To the editor:

We read with interest the recently published report by Smalberg et al, which describes the frequency of the JAK2 46/1 haplotype among patients with splanchnic vein thrombosis (SVT).1  Indeed, recent studies revealed that the 46/1 haplotype located in the JAK2 gene is strongly associated with the development of a JAK2V617F (JAK2VF)–positive myeloproliferative neoplasm (MPN)2-4  but also with JAK2 exon 12– or MPL gene mutation–positive MPNs.5,6 

We studied this haplotype in a cohort of 170 patients with SVT (sex ratio M/F = 1.12). Approval was obtained from the PV-Nord Institutional Review Board. Informed consent was obtained in accordance with the Declaration of Helsinki. As controls we studied 58 non-MPN patients with peripheral vein thrombosis (PVT) and 31 patients with JAK2VF-positive polycythemia vera (PV). We studied 2 tag single-nucleotide polymorphisms (rs10974944 and rs12343867) on peripheral blood DNA using Taqman allelic discrimination assays (Applied Biosystems). In 170 patients with SVT, the frequency of the 46/1 haplotype was 0.28 (Table 1), which is not significantly different from the published population controls from the Wellcome Trust Case Control Consortium (WTCCC) (0.24; P = .11 by the Fisher exact test). Thus, in accordance with Smalberg et al, our results suggest that the 46/1 haplotype is not a susceptibility locus for the development of SVT.

Table 1

Frequency of the single-nucleotide polymorphism genotype among patients

No. of patientsrs10974944 genotype
G allele frequency% of 46/1 haplotypeP*
CC, n (%)CG, n (%)GG, n (%)
Splanchnic vein thrombosis 170 89 (52) 67 (40) 14 (8) 0.28 48 .11 
    V617F positive 75 40 (53) 29 (39) 6 (8) 0.27 47  
    V617F negative 95 49 (52) 38 (40) 8 (8) 0.28 48  
Polycythemia vera patients (V617F positive) 31 7 (22) 16 (52) 8 (26) 0.52 77 .0005 
Peripheral vein thrombosis patients 58 36 (62) 19 (33) 3 (5) 0.22 38 .24 
No. of patientsrs10974944 genotype
G allele frequency% of 46/1 haplotypeP*
CC, n (%)CG, n (%)GG, n (%)
Splanchnic vein thrombosis 170 89 (52) 67 (40) 14 (8) 0.28 48 .11 
    V617F positive 75 40 (53) 29 (39) 6 (8) 0.27 47  
    V617F negative 95 49 (52) 38 (40) 8 (8) 0.28 48  
Polycythemia vera patients (V617F positive) 31 7 (22) 16 (52) 8 (26) 0.52 77 .0005 
Peripheral vein thrombosis patients 58 36 (62) 19 (33) 3 (5) 0.22 38 .24 

WTCCC indicates Wellcome Trust Case Control Consortium.

*

Comparison with the WTCCC controls.

In our control populations, the frequency of the 46/1 haplotype was similar to the WTCCC controls in 58 non-MPN patients with PVT (P = .24) and was significantly higher in the group of 31 JAK2VF-positive PV patients (0.52; P = .0005), in agreement with previous studies.2-4  However, we found no difference in the frequency of the 46/1 haplotype between JAK2VF-positive (0.27; n = 75) and JAK2VF-negative patients (0.28; n = 95) (P = .90). This finding is in contrast with the study by Smalberg et al, which reported a significantly higher frequency of the 46/1 haplotype in 54 patients with JAK2VF-positive SVT compared with controls (0.43 vs 0.27, respectively; P < .01).

The discrepancy between the 2 studies may depend on the populations studied. The proportion of JAK2VF-positive versus -negative patients is higher in our study (75/95 vs 54/145), making it possible that the high 46/1 haplotype frequency found by Smalberg et al would not be confirmed in a larger cohort with greater statistical power. Next, it recently appeared that the 46/1 haplotype frequency is correlated with the JAK2VF allele burden, VF-positive patients with low mutation burden displaying 46/1 haplotype frequency similar to VF-negative patients.7-9  In our study, concordantly with the literature,10  mutant allele burden was < 50% in 89% of patients (median: 19%) whereas in the study by Smalberg et al, JAK2VF allele burden was available in 45 patients only. In summary, in a larger cohort of JAK2VF-positive patients with comprehensive mutant allele burden data, we did not confirm the higher frequency of the 46/1 haplotype in SVT patients with MPNs found by Smalberg et al.

Acknowledgments: We thank Bernard Grandchamp for helpful discussion during results interpretation.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Jean-Jacques Kiladjian, Centre d'Investigations Cliniques, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75010 Paris, France; e-mail: jean-jacques.kiladjian@sls.aphp.fr.

1
Smalberg
 
JH
Koehler
 
E
Murad
 
SD
, et al. 
The JAK2 46/1 haplotype in Budd-Chiari syndrome and portal vein thrombosis.
Blood
2011
, vol. 
117
 
15
(pg. 
3968
-
3973
)
2
Olcaydu
 
D
Harutyunyan
 
A
Jäger
 
R
, et al. 
A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms.
Nat Genet
2009
, vol. 
41
 
4
(pg. 
450
-
454
)
3
Kilpivaara
 
O
Mukherjee
 
S
Schram
 
AM
, et al. 
A germline JAK2 SNP is associated with predisposition to the development of JAK2(V617F)-positive myeloproliferative neoplasms.
Nat Genet
2009
, vol. 
41
 
4
(pg. 
455
-
459
)
4
Jones
 
AV
Chase
 
A
Silver
 
RT
, et al. 
JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms.
Nat Genet
2009
, vol. 
41
 
4
(pg. 
446
-
449
)
5
Olcaydu
 
D
Skoda
 
RC
Looser
 
R
, et al. 
The ‘GGCC’ haplotype of JAK2 confers susceptibility to JAK2 exon 12 mutation-positive polycythemia vera.
Leukemia
2009
, vol. 
23
 
10
(pg. 
1924
-
1926
)
6
Jones
 
AV
Campbell
 
PJ
Beer
 
PA
, et al. 
The JAK2 46/1 haplotype predisposes to MPL-mutated myeloproliferative neoplasms.
Blood
2010
, vol. 
115
 
22
(pg. 
4517
-
4523
)
7
Tefferi
 
A
Lasho
 
TL
Patnaik
 
MM
, et al. 
JAK2 germline genetic variation affects disease susceptibility in primary myelofibrosis regardless of V617F mutational status: nullizygosity for the JAK2 46/1 haplotype is associated with inferior survival.
Leukemia
2010
, vol. 
24
 
1
(pg. 
105
-
109
)
8
Guglielmelli
 
P
Biamonte
 
F
Spolverini
 
A
, et al. 
Frequency and clinical correlates of JAK2 46/1 (GGCC) haplotype in primary myelofibrosis.
Leukemia
2010
, vol. 
24
 
8
(pg. 
1533
-
1537
)
9
Trifa
 
AP
Cucuianu
 
A
Petrov
 
L
, et al. 
The G allele of the JAK2 rs10974944 SNP, part of JAK2 46/1 haplotype, is strongly associated with JAK2 V617F-positive myeloproliferative neoplasms.
Ann Hematol
2010
, vol. 
89
 
10
(pg. 
979
-
983
)
10
Kiladjian
 
J-J
Cervantes
 
F
Leebeek
 
FW
, et al. 
The impact of JAK2 and MPL mutations on diagnosis and prognosis of splanchnic vein thrombosis: a report on 241 cases.
Blood
2008
, vol. 
111
 
10
(pg. 
4922
-
4929
)
Sign in via your Institution