title: Genetic association between germline JAK2 polymorphisms and myeloproliferative neoplasms in Hong Kong Chinese population: a case-control study.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.forename: Su Pin
authors.initials: SP
authors.lastname: Koh
authors.forename: Shea Ping
authors.initials: SP
authors.lastname: Yip
authors.forename: Kwok Kuen
authors.initials: KK
authors.lastname: Lee
authors.forename: Chi Chung
authors.initials: CC
authors.lastname: Chan
authors.forename: Sze Man
authors.initials: SM
authors.lastname: Lau
authors.forename: Chi Shan
authors.initials: CS
authors.lastname: Kho
authors.forename: Chi Kuen
authors.initials: CK
authors.lastname: Lau
authors.forename: Shek Ying
authors.initials: SY
authors.lastname: Lin
authors.forename: Yat Ming
authors.initials: YM
authors.lastname: Lau
authors.forename: Lap Gate
authors.initials: LG
authors.lastname: Wong
authors.forename: Ka Leung
authors.initials: KL
authors.lastname: Au
authors.forename: Kit Fai
authors.initials: KF
authors.lastname: Wong
authors.forename: Raymond W
authors.initials: RW
authors.lastname: Chu
authors.forename: Pui Hung
authors.initials: PH
authors.lastname: Yu
authors.forename: Eudora Y D
authors.initials: EY
authors.lastname: Chow
authors.forename: Kate F S
authors.initials: KF
authors.lastname: Leung
authors.forename: Wai Chiu
authors.initials: WC
authors.lastname: Tsoi
authors.forename: Benjamin Y M
authors.initials: BY
authors.lastname: Yung
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000235:genetics*; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006239:Haplotypes; D006723:Hong Kong; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009196:Myeloproliferative Disorders / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: C507924:JAK2 protein, human; D053614:Janus Kinase 2