JAK2V617F Variant Allele Frequency Identifies Patients with Polycythemia Vera (PV) at High Risk for Venous Thrombosis

Abstract Background. Cardiovascular (CV) events are leading cause of morbidity and mortality in PV. Current risk stratification is based on variables predicting thrombotic risk, ie age >60y and history of thrombosis. Recent studies focused on additional thrombotic risk factors in PV, including generic CV factors and leukocytosis. PV patients (pts) are JAK2V617F mutated, and present wide heterogeneity in variant allele frequency (VAF); it was shown that a VAF >75% was associated with higher number of thrombotic events after diagnosis (Vannucchi AM, Leukemia 2007), but the prognostic role of JAK2 VAF is still debated. Aim. The aim of the study was to evaluate the impact of JAK2V617F VAF on rate of thrombosis in WHO-2016 defined PV pts. Patients and Method. In the CRIMM (Florence) database, a total of 577 pts with a JAK2VF VAF determined within 3 years from diagnosis, who met the 2016 WHO criteria for PV, were identified. All pts had information regarding thromboembolic events, including history of thrombosis, occurrence, type and date of thrombosis in the follow-up (FU) and presence of CV risk factors (smoking, hypertension, and diabetes mellitus). Thrombosis‐free survival (TFS) was determined from the time of diagnosis to the time the first thrombotic event occurred. Pts in whom thrombosis did not occur were censored at the time of last FU. Pre-receiver operating characteristic (ROC) plots were used to determine cutoff levels for continuous variables of interest. Differences in the distribution of continuous variables between categories were analyzed by Mann-Whitney or Kruskal-Wallis test. Pts' groups with nominal variables were compared by χ2 test. TFS was estimated by Kaplan Meier analysis; log rank test was used to compare TFS difference between groups. Cox proportional hazards regression was used for multivariable analysis. A two tailed P ≤ 0.05 was considered statistically significant. Results. The median age of pts at diagnosis was 61y, 308 (53.4%) were above 60y; 57.2% were males. All pts were mutated for JAK2V617F with a median VAF 43% (range 1-100%), 62% had at least one CV risk factor; 83 (14.4%) pts suffered from an episode of thrombosis within 3 yr from, or coincident with, diagnosis. The median FU was 7.3y (0.6-35.9y) during which 87 pts (15.1%) developed thrombosis. (50 arterial and 45 venous thrombosis). During the FU, 110 pts (19.1%) died. A JAK2VAF of ≥60% cutoff level, as determined by ROC analysis, correlated with measurements of stimulated erythropoiesis (higher hematocrit, lower mean cell volume and serum ferritin; all P<.01), leukocytosis (P<.0001), lower platelets count (P=.02) and elevated serum lactate dehydrogenase (LDH) (P<.03). Pts with ≥60% JAK2V617F VAF were at higher relative risk (RR) of having splenomegaly (RR 3.1; P<0.001), suffering from pruritus (RR 2.5; P<0.001) or constitutional symptoms (RR 1.9; P=0.01), harboring a BM fibrosis grade-1 (RR 3.1; P<0.001). Additionally, pts with a VAF>60% had greater risk to progress to PPV-MF (RR 8.5, P<.0001) and acute leukemia (RR 4.4, P=0.04) or to die (RR 3.8, P<0.0001). The JAK2VF VAF (continuous or ≥60%) did not correlate with occurrence of thrombosis at diagnosis, while the rate of thrombosis during FU was significantly increased in pts with VAF ≥60% (23.4% vs 11.0%, RR 2.4, 95%CI = 1.4-4.0; P<0.0001), more marked for venous (RR 3.7, 95%CI = 2.0-6.8; P<0.0001) than arterial (RR 1.8, 95%CI = 0.9-3.3; P=0.05) thrombosis. The impact of VAF on thrombosis during FU was then estimated according to the conventional risk category. In low risk pts (LR) (n=236), factors significantly associated with occurrence of FU thrombosis were CV risk factors (dyslipidemia (RR 3.3, P = 0.02) and hypertension (RR 1.8, P=0.048)), a G1 BM fibrosis (RR 5.3, P=0.006), presence of splenomegaly (RR, 3.2, P=0.001) or constitutional symptoms (RR 3.3, P=0.003) and a VAF ≥60% (RR 2.2, P = 0.024). In high risk pts (HR) (n=341), factors significant for FU thrombosis were splenomegaly (RR 2.0, P=0.03), elevated LDH (RR 4.0, P=0.009) and a VAF ≥60% (RR 2.3, P = 0.012). A VAF ≥60% was correlated with shortened venous TFS after diagnosis in HR (P = 0.01, HR = 3.2, 95%CI = 1.2−8.3; fig.) but not in LR pts (P = 0.20, HR = 1.1, 95%CI = 0.5−2.9). Conclusions. This study indicates that conventionally-defined high-risk PV pts with a JAK2V617F VAF ≥60% suffer from increased rate of venous events and might be worthwhile of more intensive antithrombotic prophylaxis. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

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JAK2V617F variant allele frequency >50% identifies patients with polycythemia vera at high risk for venous thrombosis

Blood Cancer Journal ◽

10.1038/s41408-021-00581-6 ◽

2021 ◽

Vol 11 (12) ◽

Author(s):

Paola Guglielmelli ◽

Giuseppe G. Loscocco ◽

Carmela Mannarelli ◽

Elena Rossi ◽

Francesco Mannelli ◽

...

Keyword(s):

Risk Factors ◽

Polycythemia Vera ◽

Allele Frequency ◽

Validation Cohort ◽

Multivariable Analysis ◽

Variant Allele ◽

Variant Allele Frequency ◽

Training Cohort ◽

Independent Risk Factors ◽

The Impact

AbstractArterial (AT) and venous (VT) thrombotic events are the most common complications in patients with polycythemia vera (PV) and are the leading causes of morbidity and mortality. In this regard, the impact of JAK2V617F variant allele frequency (VAF) is still debated. The purpose of the current study was to analyze the impact of JAK2V617F VAF in the context of other established risk factors for thrombosis in a total of 865 2016 WHO-defined PV patients utilizing two independent cohorts: University of Florence (n = 576) as a training cohort and Policlinico Gemelli, Catholic University, Rome (n = 289) as a validation cohort. In the training cohort VT free-survival was significantly shorter in the presence of a JAK2V617F VAF > 50% (HR 4; p < 0.0001), whereas no difference was found for AT (HR 0.9; p = 0.8). Multivariable analysis identified JAK2V617F VAF > 50% (HR 3.8, p = 0.001) and previous VT (HR 2.2; p = 0.04) as independent risk factors for future VT whereas diabetes (HR 2.4; p = 0.02), hyperlipidemia (HR 2.3; p = 0.01) and previous AT (HR 2; p = 0.04) were independent risk factors for future AT. Similarly, JAK2V617F VAF > 50% (HR 2.4; p = 0.01) and previous VT (HR 2.8; p = 0.005) were confirmed as independent predictors of future VT in the validation cohort. Impact of JAK2V617F VAF > 50% on VT was particularly significant in conventional low-risk patients, both in Florence (HR 10.6, p = 0.005) and Rome cohort (HR 4; p = 0.02). In conclusion, we identified JAK2V617F VAF > 50% as an independent strong predictor of VT, supporting that AT and VT are different entities which might require distinct management.

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A JAK2V617F Variant Allele Frequency Greater Than 50% Identifies Patients with Polycythemia Vera at High Risk for Venous Thrombosis

Blood ◽

10.1182/blood-2021-147869 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 237-237

Author(s):

Giuseppe Gaetano Loscocco ◽

Paola Guglielmelli ◽

Carmela Mannarelli ◽

Elena Rossi ◽

Francesco Mannelli ◽

...

Keyword(s):

Risk Factors ◽

High Risk ◽

Venous Thrombosis ◽

Board Of Directors ◽

Univariate Analysis ◽

Multivariable Analysis ◽

Advisory Committees ◽

Free Survival ◽

History Of ◽

Independent Risk Factors

Abstract Background: Thrombosis is the main cause of morbidity and mortality in pts with Polycythemia Vera (PV). Current risk stratification is based on 2 variables: age >60y and history of thrombosis. Additional thrombotic risk factors in PV are generic cardiovascular risk factors and leukocytosis. JAK2V617F (JAK2VF) variant allele frequency (VAF) at diagnosis is highly heterogeneous. A VAF>75% was associated with higher rate of all thrombosis after diagnosis (Vannucchi AM et al, Leukemia 2007), and a VAF ≥ 60% correlated with increased rate of venous thrombosis (VT) in high-risk pts (Guglielmelli P et al, ASH 2018); however, predictive role of JAK2VF VAF is still debated. Aim: To evaluate the impact of JAK2VF VAF on rate of arterial and venous thrombosis in PV pts. Patients and methods: A cohort of 576 strictly 2016 WHO-defined PV pts followed at Univ. of Florence (1981-2020) were included. All pts were annotated for JAK2VF VAF, determined <3 years from diagnosis, and thrombosis at diagnosis and follow-up (FU). Arterial thromboses (AT) included stroke, transient ischemic attacks, retinal artery occlusion, coronary artery disease, and peripheral arterial disease; VT included cerebral venous thrombosis, deep vein thrombosis, pulmonary embolism. Splanchnic vein thromboses (SVT) were excluded. Only first occurring event was considered. Cox proportional hazard regression model was used for univariate and multivariable analysis. Kaplan-Meier (KM) analysis was used for time-to-event assessment, compared by log-rank test. Results: Median age was 61.4 y (range, 16.2-91.8), 58.2% were male; 62% were high-risk based on current classification. Median JAK2VF VAF was 41.5% (range, 0.3-100). A total of 76 (13.2%) pts had an AT event before/at PV diagnosis and 49 (8.5%) pts had an AT during FU. As regards VT, 64 (11.1%) and 39 (6.8%) pts had a VT before/at or after PV diagnosis, respectively. We found that JAK2 VAF as a continue variable was correlated with the risk of VT in FU (p=0.003) but not with AT (p=0.8). ROC analysis to determine the best cut-off level for JAK2 VAF predicting VT had an AUC of 0.72 and a best cut-off value of VAF=50%. VT at FU were significantly enriched in pts with VAF >50%: 14.5% versus 2.4%, p=<0.0001. VT -free survival (VT-FS) by KM was significantly shorter in the presence of a JAK2 VAF >50% (HR 4, CI 1.9-8.6, p<0.0001) (Figure 1A), whereas no difference was found for AT (HR 0.9). In addition to JAK2VF VAF>50%, univariate analysis for VT-FS identified history of VT (HR 2.9; CI 1.4-6.1, p=0.006), leukocytosis ≥11x10 9/L (HR 1.9; CI 1.1-3.4, p=0.02) and palpable splenomegaly (HR 1.9, CI 1-3.6; p=0.04) as risk factors. Multivariable analysis confirmed VAF>50% (HR 3.8, CI 1.8-8.1, p=0.0006) and previous VT (HR 2.4, CI 1.1-5.1; p=0.02) as independent risk factors for future VT. In contrast, univariate analysis for AT-free survival (AT-FS) identified history of AT (HR 2.5; CI 1.3-4.9, p=0.007), diabetes (HR 3.3; CI 1.6-6.5, p=0.0007), hyperlipidemia (HR 3.1; CI 1.7-5.6, p=0.0003) and hypertension (HR 2, CI 1.1-3.8; p=0.03) as predictors of future AT; age >60y showed only a trend (p=0.08). Multivariable analysis for AT-FS identified diabetes (HR 2.4, CI 1.2-5; p=0.02), hyperlipidemia (HR 2.3; CI 1.2-4.3, p=0.01) and previous AT (HR 2.1, CI 1-4.2; p=0.04) as independent predictors of future AT. Validation: Our findings were validated in an independent cohort of 315 2016-WHO defined PV pts from Policlinico Gemelli, Catholic Univ., Rome. After exclusion of 26 pts with SVT, analysis was conducted on 289 pts, 38 of them with thrombosis as heralding event (21 AT and 17 VT). Multivariable analysis confirmed JAK2VF VAF >50% (HR 2.3, CI 1.03-5.0, p=0.04) and previous VT (HR 4.5, CI 2.0-10.1; p=0.0003) as independent risk factors for future VT. In pts with VAF >50%, the rate of VT at FU was 19.9% vs 7.7%, P=0.005. KM curve showed that VT-FS was significantly shorter in pts with a JAK2VF VAF >50% (HR 2.2, CI 1.2-4.2; p=0.01) (Figure 1B). Of note, impact of JAK2 VAF>50% on VT at FU was statistically significant particularly in conventionally low-risk pts, accounting for an HR of 9.4 (CI 1.2-72) and HR 3.6 (CI 1.3-10) in Florence and Rome cohorts, respectively. Conclusions: These data support JAK2VF VAF as a strong independent predictor for future venous thrombosis in PV, in association with history of prior venous events, reinforcing that AT and VT are associated with unique risk factors in pts with PV. Supported by AIRC, Project Mynerva n.21267 Figure 1 Figure 1. Disclosures Vannucchi: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

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The risk of venous thrombosis in individuals with a history of superficial vein thrombosis and acquired venous thrombotic risk factors

Blood ◽

10.1182/blood-2013-07-518159 ◽

2013 ◽

Vol 122 (26) ◽

pp. 4264-4269 ◽

Cited By ~ 30

Author(s):

Rachel E. J. Roach ◽

Willem M. Lijfering ◽

Astrid van Hylckama Vlieg ◽

Frans M. Helmerhorst ◽

Frits R. Rosendaal ◽

...

Keyword(s):

Risk Factors ◽

Risk Factor ◽

Venous Thrombosis ◽

Superficial Vein ◽

Thrombotic Risk ◽

Vein Thrombosis ◽

Thrombotic Risk Factor ◽

Key Points ◽

Superficial Vein Thrombosis ◽

History Of

Key Points Superficial vein thrombosis combined with an acquired thrombotic risk factor increases the risk of venous thrombosis 10- to 100-fold. If confirmed, these findings have important implications for the future prevention of venous thrombosis.

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Venous thrombosis and multiple prothrombotic gene defects

Hämostaseologie ◽

10.1055/s-0037-1619580 ◽

2003 ◽

Vol 23 (03) ◽

pp. 117-120

Author(s):

C. Mengis ◽

F. Demarmels Biasiutti

Keyword(s):

Risk Factors ◽

Venous Thrombosis ◽

Thrombotic Event ◽

Prothrombin G20210a ◽

Thrombotic Risk ◽

History Of ◽

Fv Leiden ◽

Gene Defects

SummaryWe describe the case of a 30-year-old woman with homozygous prothrombin G20210A transition and heterozygous FV Leiden mutation and a history of postpartum venous thrombosis. Despite the high thrombotic risk to be assumed in the presence of this combined thrombophilia our patient suffered her first venous thrombotic event only at the age of 29 years during the puerperium of her first pregnancy. This fact supports the concept of venous thrombosis as a multicausal disease, with interaction of genetic and acquired risk factors. The case presented also stresses the importance of performing complete thrombophilia investigation.

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138P The impact of variant allele frequency in EGFR mutated NSCLC patients on targeted therapy

Journal of Thoracic Oncology ◽

10.1016/s1556-0864(21)01980-8 ◽

2021 ◽

Vol 16 (4) ◽

pp. S772

Author(s):

A. Addeo ◽

A. Friedlaender ◽

M. Chevallier ◽

C. De Vito ◽

P. Tsantoulis

Keyword(s):

Targeted Therapy ◽

Allele Frequency ◽

Variant Allele ◽

Variant Allele Frequency ◽

Nsclc Patients ◽

The Impact ◽

Egfr Mutated

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CYP2D6 polymorphisms and the therapeutic outcome with Tamoxifen therapy in breast cancer patients from Kosovo

Macedonian Pharmaceutical Bulletin ◽

10.33320/maced.pharm.bull.2018.64.02.004 ◽

2019 ◽

Vol 64 (02) ◽

pp. 35-42

Author(s):

Selvete Shuleta-Qehaja ◽

Aleksandra Kapedanovska Nestorovska ◽

Zorica Naumovska ◽

Petar Stefanovski ◽

Aleksandar Dimovski ◽

...

Keyword(s):

Breast Cancer ◽

Allele Frequency ◽

Early Stage ◽

Tamoxifen Therapy ◽

Therapeutic Outcome ◽

Variant Allele ◽

Small Scale ◽

Variant Allele Frequency ◽

The Impact ◽

Cyp2d6 Polymorphisms

Tamoxifen is a selective estrogen receptor modulator (SERM) used for the prevention of breast cancer and for the treatment of metastatic and early stage receptor positive breast cancer. It has been shown than tamoxifen is metabolized by the cytochrome P450 2D6 (CYP2D6) enzymes, especially with the CYP26 isoform. The aim of this study was to examine the prevalence of CYP2D6*4, CYP2D6*9 and CYP2D6*10 variants in patients with breast cancer in Kosovo as well as the association between CYP2D6 polymorphisms and the therapeutic outcome in tamoxifen treated patients. The study included 111 patients who were at the age of 25 to 70 years (45.75 ± 9.50). The overall variant allele frequency of CYP2D6*4 was 0.16. The genotypic frequencies of the CYP2D6*4 polymorphism in all patients were 0.02 for *4/*4, 0.28 for *1/*4 and 0.70 for the *1/*1 genotype. The overall CYP2D6*10 variant allele frequency was 0.30 and the frequency of *10/*10, *1/*10 and *1/*1 genotypes was 0.11, 0.37 and 0.52, respectively. In our study, a population of the CYP2D6∗9 variant allele was not detected. In addition, we did not find any correlation between the evaluated genotypes for CYP2D6 polymorphisms and the therapeutic outcome with tamoxifen therapy. Although our study is a rather small- scale compared to large multicentre studies, we believe that it will contribute to determining the impact of CYP2D6 polymorphisms on the success of tamoxifen therapy in patients with a diagnosed breast cancer. Our results are pointing to the direction of the growing number of claims that there is still no strong evidence of any therapeutic connection between the polymorphisms examined and the outcome of the therapy. Keywords: Tamoxifen, breast cancer, CY2D6*4, CYP2D6*9, CYP2D6*10

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Risk factors for early severe preeclampsia in obstetric antiphospholipid syndrome with conventional treatment. The impact of hydroxychloroquine

Lupus ◽

10.1177/0961203320952850 ◽

2020 ◽

Vol 29 (13) ◽

pp. 1736-1742

Author(s):

José Omar Latino ◽

Sebastián Udry ◽

Federico Aranda ◽

Silvia Perés Wingeyer ◽

Diego Santiago Fernández Romero ◽

...

Keyword(s):

Risk Factors ◽

High Risk ◽

Antiphospholipid Syndrome ◽

Conventional Treatment ◽

Severe Preeclampsia ◽

Factors Associated ◽

High Risk Factors ◽

History Of ◽

Obstetric Antiphospholipid Syndrome ◽

The Impact

Objective The first aim was to retrospectively identify risk factors for the development of early severe preeclampsia (sPE) in patients with obstetric antiphospholipid syndrome (OAPS) who received conventional treatment (CT). The second aim was to evaluate the impact of hydroxychloroquine (HCQ) in preventing early sPE among a subgroup of patients considered at high risk. Methods A total of 102 women diagnosed with OAPS and treated with CT since the diagnosis of pregnancy were selected. At the end of pregnancy, we identified risk factors associated with early sPE. According to these risk factors, we collected a new cohort of 42 patients who presented high-risk factors for developing early sPE and split them into two groups according to the treatment received: group A, CT (30 patients); and group B, CT+HCQ (12 patients). We evaluated and compared pregnancy outcomes in both groups. Results According to the multivariate analysis, risk factors associated with early sPE and CT were triple positivity for antiphospholipid antibodies (aPL) (OR = 24.70, [4.27–142.92], p < 0.001) and a history of early sPE (OR = 7.11, [1.13–44.64], p = 0.036). A low-risk aPL profile was associated with a good response to CT in preventing early sPE (OR = 0.073, [0.014–0.382], p = 0.002). High-risk patients treated with CT+HCQ had a significantly lower early sPE rate than those treated with CT only (8.3% vs 40.0%; p = 0.03). Conclusion Triple positivity for aPL and a history of early sPE are potential strong risk factors for the development of early sPE. HCQ might be an interesting therapeutic option for patients with high-risk factors for early sPE.

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Allogeneic Hematopoietic Transplantation in Patients with CLL: Results of a Large Disease-Specific Risk Factor Analysis

Blood ◽

10.1182/blood.v126.23.3209.3209 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3209-3209

Author(s):

Johannes Schetelig ◽

Liesbeth de Wreede ◽

Michel van Gelder ◽

Niels Smedegaard Andersen ◽

Carol Moreno ◽

...

Keyword(s):

Risk Factors ◽

High Risk ◽

Disease Control ◽

Karnofsky Performance Status ◽

Performance Status ◽

Risk Profile ◽

Poor Risk ◽

History Of ◽

The Impact

Abstract Objectives: For medically-fit young patients with high-risk chronic lymphocytic leukemia (CLL) BTK-/PI3K-inhibitors or allogeneic stem cell transplantation (alloHCT) are considered. We hypothesized that given the choice between these drugs and transplantation in future only patients with a low risk of treatment failure will be selected for alloHCT. Therefore, we searched for risk factors for 2-year non-relapse mortality (NRM) and 5-year event-free survival (EFS) after alloHCT, the latter as a surrogate for long-term disease-control. Methods: Data from patients with CLL who had received a first alloHCT from a HLA-identical sibling (SIB) or unrelated donor between 2000 and 2011 were updated in an EBMT data quality initiative. Multivariable Cox regression models were fitted to assess the impact of baseline risk factors for NRM and EFS. Results: Data on 694 patients were included into the analysis. The median age of the cohort of patients was 55 years (19 years to 74 years). Seventy-nine percent of patients had a Karnofsky performance status of 90% or higher. A disease history of less than two years was reported in 20% of patients and 44% of patients had a disease history of more than 5 years. The median number of pretreatments was 3 (range, 0-15). Eleven percent of patients had received a previous autologous HCT. Only 9% of patients had never received purine-analogs (PA) during their treatment history. Sixty-three percent of patients had either PA-refractory disease or relapse within 24 months from the last PA-containing chemotherapy at the time of HCT. A deletion 17p had been diagnosed in 28% of patients in this cohort. Information on PA-sensitivity, early relapse after autologous transplantation or PA-combination therapy and del(17p)/TP53 is used to select patients for allogeneic HCT according to the EBMT 2007 consensus. EBMT consensus criteria were met in 76% of evaluable patients. Overall, the majority of patients analyzed in this subset of all registered patients had high-risk CLL. For the whole cohort 2-year NRM was 28% (95%-CI, 24% to 32%). The baseline risk factors age, Karnofsky performance status, donor type, and donor-recipient sex mismatch had a significant impact on 2-year-NRM. With the help of these risk factors the outcome of good risk and poor risk reference patients was predicted whose linear predictors were close to the 10th and the 90th percentile of all patients in the dataset. The good risk male reference patient has an age of 45 years, a Karnofsky performance index of 100%, is in partial remission at HCT and has a matched related male donor. The poor risk male reference patient has 55 years of age a Karnofsky performance index of 80%, SD/PD at HCT, and a matched unrelated female donor. The female reference patients had the same characteristics, apart from the donor sex. Two-year-NRM was predicted to be 11% (12%) for male (female) patients with a favorable risk compared to 40% (32%) with a poor risk profile (see Figure). The same approach was used to analyze risk factors for long-term disease control. Five-year-EFS was 37% (95%-CI, 33% to 41%) for all patients. Age, Karnofsky performance status, history of an autologous HCT, remission status, and donor-recipient sex mismatch had a significant impact. The model-based prediction of 5-year EFS was 54% (64%) for a male (female) patient with a favorable risk profile compared to 15% (30%) with a poor risk profile. Current knowledge suggests that allogeneic HCT can overcome the negative prognostic impact of high risk cytogenetic abnormalities, especially of a deletion(17p) or TP53 -mutation. Even in this large cohort we observed only a trend for a lower incidence of relapse/progression in patients without deletion(17p) CLL within the first two years after HCT with translated into a trend for better EFS at that time. The impact on long-term disease-control and mortality was even smaller. Conclusion: Information on predicted 2-year-NRM and 5-year-EFS for good and poor risk reference patients derived from a large CLL dataset may be instrumental to select patients for future alloHCT. Model-based prediction of non-relapse mortality and relapse/progression. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.

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Stress, Cortisol and Suicide Risk

10.31234/osf.io/92b7z ◽

2019 ◽

Author(s):

Daryl Brian O'Connor

Keyword(s):

Risk Factors ◽

Suicidal Behavior ◽

Suicide Risk ◽

Stressful Events ◽

Additional Risk ◽

Global Health Issue ◽

History Of ◽

Hpa Axis Activity ◽

The Impact

Suicide is a global health issue accounting for at least 800,000 deaths per annum. Numerous models have been proposed that differ in their emphasis on the role of psychological, social, psychiatric and neurobiological factors in explaining suicide risk. Central to many models is a stress-diathesis component which states that suicidal behavior is the result of an interaction between acutely stressful events and a susceptibility to suicidal behavior (a diathesis). This article presents an overview of studies that demonstrate that stress and dysregulated hypothalamic-pituitary-adrenal (HPA) axis activity, as measured by cortisol levels, are important additional risk factors for suicide. Evidence for other putative stress-related suicide risk factors including childhood trauma, impaired executive function, impulsivity and disrupted sleep are considered together with the impact of family history of suicide, perinatal and epigenetic influences on suicide risk.

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Examination of the predicted prevalence of Gitelman syndrome by ethnicity based on genome databases

Scientific Reports ◽

10.1038/s41598-021-95521-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Atsushi Kondo ◽

China Nagano ◽

Shinya Ishiko ◽

Takashi Omori ◽

Yuya Aoto ◽

...

Keyword(s):

Allele Frequency ◽

Carrier Frequency ◽

Japanese Population ◽

Autosomal Recessive ◽

Disease Prevalence ◽

Gitelman Syndrome ◽

Variant Allele ◽

Variant Allele Frequency ◽

Genome Databases ◽

Heterozygous Carriers

AbstractGitelman syndrome is an autosomal recessive inherited salt-losing tubulopathy. It has a prevalence of around 1 in 40,000 people, and heterozygous carriers are estimated at approximately 1%, although the exact prevalence is unknown. We estimated the predicted prevalence of Gitelman syndrome based on multiple genome databases, HGVD and jMorp for the Japanese population and gnomAD for other ethnicities, and included all 274 pathogenic missense or nonsense variants registered in HGMD Professional. The frequencies of all these alleles were summed to calculate the total variant allele frequency in SLC12A3. The carrier frequency and the disease prevalence were assumed to be twice and the square of the total allele frequency, respectively, according to the Hardy–Weinberg principle. In the Japanese population, the total carrier frequencies were 0.0948 (9.5%) and 0.0868 (8.7%) and the calculated prevalence was 0.00225 (2.3 in 1000 people) and 0.00188 (1.9 in 1000 people) in HGVD and jMorp, respectively. Other ethnicities showed a prevalence varying from 0.000012 to 0.00083. These findings indicate that the prevalence of Gitelman syndrome in the Japanese population is higher than expected and that some other ethnicities also have a higher prevalence than has previously been considered.

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