scholarly journals Influence of Genetic Polymorphisms in P2Y12 Receptor Signaling Pathway on Antiplatelet Response to Clopidogrel in Coronary Heart Disease

2021 ◽  
Author(s):  
Dongjie Li ◽  
Yanjiao Zhang ◽  
Zhongyi Li ◽  
Xiaolei Hu ◽  
He Li ◽  
...  
Keyword(s):  
Genetic Polymorphisms ◽  
Interindividual Variability ◽  
Signal Pathway ◽  
Loss Of Function ◽  
Platelet Activity ◽  
Clopidogrel Resistance ◽  
Reaction Index ◽  
Increased Risk ◽  
Receptor Signaling Pathway ◽  
Platelet Reaction

Abstract Backgrounds: Remarkable interindividual variability in clopidogrel response is observed, genetic polymorphisms in P2RY12 and its signal pathway is supposed to affect clopidogrel response in CHD patients. Methods: 539 CHD patients treated with clopidogrel were recruited. The platelet reaction index (PRI) indicated by VASP-P level were detected in 12-24h after clopidogrel loading dose (LD) or within 5-7 days after initiation of maintain dose (MD) clopidogrel. A total of 13 SNPs in relevant genes were genotyped in sample A (239 CHD patients). The SNPs which have significant differences in PRI will be validated in another sample (sample B, 300 CHD patients). Results: CYP2C19*2 increased the risk of clopidogrel resistance significantly. When CYP2C19*2 and CYP2C19*3 were considered, CYP2C19 loss of function (LOF) alleles were associated with more obviously increased the risk of clopidogrel resistance; P2RY12 rs6809699 C>A polymorphism was also associated with increased risk of clopidogrel resistance (AA vs CC: P=0.0398). This difference still existed after stratification by CYP2C19 genotypes. It was also validated in sample B. The association was also still significant even in the case of stratification by CYP2C19 genotypes in all patients (sample A+B). Conclusion: Our data suggest that P2RY12 rs6809699 is associated with clopidogrel resistance in CHD patients. Meanwhile, the rs6809699 AA genotype can increase on-treatment platelet activity independent of CYP2C19 LOF polymorphisms.

Influence of CYP2C19 genetic polymorphisms on clinical outcomes of intracranial aneurysms treated with stent-assisted coiling

2016 ◽  
Vol 9 (10) ◽  
pp. 958-962 ◽  
Author(s):  
Huijian Ge ◽  
Xianli Lv ◽  
Hui Ren ◽  
Hengwei Jin ◽  
Yuhua Jiang ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Genetic Polymorphisms ◽  
Intracranial Aneurysms ◽  
Loss Of Function ◽  
Bleeding Events ◽  
Clopidogrel Resistance ◽  
Increased Risk ◽  
Posterior Circulation Aneurysms ◽  
Cerebral Ischemic ◽  
Ischemic Events

ObjectiveTo investigate the influence of CYP2C19 genetic polymorphisms on clinical outcomes of intracranial aneurysms treated with stent-assisted coiling.MethodsBetween September 2014 and October 2015, we prospectively recruited 215 patients with intracranial aneurysms who were treated with stent-assisted coiling. CYP2C19 genotypes were determined and clopidogrel response was tested. The primary endpoints included symptomatic or silent ischemic events, and bleeding events. The secondary endpoint was clinical outcome at 3 months.ResultsOf the 215 patients, 108 (50.2%) were classified as intermediate metabolizers (IMs, CYP2C19*1/*2, *1/*3), 76 (35.3%) as extensive metabolizers (EMs, CYP2C19*1/*1) and 31 (14.4%) as poor metabolizers (PMs, CYP2C19*2/*2, *2/*3, *3/*3). Carriers of CYP2C19 loss-of-function (LOF) alleles (*2 or *3, p=0.001), especially PMs (p=0.004), had an increased risk for clopidogrel resistance. After the procedures, cerebral ischemic events occurred in 69 patients (32.1%) and bleeding was seen in 20 patients (9.3%). In comparison with IMs and PMs, EMs had a lower risk for ischemic events (21.1% vs 37.0% and 41.9%, p=0.02 and 0.027, respectively) and a relatively higher risk for bleeding events (18.4% vs 5.6% and 0%, p=0.006 and 0.01, respectively). Based on multivariate analysis, the carriage of CYP2C19 LOF alleles (p=0.032) and clopidogrel resistance (p=0.047) were considered as predictors of cerebral ischemic events, and EMs were significantly associated with bleeding (p=0.002). Posterior circulation aneurysms (p=0.038), hemorrhagic history (p=0.001) and poor metabolic genotypes (p=0.001) could result in poor clinical outcomes (modified Rankin Scale >2).ConclusionsCYP2C19 genetic polymorphisms had significant influence on the antiplatelet effect of clopidogrel, and could be considered as risk factors of ischemic or bleeding events and even clinical outcomes of patients with intracranial aneurysms treated with stent-assisted coiling.

Platelet monitoring for PCI

2009 ◽  
Vol 29 (04) ◽  
pp. 376-380 ◽  
Author(s):  
D. Capodanno ◽  
D. J. Angiolillo
Keyword(s):  
Interindividual Variability ◽  
State Of The Art ◽  
Coronary Intervention ◽  
Functional Tests ◽  
Treatment Regimens ◽  
Advantages And Disadvantages ◽  
Coronary Syndrome ◽  
Combined Use ◽  
Increased Risk ◽  
Percutaneous Coronary

SummaryDespite the clinical benefit associated with the combined use of aspirin and clopidogrel in patients with acute coronary syndrome or those undergoing percutaneous coronary intervention, a considerable interindividual variability in response to these drugs have been consistently reported. There is a growing interest on applying platelet functional tests with the goal of identifying patients at increased risk of recurrent ischaemic events and potentially tailoring antiplatelet treatment regimens.This manuscript will review the state of the art on the most commonly available platelet functional tests, describing their advantages and disadvantages and exploring their applicability in clinical practice.

TLR1 and PRKAA1 Gene Polymorphisms in the Development of Atrophic Gastritis and Gastric Cancer

2018 ◽  
Vol 27 (4) ◽  
pp. 363-369 ◽  
Author(s):  
Gintare Dargiene ◽  
Greta Streleckiene ◽  
Jurgita Skieceviciene ◽  
Marcis Leja ◽  
Alexander Link ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Atrophic Gastritis ◽  
Genetic Polymorphisms ◽  
Association Studies ◽  
Control Group ◽  
Similar Distribution ◽  
Genome Wide Association Studies ◽  
Increased Risk ◽  
Infection Susceptibility ◽  
H Pylori

Background & Aims: Previous genome-wide association studies showed that genetic polymorphisms in toll-like receptor 1 (TLR1) and protein kinase AMP-activated alpha 1 catalytic subunit (PRKAA1) genes were associated with gastric cancer (GC) or increased Helicobacter pylori (H. pylori) infection susceptibility. The aim of this study was to evaluate the association between TLR1 and PRKAA1 genes polymorphisms and H.pylori infection, atrophic gastritis (AG) or GC in the European population.Methods: Single-nucleotide polymorphisms (SNPs) were analysed in 511 controls, 340 AG patients and 327 GC patients. TLR1 C>T (rs4833095) and PRKAA1 C>T (rs13361707) were genotyped by the real-time polymerase chain reaction. H. pylori status was determined by testing for anti-H. pylori IgG antibodies in the serum.Results: The study included 697 (59.2%) H. pylori positive and 481 (40.8%) H. pylori negative cases. We observed similar distribution of TLR1 and PRKAA1 alleles and genotypes in H. pylori positive and negative cases. TLR1 and PRKAA1 SNPs were not linked with the risk of AG. TC genotype of TLR1 gene was more prevalent in GC patients compared to the control group (29.7% and 22.3% respectively, p=0.002). Carriers of TC genotype had a higher risk of GC (aOR=1.89, 95% CI: 1.26–2.83, p=0.002). A similar association was observed in a dominant inheritance model for TLR1 gene SNP, where comparison of CC+TC vs. TT genotypes showed an increased risk of GC (aOR=1.86, 95% CI: 1.26–2.75, p=0.002). No association between genetic polymorphism in PRKAA1 gene and GC was observed.Conclusions: TLR1 rs4833095 SNP was associated with an increased risk of GC in a European population, while PRKAA1 rs13361707 genetic variant was not linked with GC. Both genetic polymorphisms were not associated with H. pylori infection susceptibility or the risk of AG.

scholarly journals GWAS of serum ALT and AST reveals an association of SLC30A10 Thr95Ile with hypermanganesemia symptoms

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lucas D. Ward ◽  
Ho-Chou Tu ◽  
Chelsea B. Quenneville ◽  
Shira Tsour ◽  
Alexander O. Flynn-Carroll ◽  
...  
Keyword(s):  
Bile Duct ◽  
Extrahepatic Bile Duct ◽  
Association Studies ◽  
Missense Variant ◽  
Deficiency Anemia ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Extrahepatic Bile Duct Cancer ◽  
Hepatocellular Damage ◽  
Increased Risk

AbstractUnderstanding mechanisms of hepatocellular damage may lead to new treatments for liver disease, and genome-wide association studies (GWAS) of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum activities have proven useful for investigating liver biology. Here we report 100 loci associating with both enzymes, using GWAS across 411,048 subjects in the UK Biobank. The rare missense variant SLC30A10 Thr95Ile (rs188273166) associates with the largest elevation of both enzymes, and this association replicates in the DiscovEHR study. SLC30A10 excretes manganese from the liver to the bile duct, and rare homozygous loss of function causes the syndrome hypermanganesemia with dystonia-1 (HMNDYT1) which involves cirrhosis. Consistent with hematological symptoms of hypermanganesemia, SLC30A10 Thr95Ile carriers have increased hematocrit and risk of iron deficiency anemia. Carriers also have increased risk of extrahepatic bile duct cancer. These results suggest that genetic variation in SLC30A10 adversely affects more individuals than patients with diagnosed HMNDYT1.

scholarly journals NCMP-17. MISMATCH REPAIR MUTATIONS AND THE CENTRAL NERVOUS SYSTEM: A CASE SERIES OF GERMLINE MUTATIONS AND CNS MALIGNANCY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii126-ii126
Author(s):  
Amber Ruiz ◽  
Jerome Graber
Keyword(s):  
Treatment Response ◽  
Mismatch Repair ◽  
Case Series ◽  
Germline Mutations ◽  
Molecular Characteristics ◽  
Loss Of Function ◽  
Dna Mismatch ◽  
Mutational Burden ◽  
Increased Risk ◽  
Tumor Mutational Burden

Abstract Our understanding of genetic predispositions for malignancy is continually evolving. One family of germline mutations well described in the literature is that of the DNA mismatch repair mechanism (MMR). Lynch syndrome (LS) is due to a loss of function mutation of several MMR genes- MSH2, MLH1, MSH6, and PMS2. Germline MMR mutations lead to microsatellite instability and loss of genomic integrity resulting in an increased risk for various cancers (colorectal, genitourinary, etc). LS may be as common as 1 in 400 people and some MMR mutations have been associated with gliomas. There is a paucity of information regarding frequency of glioma subtypes as well as tumor genetic and molecular characteristics which have important clinical implications. We describe a case series of 6 individuals with germline MMR mutations and brain tumors. Those with MSH2 and PMS2 mutations (n=3) developed glioblastomas at a mean age at diagnosis of 48 years. These tumors expressed MGMT hyper-methylation and high tumor mutational burden. Only one had IDH-1 mutation. Those with MLH1 mutations (n=3), did not develop gliomas. This raises the question of differential glioma subtype development based on MMR gene. It also highlights the possibility of Lynch-associated gliomas having more favorable treatment response due to MGMT methylation and potential response to immunotherapy based on high tumor mutational burden. Though the sample size is small, there appears to be a preponderance of women compared to men (5:1 respectively). Larger studies are needed to verify CNS involvement in germline MMR mutations. In doing so, we hope to identify factors that may influence clinical management and lead to a better understanding of treatment response and disease prognosis.

scholarly journals LINC01414/LINC00824 genetic polymorphisms in association with the susceptibility of chronic obstructive pulmonary disease

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xiaoman Zhou ◽  
Yunjun Zhang ◽  
Yutian Zhang ◽  
Quanni Li ◽  
Mei Lin ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Genetic Polymorphisms ◽  
Chronic Obstructive ◽  
Nucleotide Polymorphisms ◽  
Obstructive Pulmonary Disease ◽  
Logistic Analysis ◽  
Copd Patients ◽  
Increased Risk ◽  
And Gender

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.

scholarly journals The role of the renin–angiotensin–aldosterone system in preeclampsia: genetic polymorphisms and microRNA

2013 ◽  
Vol 50 (2) ◽  
pp. R53-R66 ◽  
Author(s):  
Jie Yang ◽  
Jianyu Shang ◽  
Suli Zhang ◽  
Hao Li ◽  
Huirong Liu
Keyword(s):  
Genetic Polymorphisms ◽  
Large Scale ◽  
Salt Water ◽  
Prognostic Significance ◽  
Neonatal Morbidity ◽  
Well Being ◽  
Normal Pregnancy ◽  
Placental Perfusion ◽  
Familial Predisposition ◽  
Increased Risk

The compensatory alterations in the rennin–angiotensin–aldosterone system (RAAS) contribute to the salt–water balance and sufficient placental perfusion for the subsequent well-being of the mother and fetus during normal pregnancy and is characterized by an increase in almost all the components of RAAS. Preeclampsia, however, breaks homeostasis and leads to a disturbance of this delicate equilibrium in RAAS both for circulation and the uteroplacental unit. Despite being a major cause for maternal and neonatal morbidity and mortality, the pathogenesis of preeclampsia remains elusive, where RAAS has been long considered to be involved. Epidemiological studies have indicated that preeclampsia is a multifactorial disease with a strong familial predisposition regardless of variations in ethnic, socioeconomic, and geographic features. The heritable allelic variations, especially the genetic polymorphisms in RAAS, could be the foundation for the genetics of preeclampsia and hence are related to the development of preeclampsia. Furthermore, at a posttranscriptional level, miRNA can interact with the targeted site within the 3′-UTR of the RAAS gene and thereby might participate in the regulation of RAAS and the pathology of preeclampsia. In this review, we discuss the recent achievements of genetic polymorphisms, as well as the interactions between maternal and fetal genotypes, and miRNA posttranscriptional regulation associated with RAAS in preeclampsia. The results are controversial but utterly inspiring and attractive in terms of potential prognostic significance. Although many studies suggest positive associations with genetic mutations and increased risk for preeclampsia, more meticulously designed large-scale investigations are needed to avoid the interference from different variations.

Increased Risk for Other Cancers in Addition to Breast Cancer for CHEK2*1100delC Heterozygotes Estimated From the Copenhagen General Population Study

2016 ◽  
Vol 34 (11) ◽  
pp. 1208-1216 ◽  
Author(s):  
Charlotte Näslund-Koch ◽  
Børge G. Nordestgaard ◽  
Stig E. Bojesen
Keyword(s):  
Breast Cancer ◽  
General Population ◽  
Population Study ◽  
Cell Cycle Checkpoint ◽  
Loss Of Function ◽  
General Population Study ◽  
Chek2 1100Delc ◽  
Hazard Ratios ◽  
Increased Risk ◽  
Age And Sex

Purpose CHEK2 is a cell cycle checkpoint regulator, and the CHEK2*1100delC germline mutation leads to loss of function and increased breast cancer risk. It seems plausible that this mutation could also predispose to other cancers. Therefore, we tested the hypothesis that CHEK2*1100delC heterozygosity is associated with increased risk for other cancers in addition to breast cancer in the general population. Patients and Methods We examined 86,975 individuals from the Copenhagen General Population Study, recruited from 2003 through 2010. The participants completed a questionnaire on health and lifestyle, were examined physically, had blood drawn for DNA extraction, were tested for presence of CHEK2*1100delC using Taqman assays and sequencing, and were linked over 1943 through 2011 to the Danish Cancer Registry. Incidences and risks of individual cancer types, including breast cancer, were calculated using Kaplan-Meier estimates, Fine and Gray competing-risks regressions, and stratified analyses with interaction tests. Results Among 86,975 individuals, 670 (0.8%) were CHEK2*1100delC heterozygous, 2,442 developed breast cancer, and 6,635 developed other cancers. The age- and sex-adjusted hazard ratio for CHEK2*1100delC heterozygotes compared with noncarriers was 2.08 (95% CI, 1.51 to 2.85) for breast cancer and 1.45 (95% CI, 1.15 to 1.82) for other cancers. When stratifying for sex, the age-adjusted hazard ratios for other cancers were 1.54 (95% CI, 1.08 to 2.18) for women and 1.37 (95% CI, 1.01 to 1.85) for men (sex difference: P = .63). For CHEK2*1100delC heterozygotes compared with noncarriers, the age- and sex-adjusted hazard ratios were 5.76 (95% CI, 2.12 to 15.6) for stomach cancer, 3.61 (95% CI, 1.33 to 9.79) for kidney cancer, 3.45 (95% CI, 1.09 to 10.9) for sarcoma, and 1.60 (95% CI, 1.00 to 2.56) for prostate cancer. Conclusion CHEK2*1100delC heterozygosity is associated with 15% to 82% increased risk for at least some cancers in addition to breast cancer. This information may be useful in clinical counseling of patients with this loss-of-function mutation.

scholarly journals Human Sex Matters: Y-linked lysine demethylase 5D drives accelerated male osteogenic differentiation

2021 ◽  
Author(s):  
Madlen Merten ◽  
Johannes F.W. Greiner ◽  
Tarek Niemann ◽  
Meike Grosse Venhaus ◽  
Daniel Kronenberg ◽  
...  
Keyword(s):  
Osteogenic Differentiation ◽  
Molecular Mechanisms ◽  
Female Rats ◽  
Sexually Dimorphic ◽  
Loss Of Function ◽  
Calvarial Bone ◽  
Sexual Dimorphisms ◽  
Increased Risk ◽  
Elevated Expression ◽  
Lysine Demethylase

Female sex is increasingly associated to a loss of bone mass during aging and an increased risk for fractures developing nonunion. Hormonal factors and cell-intrinsic mechanisms are suggested to drive these sexual dimorphisms, although underlying molecular mechanisms are still a matter of debate. Here, we observed a decreased capacity of calvarial bone recovery in female rats and a profound sexually dimorphic osteogenic differentiation human adult neural crest-derived stem cells (NCSCs). Next to an elevated expression of pro-osteogenic regulators, global trancriptomics revealed Lysine Demethylase 5D (KDM5D) to be highly upregulated in differentiating male NCSCs. Loss of function by siRNA or pharmacological inhibition of KDM5D significantly reduced the osteogenic differentiation capacity of male NCSCs. In summary, we demonstrate craniofacial osteogenic differentiation to be sexually dimorphic with the expression of KDM5D as a prerequisite for accelerated male osteogenic differentiation, emphasizing the analysis of sex-specific differences as a crucial parameter for treating bone defects.

scholarly journals CIC missense variants contribute to susceptibility for spina bifida

2021 ◽  
Author(s):  
Xiao Han ◽  
Xuanye Cao ◽  
Vanessa Aguiar-Pulido ◽  
Wei Yang ◽  
Menuka Karki ◽  
...  
Keyword(s):  
Spina Bifida ◽  
Cell Line ◽  
Neural Tube ◽  
Folate Receptor ◽  
Spinocerebellar Ataxia Type ◽  
Loss Of Function ◽  
Missense Variants ◽  
Increased Risk ◽  
Cell Line Hela

Neural Tube Defects (NTDs) are congenital malformations resulting from abnormal embryonic development of the brain, spine, or spinal column. The genetic etiology of human NTDs remains poorly understood despite intensive investigation. CIC, homolog of the Capicua transcription repressor, has been reported to interact with ataxin-1 (ATXN1) and participate in the pathogenesis of spinocerebellar ataxia type 1. Our previous study demonstrated that CIC loss of function (LoF) variants contributed to cerebral folate deficiency by downregulating folate receptor 1 (FOLR1) expression. Given the importance of folate transport in neural tube formation, we hypothesized that CIC variants could contribute to increased risk for NTDs by depressing embryonic folate concentrations. In this study, we examined CIC variants from whole genome sequencing (WGS) data of 140 isolated spina bifida cases and identified 8 missense variants of CIC gene. We tested the pathogenicity of the observed variants through multiple in vitro experiments. We determined that CIC variants decreased FOLR1 protein level and planar cell polarity (PCP) pathway signaling in a human cell line (HeLa). In a murine cell line (NIH3T3), CIC loss of function variants down regulated PCP signaling. Taken together, this study provides evidence supporting CIC as a risk gene for human NTD.

Sign in / Sign up

Export Citation Format

Share Document