986, D19S552 and D20S894. Association mapping across the candidate genes implicated by these markers in 937 UK trio families revealed modestly associated haplotypes in JAG1 (p=0.019) on chromosome 20p12.2 and POU2AF1 (p=0.003) on chromosome 11q23.1.