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High prevalence of the germline JAK2 46/1 haplotype and V617-mutationin Swedish patients with Budd-Chiari syndrome and Portal Vein Thrombosis
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences.
Department of Gastroenterology & Hepatology, Karolinska University Hospital, Stockholm.
Division of Gastroenterology & Hepatology, University Hospital, Lund.
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2010 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Background & Aims: To determine the prevalence of the somatic JAK2 V617F mutation and distribution of the germline JAK2 46/1 haplotype in Budd-Chiari Syndrome (BCS) and portal vein thrombosis (PVT).

Methods: Real-time PCR was performed to genotype for the JAK2V 617F mutation and the 46/1 haplotype (tag-SNPs rs12343867, T>C and rs12340895, C>G) in blood samples of 19 BCS and 91 PVT patients (without intra-abdominal malignancy), and 283 controls from a background population.

Results: The prevalence of JAK2 V617F-mutation was 63% in BCS and 14% in PVT patients. 10% in BCS and 2% in PVT had V617F negative MPD. Conversely, V617F positive subjects without known MPD was found in 5% of the BCS and in 1% of PVT patients. The frequency of the JAK2 46/1 haplotype was significantly higher in BCS (53%) and PVT (36%) patients compared to controls (27%) (p=0.02; OR=3.0; 95% CI 1.5-5.9 and OR=1.51; 95% CI 1.1-2.1, respectively). In PVT patients the JAK2 haplotype was highly enriched in non-cirrhotic patients (41%) (p <0.01 ; OR=1.8; 95% CI 1.2-2.6) but not in cirrhotic patients (23%) (p=0.53 ; OR= 0.8; 95% CI 0.4-1.7). An increased JAK2 46/1 haplotype frequency was evident only in V617F mutation positive patients.

Conclusions: The prevalence of JAK2 V617F was high in BCS (63%) and non-cirrhotic PVT (14%), facilitating detection of latent MPD. A negative result dose not rule out MPD. The occurrence of the JAK2 46/1 haplotype was significantly higher in V617F mutation positive patients but not in mutation negative patients, suggesting that the haplotype may not have an independent role separated from the V617F mutation in BCS and PVT patients.

Place, publisher, year, edition, pages
2010. Vol. 52, no 4, 912A-912A p.
Keyword [en]
Budd-Chiari syndrome; Portal vein thrombosis; Myeloproliferative disorders; JAK2 V617F mutation; JAK2 46/1 haplotype; Thrombophilia; Liver cirrhosis
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-68726OAI: oai:DiVA.org:liu-68726DiVA: diva2:420249
Available from: 2011-05-31 Created: 2011-05-31 Last updated: 2011-05-31Bibliographically approved
In thesis
1. Hepatic and Portal Vein Thrombosis: studies on epidemiology and risk factors
Open this publication in new window or tab >>Hepatic and Portal Vein Thrombosis: studies on epidemiology and risk factors
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Budd-Chiari syndrome (BCS) i.e. thrombosis in the hepatic veins and/or inferior vena cava, and portal vein thrombosis (PVT) are rare disorders. Epidemiological data are scarce and previous reports have been from highly specialised referral centres.

The aims of the thesis were: (i) to investigate the epidemiology, clinical features and survival of Swedish patients with BCS or PVT, and to (ii) determine common underlying risk factors i.e. thrombophilic factors and genetic markers of myeloproliferative disorders (MPD).

In the first two papers we retrospectively reviewed the medical records of all BCS (1986-2003) and PVT (1995-2004) patients identified by searching the computerized patient registers of 11 hospitals including all university hospitals and liver transplantation units. In the following two papers we excluded patients with malignancy and included new cases diagnosed during the years 2004-2009; blood samples were collected and compared with controls and other patient groups.

A total of 43 patients with BCS were identified (median age 40 years, 24 women). The mean agestandardised incidence and prevalence rates were 0.8 per million per year and 1.4 per million inhabitants respectively. Two or more risk factors were present in 44%. The overall transplantationfree survival at 1, 5 and 10 years was 47%, 28% and 17% respectively.

173 patients (median age 57 years, 93 men) with portal vein thrombosis were identified. The incidence and prevalence rates were 0.7 per 100 000 per year and 3.7 per 100 000 inhabitants, respectively. In the absence of cirrhosis and malignancy, being the most common risk factors, the survival at 1 year and 5 years was 92% and 76%, respectively.

We observed an increased plasma level of the procoagulant factor VIII in BCS (mean 1.63 kIE/L), PVT without cirrhosis (1.87 kIE/L), PVT with cirrhosis (1.97 kIE/L), deep vein thrombosis (1.41 kIE/L) and cirrhosis patients alone (2.22 kIE/L), all p <0.001 compared to healthy controls (1.04 kIE/L). Elevated factor VIII levels were found in 50% of BCS and in 85% of PVT patients without previously identified prothrombotic risk factors.

The somatic JAK2 V617F-mutation, a marker of MPD, was present in 63% of BCS and 14% of PVT patients. The frequency of the germline JAK2 46/1 haplotype was significantly higher in BCS (53%) and PVT (36%) patients compared to controls (27%) (p=0.02). However, the enrichment was only observed in JAK2 V617F positive patients.

Conclusions: The incidence and prevalence rates of BCS in Sweden were calculated to be 0.8/million inhabitants per year and 1.4/million inhabitants, respectively. The rates of PVT were higher; 0.7/100 000 inhabitants per year and 3.7/100 000 inhabitants, respectively. In BCS the transplantation-free survival was poor, whereas in PVT the survival was variable and highly dependent on the presence of underlying disease. Concurrent prothrombotic risk factors are common in both disorders. High plasma levels of procoagulant factor VIII was observed in a majority of idiopathic BCS and PVT. The prevalence of the somatic JAK2 V617F mutation was high in our cohort and associated with the presence of a germline JAK2 46/1 haplotype.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2011. 70 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1241
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-68727 (URN)978-91-7393-187-8 (ISBN)
Public defence
2011-06-09, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 13:00 (English)
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Supervisors
Available from: 2011-05-31 Created: 2011-05-31 Last updated: 2012-03-22Bibliographically approved

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Rajani, RupeshHaglund, SofieVerbaan, HansLindahl, TomasAlmer, Sven

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