Cargando…

Genetic association between germline JAK2 polymorphisms and myeloproliferative neoplasms in Hong Kong Chinese population: a case–control study

BACKGROUND: Myeloproliferative neoplasms (MPNs) are a group of haematological malignancies that can be characterised by a somatic mutation (JAK2V617F). This mutation causes the bone marrow to produce excessive blood cells and is found in polycythaemia vera (~95%), essential thrombocythaemia and prim...

Descripción completa

Detalles Bibliográficos
Autores principales: Koh, Su Pin, Yip, Shea Ping, Lee, Kwok Kuen, Chan, Chi Chung, Lau, Sze Man, Kho, Chi Shan, Lau, Chi Kuen, Lin, Shek Ying, Lau, Yat Ming, Wong, Lap Gate, Au, Ka Leung, Wong, Kit Fai, Chu, Raymond W, Yu, Pui Hung, Chow, Eudora YD, Leung, Kate FS, Tsoi, Wai Chiu, Yung, Benjamin YM
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293821/
https://www.ncbi.nlm.nih.gov/pubmed/25526816
http://dx.doi.org/10.1186/s12863-014-0147-y
_version_ 1782352652746620928
author Koh, Su Pin
Yip, Shea Ping
Lee, Kwok Kuen
Chan, Chi Chung
Lau, Sze Man
Kho, Chi Shan
Lau, Chi Kuen
Lin, Shek Ying
Lau, Yat Ming
Wong, Lap Gate
Au, Ka Leung
Wong, Kit Fai
Chu, Raymond W
Yu, Pui Hung
Chow, Eudora YD
Leung, Kate FS
Tsoi, Wai Chiu
Yung, Benjamin YM
author_facet Koh, Su Pin
Yip, Shea Ping
Lee, Kwok Kuen
Chan, Chi Chung
Lau, Sze Man
Kho, Chi Shan
Lau, Chi Kuen
Lin, Shek Ying
Lau, Yat Ming
Wong, Lap Gate
Au, Ka Leung
Wong, Kit Fai
Chu, Raymond W
Yu, Pui Hung
Chow, Eudora YD
Leung, Kate FS
Tsoi, Wai Chiu
Yung, Benjamin YM
author_sort Koh, Su Pin
collection PubMed
description BACKGROUND: Myeloproliferative neoplasms (MPNs) are a group of haematological malignancies that can be characterised by a somatic mutation (JAK2V617F). This mutation causes the bone marrow to produce excessive blood cells and is found in polycythaemia vera (~95%), essential thrombocythaemia and primary myelofibrosis (both ~50%). It is considered as a major genetic factor contributing to the development of these MPNs. No genetic association study of MPN in the Hong Kong population has so far been reported. Here, we investigated the relationship between germline JAK2 polymorphisms and MPNs in Hong Kong Chinese to find causal variants that contribute to MPN development. We analysed 19 tag single nucleotide polymorphisms (SNPs) within the JAK2 locus in 172 MPN patients and 470 healthy controls. Three of these 19 SNPs defined the reported JAK2 46/1 haplotype: rs10974944, rs12343867 and rs12340895. Allele and haplotype frequencies were compared between patients and controls by logistic regression adjusted for sex and age. Permutation test was used to correct for multiple comparisons. With significant findings from the 19 SNPs, we then examined 76 additional SNPs across the 148.7-kb region of JAK2 via imputation with the SNP data from the 1000 Genomes Project. RESULTS: In single-marker analysis, 15 SNPs showed association with JAK2V617F-positive MPNs (n = 128), and 8 of these were novel MPN-associated SNPs not previously reported. Exhaustive variable-sized sliding-window haplotype analysis identified 184 haplotypes showing significant differences (P < 0.05) in frequencies between patients and controls even after multiple-testing correction. However, single-marker alleles exhibited the strongest association with V617F-positive MPNs. In local Hong Kong Chinese, rs12342421 showed the strongest association signal: asymptotic P = 3.76 × 10(−15), empirical P = 2.00 × 10(−5) for 50,000 permutations, OR = 3.55 for the minor allele C, and 95% CI, 2.59-4.87. Conditional logistic regression also signified an independent effect of rs12342421 in significant haplotype windows, and this independent effect remained unchanged even with the imputation of additional 76 SNPs. No significant association was found between V617F-negative MPNs and JAK2 SNPs. CONCLUSION: With a large sample size, we reported the association between JAK2V617F-positive MPNs and 15 tag JAK2 SNPs and the association of rs12342421 being independent of the JAK2 46/1 haplotype in Hong Kong Chinese population. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12863-014-0147-y) contains supplementary material, which is available to authorized users.
format Online
Article
Text
id pubmed-4293821
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-42938212015-01-15 Genetic association between germline JAK2 polymorphisms and myeloproliferative neoplasms in Hong Kong Chinese population: a case–control study Koh, Su Pin Yip, Shea Ping Lee, Kwok Kuen Chan, Chi Chung Lau, Sze Man Kho, Chi Shan Lau, Chi Kuen Lin, Shek Ying Lau, Yat Ming Wong, Lap Gate Au, Ka Leung Wong, Kit Fai Chu, Raymond W Yu, Pui Hung Chow, Eudora YD Leung, Kate FS Tsoi, Wai Chiu Yung, Benjamin YM BMC Genet Research Article BACKGROUND: Myeloproliferative neoplasms (MPNs) are a group of haematological malignancies that can be characterised by a somatic mutation (JAK2V617F). This mutation causes the bone marrow to produce excessive blood cells and is found in polycythaemia vera (~95%), essential thrombocythaemia and primary myelofibrosis (both ~50%). It is considered as a major genetic factor contributing to the development of these MPNs. No genetic association study of MPN in the Hong Kong population has so far been reported. Here, we investigated the relationship between germline JAK2 polymorphisms and MPNs in Hong Kong Chinese to find causal variants that contribute to MPN development. We analysed 19 tag single nucleotide polymorphisms (SNPs) within the JAK2 locus in 172 MPN patients and 470 healthy controls. Three of these 19 SNPs defined the reported JAK2 46/1 haplotype: rs10974944, rs12343867 and rs12340895. Allele and haplotype frequencies were compared between patients and controls by logistic regression adjusted for sex and age. Permutation test was used to correct for multiple comparisons. With significant findings from the 19 SNPs, we then examined 76 additional SNPs across the 148.7-kb region of JAK2 via imputation with the SNP data from the 1000 Genomes Project. RESULTS: In single-marker analysis, 15 SNPs showed association with JAK2V617F-positive MPNs (n = 128), and 8 of these were novel MPN-associated SNPs not previously reported. Exhaustive variable-sized sliding-window haplotype analysis identified 184 haplotypes showing significant differences (P < 0.05) in frequencies between patients and controls even after multiple-testing correction. However, single-marker alleles exhibited the strongest association with V617F-positive MPNs. In local Hong Kong Chinese, rs12342421 showed the strongest association signal: asymptotic P = 3.76 × 10(−15), empirical P = 2.00 × 10(−5) for 50,000 permutations, OR = 3.55 for the minor allele C, and 95% CI, 2.59-4.87. Conditional logistic regression also signified an independent effect of rs12342421 in significant haplotype windows, and this independent effect remained unchanged even with the imputation of additional 76 SNPs. No significant association was found between V617F-negative MPNs and JAK2 SNPs. CONCLUSION: With a large sample size, we reported the association between JAK2V617F-positive MPNs and 15 tag JAK2 SNPs and the association of rs12342421 being independent of the JAK2 46/1 haplotype in Hong Kong Chinese population. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12863-014-0147-y) contains supplementary material, which is available to authorized users. BioMed Central 2014-12-20 /pmc/articles/PMC4293821/ /pubmed/25526816 http://dx.doi.org/10.1186/s12863-014-0147-y Text en © Koh et al.; licensee BioMed Central. 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Koh, Su Pin
Yip, Shea Ping
Lee, Kwok Kuen
Chan, Chi Chung
Lau, Sze Man
Kho, Chi Shan
Lau, Chi Kuen
Lin, Shek Ying
Lau, Yat Ming
Wong, Lap Gate
Au, Ka Leung
Wong, Kit Fai
Chu, Raymond W
Yu, Pui Hung
Chow, Eudora YD
Leung, Kate FS
Tsoi, Wai Chiu
Yung, Benjamin YM
Genetic association between germline JAK2 polymorphisms and myeloproliferative neoplasms in Hong Kong Chinese population: a case–control study
title Genetic association between germline JAK2 polymorphisms and myeloproliferative neoplasms in Hong Kong Chinese population: a case–control study
title_full Genetic association between germline JAK2 polymorphisms and myeloproliferative neoplasms in Hong Kong Chinese population: a case–control study
title_fullStr Genetic association between germline JAK2 polymorphisms and myeloproliferative neoplasms in Hong Kong Chinese population: a case–control study
title_full_unstemmed Genetic association between germline JAK2 polymorphisms and myeloproliferative neoplasms in Hong Kong Chinese population: a case–control study
title_short Genetic association between germline JAK2 polymorphisms and myeloproliferative neoplasms in Hong Kong Chinese population: a case–control study
title_sort genetic association between germline jak2 polymorphisms and myeloproliferative neoplasms in hong kong chinese population: a case–control study
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293821/
https://www.ncbi.nlm.nih.gov/pubmed/25526816
http://dx.doi.org/10.1186/s12863-014-0147-y
work_keys_str_mv AT kohsupin geneticassociationbetweengermlinejak2polymorphismsandmyeloproliferativeneoplasmsinhongkongchinesepopulationacasecontrolstudy
AT yipsheaping geneticassociationbetweengermlinejak2polymorphismsandmyeloproliferativeneoplasmsinhongkongchinesepopulationacasecontrolstudy
AT leekwokkuen geneticassociationbetweengermlinejak2polymorphismsandmyeloproliferativeneoplasmsinhongkongchinesepopulationacasecontrolstudy
AT chanchichung geneticassociationbetweengermlinejak2polymorphismsandmyeloproliferativeneoplasmsinhongkongchinesepopulationacasecontrolstudy
AT lauszeman geneticassociationbetweengermlinejak2polymorphismsandmyeloproliferativeneoplasmsinhongkongchinesepopulationacasecontrolstudy
AT khochishan geneticassociationbetweengermlinejak2polymorphismsandmyeloproliferativeneoplasmsinhongkongchinesepopulationacasecontrolstudy
AT lauchikuen geneticassociationbetweengermlinejak2polymorphismsandmyeloproliferativeneoplasmsinhongkongchinesepopulationacasecontrolstudy
AT linshekying geneticassociationbetweengermlinejak2polymorphismsandmyeloproliferativeneoplasmsinhongkongchinesepopulationacasecontrolstudy
AT lauyatming geneticassociationbetweengermlinejak2polymorphismsandmyeloproliferativeneoplasmsinhongkongchinesepopulationacasecontrolstudy
AT wonglapgate geneticassociationbetweengermlinejak2polymorphismsandmyeloproliferativeneoplasmsinhongkongchinesepopulationacasecontrolstudy
AT aukaleung geneticassociationbetweengermlinejak2polymorphismsandmyeloproliferativeneoplasmsinhongkongchinesepopulationacasecontrolstudy
AT wongkitfai geneticassociationbetweengermlinejak2polymorphismsandmyeloproliferativeneoplasmsinhongkongchinesepopulationacasecontrolstudy
AT churaymondw geneticassociationbetweengermlinejak2polymorphismsandmyeloproliferativeneoplasmsinhongkongchinesepopulationacasecontrolstudy
AT yupuihung geneticassociationbetweengermlinejak2polymorphismsandmyeloproliferativeneoplasmsinhongkongchinesepopulationacasecontrolstudy
AT choweudorayd geneticassociationbetweengermlinejak2polymorphismsandmyeloproliferativeneoplasmsinhongkongchinesepopulationacasecontrolstudy
AT leungkatefs geneticassociationbetweengermlinejak2polymorphismsandmyeloproliferativeneoplasmsinhongkongchinesepopulationacasecontrolstudy
AT tsoiwaichiu geneticassociationbetweengermlinejak2polymorphismsandmyeloproliferativeneoplasmsinhongkongchinesepopulationacasecontrolstudy
AT yungbenjaminym geneticassociationbetweengermlinejak2polymorphismsandmyeloproliferativeneoplasmsinhongkongchinesepopulationacasecontrolstudy