Heterozygous carriers of the I171V mutation of the NBS1 gene have a significantly increased risk of solid malignant tumours

2008 ◽  
Vol 44 (4) ◽  
pp. 627-630 ◽  
Author(s):  
Jerzy Nowak ◽  
Maria Mosor ◽  
Iwona Ziółkowska ◽  
Malgorzta Wierzbicka ◽  
Monika Pernak-Schwarz ◽  
...  
Keyword(s):  
Malignant Tumours ◽  
Nbs1 Gene ◽  
Increased Risk ◽  
Heterozygous Carriers ◽  
I171v Mutation

Increased risk of larynx cancer in heterozygous carriers of the I171V mutation of the NBS1 gene

2007 ◽  
Vol 98 (11) ◽  
pp. 1701-1705 ◽  
Author(s):  
Iwona Ziólkowska ◽  
Maria Mosor ◽  
Malgorzata Wierzbicka ◽  
Malgorzata Rydzanicz ◽  
Monika Pernak-Schwarz ◽  
...  
Keyword(s):  
Larynx Cancer ◽  
Nbs1 Gene ◽  
Increased Risk ◽  
Heterozygous Carriers ◽  
I171v Mutation

scholarly journals Exploring the Genotype–Phenotype Correlation in GBA-Parkinson Disease: Clinical Aspects, Biomarkers, and Potential Modifiers

2021 ◽  
Vol 12 ◽  
Author(s):  
Elisa Menozzi ◽  
Anthony H. V. Schapira
Keyword(s):  
Parkinson Disease ◽  
Progressive Disease ◽  
Clinical Aspects ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
Risk Variants ◽  
Increased Risk ◽  
Severe Motor ◽  
Heterozygous Carriers

Variants in the glucocerebrosidase (GBA) gene are the most common genetic risk factor for Parkinson disease (PD). These include pathogenic variants causing Gaucher disease (GD) (divided into “severe,” “mild,” or “complex”—resulting from recombinant alleles—based on the phenotypic effects in GD) and “risk” variants, which are not associated with GD but nevertheless confer increased risk of PD. As a group, GBA-PD patients have more severe motor and nonmotor symptoms, faster disease progression, and reduced survival compared with noncarriers. However, different GBA variants impact variably on clinical phenotype. In the heterozygous state, “complex” and “severe” variants are associated with a more aggressive and rapidly progressive disease. Conversely, “mild” and “risk” variants portend a more benign course. Homozygous or compound heterozygous carriers usually display severe phenotypes, akin to heterozygous “complex” or “severe” variants carriers. This article reviews genotype–phenotype correlations in GBA-PD, focusing on clinical and nonclinical aspects (neuroimaging and biochemical markers), and explores other disease modifiers that deserve consideration in the characterization of these patients.

scholarly journals Risk factors for post-thyroidectomy haemorrhage: a meta-analysis

2017 ◽  
Vol 176 (5) ◽  
pp. 591-602 ◽  
Author(s):  
Jinhao Liu ◽  
Wei Sun ◽  
Wenwu Dong ◽  
Zhihong Wang ◽  
Ping Zhang ◽  
...  
Keyword(s):  
Risk Factors ◽  
Neck Dissection ◽  
Thyroid Surgery ◽  
Meta Analysis ◽  
Older Age ◽  
Graves Disease ◽  
Malignant Tumours ◽  
Antithrombotic Agents ◽  
Increased Risk ◽  
Male Sex

BackgroundPost-thyroidectomy haemorrhage is a rare but potentially life-threatening and unpredictable complication of thyroid surgery. In this study, we analysed the potential risk factors for the occurrence of post-thyroidectomy haemorrhage.MethodsThe PubMed and SCIE databases were comprehensively searched for studies published before June 30, 2016. Studies on patients who underwent an open thyroidectomy with or without neck dissection were included, and RevMan 5.3 software was used to analyse the data.ResultsTwenty-five studies and 424 563 patients were included in this meta-analysis, and post-thyroidectomy haemorrhage occurred in 6277 patients (incidence rate = 1.48%). The following variables were associated with an increased risk of post-thyroidectomy haemorrhage: older age (MD = 4.30, 95% CI = 3.09–5.52,P < 0.00001), male sex (OR = 1.73, 95% CI = 1.54–1.94,P < 0.00001), Graves’ disease (OR = 1.76, 95% CI = 1.44–2.15,P < 0.00001), antithrombotic agents use (OR = 1.96, 95% CI 1.55–2.49,P < 0.00001), bilateral operation (OR = 1.71, 95% CI = 1.50–1.96,P < 0.00001), neck dissection (OR = 1.53, 95% CI = 1.11–2.11,P = 0.01) and previous thyroid surgery (OR = 1.62, 95% CI = 1.12–2.34,P = 0.01). Malignant tumours (OR = 1.07, 95% CI = 0.89–1.28,P = 0.46) and drainage device use (OR = 1.27, 95% CI = 0.74–2.18,P = 0.4) were not associated with post-thyroidectomy haemorrhage.ConclusionOur systematic review identified a number of risk factors for post-thyroidectomy haemorrhage, including older age, male sex, Graves’ disease, antithrombotic agents use, bilateral operation, neck dissection and previous thyroid surgery. Early control of modifiable risk factors could improve patient outcomes and satisfaction.

scholarly journals The HR2 Haplotype of Factor V Is not Associated with the Risk of Myocardial Infarction

2000 ◽  
Vol 84 (11) ◽  
pp. 815-818 ◽  
Author(s):  
Carine Doggen ◽  
Marieke de Visser ◽  
Hans Vos ◽  
Rogier Bertina ◽  
Volkert Cats ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Factor V Leiden ◽  
Myocardial Infarctions ◽  
Control Group ◽  
Factor V ◽  
Increased Risk ◽  
Factor V Gene ◽  
Heterozygous Carriers ◽  
First Myocardial Infarction ◽  
Control Study

SummaryThe HR2 haplotype of the factor V gene, which contains the histidine to arginine substitution at position 1299, has been reported to be associated with reduced factor V levels. Because high factor V levels have been found to be associated with an increased risk of myocardial infarction, we examined how the presence of the R2 allele affected the risk of myocardial infarction in the case-control “Study of Myocardial Infarctions Leiden”.Among 560 men with a first myocardial infarction before the age of 70 years, 9.5% were heterozygous carriers of the R2 allele. The control group consisted of 646 men, in which 9.9% were heterozygous and 0.2% homozygous carriers of the R2 allele. The risk of myocardial infarction in the presence of the R2 allele was not increased (odds ratio, 0.9; 95% confidence interval 0.6 to 1.4). Exclusion of factor V Leiden carriers did not change this result. The risk was 4.4-fold increased for smokers who carried the R2 allele compared to non-smoking noncarriers. No synergy was found between metabolic risk factors and the presence of the R2 allele.We conclude that the risk of myocardial infarction for men in the presence of the R2 allele of the His1299Arg polymorphism is neither increased nor decreased.

scholarly journals Heterozygous ABCG5 Gene Deficiency and Risk of Coronary Artery Disease

2020 ◽  
Vol 13 (5) ◽  
pp. 417-423 ◽  
Author(s):  
Akihiro Nomura ◽  
Connor A. Emdin ◽  
Hong Hee Won ◽  
Gina M. Peloso ◽  
Pradeep Natarajan ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Large Scale ◽  
Carrier Status ◽  
Loss Of Function ◽  
Increased Risk ◽  
Genetic Deficiency ◽  
Heterozygous Carriers ◽  
Artery Disease ◽  
The Impact

Background: Familial sitosterolemia is a rare Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency—homozygous loss-of-function (LoF) variants—in the ABCG5 or ABCG8 genes and have substantially elevated plasma sitosterol and LDL (low-density lipoprotein) cholesterol (LDL-C) levels. The impact of partial genetic deficiency of ABCG5 or ABCG8 —as occurs in heterozygous carriers of LoF variants—on LDL-C and risk of coronary artery disease (CAD) has remained uncertain. Methods: We first recruited 9 sitosterolemia families, identified causative LoF variants in ABCG5 or ABCG8 , and evaluated the associations of these ABCG5 or ABCG8 LoF variants with plasma phytosterols and lipid levels. We next assessed for LoF variants in ABCG5 or ABCG8 in CAD cases (n=29 321) versus controls (n=357 326). We tested the association of rare LoF variants in ABCG5 or ABCG8 with blood lipids and risk for CAD. Rare LoF variants were defined as protein-truncating variants with minor allele frequency <0.1% in ABCG5 or ABCG8 . Results: In sitosterolemia families, 7 pedigrees harbored causative LoF variants in ABCG5 and 2 pedigrees in ABCG8 . Homozygous LoF variants in either ABCG5 or ABCG8 led to marked elevations in sitosterol and LDL-C. Of those sitosterolemia families, heterozygous carriers of ABCG5 LoF variants exhibited increased sitosterol and LDL-C levels compared with noncarriers. Within large-scale CAD case-control cohorts, prevalence of rare LoF variants in ABCG5 and in ABCG8 was ≈0.1% each. ABCG5 heterozygous LoF variant carriers had significantly elevated LDL-C levels (25 mg/dL [95% CI, 14–35]; P =1.1×10 −6 ) and were at 2-fold increased risk of CAD (odds ratio, 2.06 [95% CI, 1.27–3.35]; P =0.004). By contrast, ABCG8 heterozygous LoF carrier status was not associated with increased LDL-C or risk of CAD. Conclusions: Although familial sitosterolemia is traditionally considered as a recessive disorder, we observed that heterozygous carriers of an LoF variant in ABCG5 had significantly increased sitosterol and LDL-C levels and a 2-fold increase in risk of CAD.

Risk of Pregnancy-related Venous Thrombosis in Carriers of Severe Inherited Thrombophilia

2001 ◽  
Vol 86 (09) ◽  
pp. 800-803 ◽  
Author(s):  
Cristina Legnani ◽  
Paolo Bucciarelli ◽  
Elvira Grandone ◽  
Valerio De Stefano ◽  
Pier Mannuccio Mannucci ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Gene Mutations ◽  
Factor V Leiden ◽  
Study Cohort ◽  
Factor V ◽  
Thrombotic Risk ◽  
Increased Risk ◽  
Prothrombin Gene ◽  
Heterozygous Carriers ◽  
Anticoagulant Prophylaxis

SummaryHomozygous carriers of factor V Leiden have an approximately 80-fold increased risk of venous thrombosis. Also double heterozygous carriers of both the factor V Leiden and the prothrombin gene mutations are at high thrombotic risk. The magnitude of the risk of venous thrombosis in pregnant women with the two severe thrombophilic conditions has not been estimated so far. We performed a multicenter retrospective family study in women with homozygous factor V Leiden, double heterozygous factor V Leiden and the prothrombin gene mutation, and women with normal coagulation. Only relatives of index patients with thrombosis formed the study cohort. Fifteen homozygous and 39 double heterozygous women were compared to 182 women with normal coagulation. Venous thrombosis occurred in 3 of 19, 2 of 50 and 1 of 221 pregnancies, respectively. One thrombotic episode occurred in the third trimester, the remaining 5 in the postpartum. The prevalence of venous thrombosis was 15.8% (95% CI 3.4-39.6) for homozygotes, 4.0% (95% CI 0.5-13.7) for double heterozygotes and 0.5% for women with normal coagulation. The relative risk of pregnancy-related venous thrombosis was 41.3 (95% CI 4.1-419.7) for homozygous and 9.2 (95% CI 0.8-103.2) for double heterozygous carriers. In conclusion, homozygous carriers of factor V Leiden and, to a lesser extent, double heterozygous carriers of factor V Leiden and of the prothrombin mutation have an increased risk of venous thrombosis during pregnancy, particularly high during the postpartum period. On the basis of these findings we recommend that these women receive anticoagulant prophylaxis at least in the postpartum, that should perhaps be extended to the whole pregnancy in homozygous carriers.

Sirolimus therapy for congenital hyperinsulinism in an infant with a novel homozygous KCNJ11 mutation

2018 ◽  
Vol 31 (1) ◽  
pp. 87-89 ◽  
Author(s):  
Sophy Korula ◽  
Aaron Chapla ◽  
Leena Priyambada ◽  
Sarah Mathai ◽  
Anna Simon
Keyword(s):  
Case Reports ◽  
Therapeutic Option ◽  
Homozygous Mutation ◽  
Congenital Hyperinsulinism ◽  
Case Presentation ◽  
The Past ◽  
Pancreatic Involvement ◽  
Increased Risk ◽  
Heterozygous Carriers ◽  
Generation Sequencing

AbstractBackground:Congenital hyperinsulinism results in refractory hypoglycemia. If a therapy with diazoxide has been unresponsive this has been treated by subtotal pancreatectomy in the past. This therapeutic option poses an increased risk of developing diabetes at a later stage. There have been a few case reports on the use of sirolimus in such situations in the recent past.Case presentation:Our patient was started on sirolimus very early, on day 29 of life and at the age of 14 months is doing well on sirolimus therapy. His growth and development have been good and he has not had any major complications so far. Genetic testing showed a novelKCNJ11homozygous mutation on next generation sequencing and the parents were heterozygous carriers.Conclusions:We report the successful use of sirolimus in the management of diazoxide unresponsive congenital hyperinsulinism with diffuse pancreatic involvement. We believe this is the youngest patient to be initiated on sirolimus so far.

Evidence of an increased risk of hearing loss in heterozygous carriers in a Wolfram syndrome family

1998 ◽  
Vol 103 (4) ◽  
pp. 470-474 ◽  
Author(s):  
Tomoaki Ohata ◽  
A. Koizumi ◽  
Tsuyoshi Kayo ◽  
Yutaka Shoji ◽  
Arata Watanabe ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Wolfram Syndrome ◽  
Increased Risk ◽  
Heterozygous Carriers

Oxidative stress and cancer: have we moved forward?

2006 ◽  
Vol 401 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Barry Halliwell
Keyword(s):  
Oxidative Damage ◽  
Oxidation Products ◽  
Cancer Development ◽  
Malignant Tumours ◽  
Age Related ◽  
Dna Base ◽  
Increased Risk ◽  
Defence Enzymes ◽  
Risk Of Cancer

‘Reactive species’ (RS) of various types are formed in vivo and many are powerful oxidizing agents, capable of damaging DNA and other biomolecules. Increased formation of RS can promote the development of malignancy, and the ‘normal’ rates of RS generation may account for the increased risk of cancer development in the aged. Indeed, knockout of various antioxidant defence enzymes raises oxidative damage levels and promotes age-related cancer development in animals. In explaining this, most attention has been paid to direct oxidative damage to DNA by certain RS, such as hydroxyl radical (OH•). However, increased levels of DNA base oxidation products such as 8OHdg (8-hydroxy-2′-deoxyguanosine) do not always lead to malignancy, although malignant tumours often show increased levels of DNA base oxidation. Hence additional actions of RS must be important, possibly their effects on p53, cell proliferation, invasiveness and metastasis. Chronic inflammation predisposes to malignancy, but the role of RS in this is likely to be complex because RS can sometimes act as anti-inflammatory agents.

Increased levels of citrullinated antithrombin in plasma of patients with rheumatoid arthritis and colorectal adenocarcinoma determined by a newly developed ELISA using a specific monoclonal antibody

2010 ◽  
Vol 104 (12) ◽  
pp. 1143-1149 ◽  
Author(s):  
Adriana Ordóñez ◽  
Jose Yélamos ◽  
Shona Pedersen ◽  
Antonia Miñano ◽  
Pablo Conesa-Zamora ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Monoclonal Antibody ◽  
Colorectal Adenocarcinoma ◽  
Anticoagulant Activity ◽  
Specific Monoclonal Antibody ◽  
Malignant Tumours ◽  
Post Translational Modification ◽  
Thrombotic Risk ◽  
Increased Risk ◽  
Anticoagulant Function

SummaryCitrullination is a post-translational modification that plays essential roles in both physiological processes and disease. Recent studies have found increased levels of citrullinated antithrombin in patients with rheumatoid arthritis and in different malignant tumours. Antithrombin, the main haemostatic serpin, loses its anticoagulant function via citrullination, which might contribute to the pathogenesis or thrombotic side effects of these disorders. We have developed a specific monoclonal antibody against citrullinated antithrombin. We determined the levels of citrullinated antithrombin and anti-FXa activity in plasma from 66 donors, 17 patients with rheumatoid arthritis and 77 patients with colorectal adenocarcinoma (42 suffering from venous thrombosis). Healthy subjects had negligible amounts of citrullinated antithrombin in plasma (7.9 ± 22.1 ng/ml), while it significantly increased in patients with rheumatoid arthritis or adenocarcinoma (159.7 ± 237.6 ng/ml and 36.8 ± 66.1 ng/ml), levels that, however, did not modify the plasma anticoagulant activity. Moreover, we did not find association between citrullinated antithrombin and the thrombotic risk in patients with adenocarcinoma. In conclusion, we have developed an antibody specific for citrullinated antithrombin that allows its quantification in biological samples, offering a new tool for the analysis of citrullination in different diseases. We confirm increased levels of citrullinated antithrombin in plasma of patients with rheumatoid arthritis and adenocarcinoma. This modification, probably local, could have pathological consequences in both disorders, but only affects a minor fraction of plasma antithrombin, resulting in no significant reduction of global anticoagulant activity. This result explains the absence of association of this marker with an increased risk of thrombosis in patients with colorectal adenocarcinoma.

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