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 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.

Chronic ulcerative gastroduodenitis as a first gastrointestinal manifestation of Hermansky-Pudlak syndrome in a 10-year-old child.

A 10-year-old Chinese boy who had a history of congenital thrombocytopathy presented with severe iron deficiency anemia secondary to chronic gastric inflammation and duodenal ulcerations. Subtle oculocutaneous albinism led to the finding of diminished dense bodies in the platelets under electron microscopy, hence the diagnosis of Hermansky-Pudlak syndrome (HPS). Biopsies from the stomach and duodenum revealed a lymphocytic infiltration in the submucosa, but H pylori infection was absent. The gastroduodenitis responded to the treatment with omeprazole while iron deficiency anemia was corrected by oral iron therapy. HPS is a rare cause of congenital bleeding disorder with multisystemic manifestations. Upper gastrointestinal involvement is rare and should be distinguished from a mere manifestation of the bleeding diathesis.

Long-term outcome of 231 patients with essential thrombocythemia: prognostic factors for thrombosis, bleeding, myelofibrosis, and leukemia.

BACKGROUND: Essential thrombocythemia (ET) is a clonal myeloproliferative disease associated with thrombohemorrhagic complications and myeloid transformation to diseases such as myelofibrosis and acute myeloid leukemia. METHODS: A multicenter study was conducted among 231 consecutive Chinese patients with ET. The literature about leukemogenic risk associated with the use of hydroxyurea therapy was reviewed. RESULTS: The median patient age was 65 years. Thrombosis rates at and after diagnosis of ET were comparable to those of white patients, but bleeding rates at and after diagnosis were much lower. The projected 10-year thrombosis-free, bleeding-free, and overall survival rates were 66%, 83%, and 80%, respectively. There were no deaths among patients 60 years or younger during a maximum follow-up of 15 years, and splenomegaly at diagnosis of ET appeared to protect against thrombosis. In multivariate analysis, advanced age predicted inferior 10-year thrombosis-free and overall survival, and male sex predicted inferior bleeding-free survival. Half the deaths were related to ET. The probability of myelofibrosis transformation was 9.7% at 10 years. Prior myelofibrosis (P = .008) and the use of melphalan treatment (P = .002) were risk factors for acute myeloid leukemia evolution. CONCLUSIONS: Essential thrombocythemia is a benign disease of older persons. Chinese patients have a low risk of bleeding, and prior myelofibrosis is a major risk factor for evolution to acute myeloid leukemia. Leukemic transformation with hydroxyurea therapy alone is rare and warrants further prospective studies.

Performance of anti-C1q, antinucleosome, and anti-dsDNA antibodies for detecting concurrent disease activity of systemic lupus erythematosus.

The objective of this study is to evaluate the specificity and sensitivity of antinucleosome, anti-C1q, and anti-dsDNA antibodies for detecting concurrent disease activity in systemic lupus erythematosus (SLE). Consecutive patients were recruited for serological testing of anti-dsDNA, IgG-antinucleosome, IgG-anti-C1q, and complement levels. SLE disease activity was assessed by SLEDAI and physician's global assessment (PGA). The levels of these antibodies, complements, and disease activity scores were correlated. The specificity and sensitivity of these antibodies in detecting SLE activity was determined. We recruited 245 SLE patients (95% women, age 40.6 ± 12.2 years). The prevalence of positive anti-dsDNA, antinucleosome and anti-C1q antibodies was 55%, 44%, and 21%, respectively. All 3 antibodies correlated significantly with SLEDAI and PGA scores but were correlated inversely with complement levels (P < 0.001 in all). Titers of anti-dsDNA and anti-C1q, but not antinucleosome, correlated significantly with the renal SLEDAI score. The sensitivity of anti-dsDNA, antinucleosome, and anti-C1q for detecting the presence of active renal disease was 75%, 47%, and 53%, respectively. Anti-C1q had the highest specificity for active lupus renal disease (84%) followed by antinucleosome (57%) and the anti-dsDNA antibody (49%). The negative predictive value (NPV) of a negative anti-dsDNA and anti-C1q for active renal disease was 91%. For concurrent extrarenal SLE activity, the specificity was also highest with anti-C1q (83%). We conclude that antinucleosome does not perform better than anti-dsDNA for detecting concurrent SLE activity. The anti-C1q antibody, however, is more specific than anti-dsDNA for both active renal and extrarenal lupus. The absence of both anti-dsDNA and anti-C1q has a high NPV for renal activity.