Combined effects of five prothrombotic genotypes and cancer on the risk of a first venous thromboembolic event

Skille, Hanne; Paulsen, Benedikte; Hveem, Kristian; Gabrielsen, Maiken Elvestad; Brumpton, Ben; Hindberg, Kristian; Gran, Olga Vikhammer; Rosendaal, Frits R.; Brækkan, Sigrid Kufaas; Hansen, John‐Bjarne

doi:10.1111/jth.15011

Cited by 14 publications

(16 citation statements)

References 50 publications

(97 reference statements)

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“…In addition, there was a combined effect among these two SNPs, and the cumulative effect of risk alleles on the risk of HNSCC increases with the increase in the number of risk alleles ( p trend = 0.003). This suggested that the combined effect analysis of multiple SNPs could help to illustrate the relationship between genetic variation and cancer better and discover more combinations of cancer‐related biomarkers 51,52 …”

Section: Discussionmentioning

confidence: 99%

Risk SNP‐mediated LINC01614 upregulation drives head and neck squamous cell carcinoma progression via PI3K/AKT signaling pathway

Hou

Zhou

et al. 2022

Molecular Carcinogenesis

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As potential biomarkers and therapeutic targets, long noncoding RNAs (lncRNAs) are involved in the tumorigenesis of various tumors. Genetic variation in long noncoding regions can lead to lncRNA dysfunction and even cancer. Nevertheless, studies on the association between lncRNA‐associated single‐nucleotide polymorphisms (SNPs) and the risk of head and neck squamous cell carcinoma (HNSCC) remain inadequate. Here, we aimed to explore the association between SNPs in LINC01614 and HNSCC risk, and the potential role of LINC01614 in tumorigenesis. In this study, we found that rs16854802 A > G (odds ratio [OR] = 1.42, 95% confidence interval [CI]: 1.22–1.77, p < 0.001) and rs3113503 G > C (OR = 1.38, 95% CI: 1.15–1.64, p < 0.001) in LINC01614 increased the risk of HNSCC in the Chinese population. Functional bioinformatic analysis and luciferase reporter assay revealed that rs3113503 G > C variant disrupted the binding of miRNA‐616‐3p to LINC01614, which resulted in the increased expression of LINC01614. Further analysis of the TCGA database demonstrated that the upregulated LINC01614 in HNSCC cancer tissues was associated with poor prognostic in HNSCC patients. In vitro experiments showed that knockdown of LINC01614 inhibited the proliferation, invasion, and migration ability of HNSCC cells. Mechanistically, allele C of rs3113503 in LINC01614 was more effective than allele G in activating the PI3K/AKT signaling pathway. Moreover, the reduced expression of LINC01614 also inhibited the activation of the PI3K/AKT signaling pathway. In summary, our findings revealed that the risk SNP rs3113503 G > C in LINC01614 altered the binding to miR‐616‐3p, which led to increased LINC01614 expression and promoted HNSCC progression by activating the PI3K/AKT signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Risk SNP‐mediated LINC01614 upregulation drives head and neck squamous cell carcinoma progression via PI3K/AKT signaling pathway

Hou

Zhou

et al. 2022

Molecular Carcinogenesis

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“…Our study also confirmed other studies (10,66) which showed that the presence of cancer increased the risk of VTE in addition to other VTE risk factors. Further studies on cancer and prothrombotic genotypes point out that VTE risk increased by 11-12-fold as a result of the simultaneous presence of cancer and rs8176719 (ABO) risk variant (67,68). The authors also found that 39% (67) and 30% (68) of VTE risk was attributed to the joint presence of cancer and non-O-blood type.…”

Section: Discussionmentioning

confidence: 96%

“…Our study also confirmed other studies ( 10 , 66 ) which showed that the presence of cancer increased the risk of VTE in addition to other VTE risk factors. Further studies on cancer and prothrombotic genotypes point out that VTE risk increased by 11–12-fold as a result of the simultaneous presence of cancer and rs8176719 (ABO) risk variant ( 67 , 68 ). The authors also found that 39% ( 67 ) and 30% ( 68 ) of VTE risk was attributed to the joint presence of cancer and non-O-blood type.…”

Section: Discussionmentioning

confidence: 99%

The Higher Prevalence of Venous Thromboembolism in the Hungarian Roma Population Could Be Due to Elevated Genetic Risk and Stronger Gene-Environmental Interactions

Natae

Kósa

Sándor

et al. 2021

Front. Cardiovasc. Med.

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Background: Interactions between genetic and environmental risk factors (GxE) contribute to an increased risk of venous thromboembolism (VTE). Understanding how these factors interact provides insight for the early identification of at-risk groups within a population and creates an opportunity to apply appropriate preventive and curative measures.Objective: To estimate and compare GxE for VTE risk in the general Hungarian and Roma populations.Methods: The study was based on data extracted from a database consisting of results previously obtained from a complex health survey with three pillars (questionnaire-based, physical, and laboratory examinations) involving 406 general Hungarian and 395 Roma subjects. DNA was genotyped for rs121909567 (SERPINC1), rs1799963 (F2), rs2036914 (F11), rs2066865 (FGG), rs6025 (F5), and rs8176719 (ABO) polymorphisms. After allele frequency comparisons, the odds ratio (OR) was calculated for individual SNPs. Furthermore, genetic risk scores (weighted GRS, unweighted GRS) were computed to estimate the joint effect of the genetic factors. Multivariable linear regression analysis was applied to test the impact of GxE on VTE risk after interaction terms were created between genetic and VTE risk factors [diabetes mellitus (DM), cancer, chronic kidney diseases (CKD), coronary artery diseases (CAD), migraine, depression, obesity, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high density lipoprotein (HDL-C), triglyceride (TG), and smoking].Results: Interestingly, the rs121909567 (SERPINC1, ATBp3 mutation) SNP was not present in the general population at all. However, the risk allele frequency was 1% among the Roma population, which might suggest a founder effect in this minority. This polymorphism multiplicatively interacted with CAD, CKD, cancer, DM, depression, migraine, and obesity. Even though interactions were not statistically significant, the trend of interaction showed the probability of an incremental VTE risk among the Roma population. The risk of VTE was 4.7 times higher (p > 0.05) for Roma subjects who had ≥3 wGRS (median value) compared with individuals having lower wGRS values but lower for the general subjects (OR = 3.1 × 10−8). Additionally, the risk of VTE was 6.6 times higher in the Roma population that had ≥3 risk alleles (median value) than in individuals with the 0–1 risk allele, and the overall risk was much higher for the Roma population (OR = 6.6; p > 0.05) than for the general Hungarian population (OR = 1.5; p > 0.05). Five positive and significant GxE interactions were identified in the Roma population. The risk of VTE was higher among depressive Roma subjects who carried the risk variant rs2036914 (β = 0.819, p = 0.02); however, this interaction was not significant for the general subjects. The joint presence of high levels of LDL-C and rs2066865 (FGG) increased the VTE risk only among Roma individuals (β = 0.389, p = 0.002). The possibility of VTE risk increment, as a result of a multiplicative interaction between rs8176719 (ABO) and cancer, was identified, which was higher for the Roma population (β = 0.370, p < 0.001) than for the general population (β = −0.042, p = 0.6). The VTE risk increased in the Roma population (β = 0.280, p = 0.001), but was higher in the general population (β = 0.423, p = 0.001) as a result of the multiplicative interaction between CAD and rs2036914 (F11). The presence of a multiplicative interaction between rs2066865 (FGG) and CAD increased the VTE risk for the Roma population (β = 0.143, p = 0.046) but not for the general population (β = −0.329, p < 0.001).Conclusions: rs121909567 (SERPINC1, ATBp3) was confirmed as a founder mutation in the Roma population. Our study revealed some evidence on the burden of the joint presence of genetic and environmental risk factors on VTE, although the finding is highly subjected to the selection and observational biases due to the very small number of VTE cases and the observational nature of the study design, respectively. As a result of higher genetic load and GxE interactions, this minority Roma population is at higher risk of VTE than the general Hungarian population. Thus, our results suggest the need for an intensive search for the rs121909567 (SERPINC1; ATBp3) founder mutation, which might be an important factor for the assessment of thrombotic disease susceptibility among the Roma population. In addition, we strongly recommend further studies among a large number of VTE cases to explore the more precise impact of genetic and environmental risk factors on VTE in the study populations.

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“…The intragenic rs505922 SNP has been shown to be responsible for differential ABO protein levels with an increasing effect for allele "C" and diminishing levels for allele "T" 27,28 . rs505922 is in LD with the O blood group SNP rs8176719, which has been repeatedly associated with an increased risk of venous thromboembolism [29][30][31][32] . The rs8176719 polymorphism has been also associated to Factor VIII levels 33 , malaria 34,35 , venous thromboembolism 36 , vWF levels 33 .…”

Section: Namementioning

confidence: 99%

Country-Level Factors Dynamics and ABO/Rh Blood Groups Contribution To COVID-19 Mortality

Monaco

Pantaleo²,

Amoroso

et al. 2021

Preprint

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Identifying factors related to COVID-19 mortality is important to deploy effective containment measures and to safeguard categories at risk. In the last months, several investigations have tried to ascertain essential features for predicting the COVID-19 mortality tolls depending on country-specific dynamics and population structure. Most studies focused on the initial outbreak of COVID-19 spanning the first half of 2020. Several variables, including obesity, health system indicators such as hospital bed density, and bacillus Calmette-Guerin vaccination have been reported as significantly associated to COVID-19 mortality. Here, we examined in different pandemic stages some of the mentioned associations as well as ABO and Rh blood group indicators, which have also been previously linked to COVID-19 severity and fatal outcome. Using a machine learning approach, we found that the “B+” blood group frequency is an important factor at all stages of the pandemic.

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Combined effects of five prothrombotic genotypes and cancer on the risk of a first venous thromboembolic event

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 14 publications

References 50 publications

Risk SNP‐mediated LINC01614 upregulation drives head and neck squamous cell carcinoma progression via PI3K/AKT signaling pathway

Risk SNP‐mediated LINC01614 upregulation drives head and neck squamous cell carcinoma progression via PI3K/AKT signaling pathway

The Higher Prevalence of Venous Thromboembolism in the Hungarian Roma Population Could Be Due to Elevated Genetic Risk and Stronger Gene-Environmental Interactions

Country-Level Factors Dynamics and ABO/Rh Blood Groups Contribution To COVID-19 Mortality

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