Evaluation of the association between the JAK2 46/1 haplotype and chronic myeloproliferative neoplasms in a Brazilian population
TL;DR: The JAK2 46/1 haplotype, represented in this study by the presence of the G allele, is an important predisposing factor in the oncogenetic development of these neoplasms in the studied population.
About: This article is published in Clinics.The article was published on 2013-01-01 and is currently open access. It has received 41 citations till now. The article focuses on the topics: Myeloproliferative neoplasm & Population.
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TL;DR: Three basic types of paternal effect are distinguished and key questions that can serve as a road map for research on the proximate basis and evolutionary implications of paternal effects are outlined.
Abstract: Maternal effects are now universally recognised as a form of nongenetic parental influence on offspring but, until recently, paternal effects were regarded as an anomaly. Although it is now clear that paternal effects are both widespread and important, their proximate basis and evolutionary consequences have received little attention and remain poorly understood. In particular, because many paternal effects are mediated by maternal responses such as differential allocation, the boundary between paternal and maternal effects is sometimes blurred. We distinguish here three basic types of paternal effect and clarify the role of maternal responses in these effects. We also outline key questions that can serve as a road map for research on the proximate basis and evolutionary implications of paternal effects.
175 citations
TL;DR: Existing evidence does not support ICSI in preference over in vitro fertilization (IVF) in the general non-male factor ART population; however, in couples with unexplained infertility, I CSI is associated with lower fertilization failure rates than IVF.
Abstract: Intracytoplasmic sperm injection (ICSI) has become the most commonly used method of fertilization in assisted reproductive technology. The primary reasons for its popularity stem from its effectiveness, the standardization of the procedure, which means that it can easily be incorporated into the routine practice of fertility centres worldwide, and the fact that it can be used to treat virtually all forms of infertility. ICSI is the clear method of choice for overcoming untreatable severe male factor infertility, but its (over)use in other male and non-male factor infertility scenarios is not evidence-based. Despite all efforts to increase ICSI efficacy and safety through the application of advanced sperm retrieval and cryopreservation techniques, as well as methods for selecting sperm with better chromatin integrity, the overall pregnancy rates from infertile men remain suboptimal. Treating the underlying male infertility factor before ICSI seems to be a promising way to improve ICSI outcomes, but data remain limited. Information regarding the health of ICSI offspring has accumulated over the past 25 years, and there are reasons for concern as risks of congenital malformations, epigenetic disorders, chromosomal abnormalities, subfertility, cancer, delayed psychological and neurological development, and impaired cardiometabolic profile have been observed to be greater in infants born as a result of ICSI than in naturally conceived children. However, as subfertility probably influences the risk estimates, it remains to be determined to what extent the observed adverse outcomes are related to parental factors or associated with ICSI.
131 citations
TL;DR: It is proposed that careful assessment of spermatozoal parameters is essential to achieve embryo development and a healthy live birth and the need for more research and the development of standardized protocols to assess the role of sperm factors affecting embryo quality.
Abstract: Advancing maternal and paternal age leads to a decrease in fertility, and hence, many infertile couples opt for assisted reproductive technologies [ART] to achieve biological parenthood. One of the key determinants of achieving a live outcome of ART, embryo quality, depends on both the quality of the oocyte and sperm that have created the embryo. Several studies have explored the effect of oocyte parameters on embryo quality, but the effects of sperm quality on the embryo have not been comprehensively evaluated. In this review, we assess the effect of various genetic factors of paternal origin on the quality and development of the embryo. The effects of sperm aneuploidy, sperm chromatin structure, deoxyribonucleic acid [DNA] fragmentation, role of protamines and histones, sperm epigenetic profile, and Y chromosome microdeletions were explored and found to negatively affect embryo quality. We propose that careful assessment of spermatozoal parameters is essential to achieve embryo development and a healthy live birth. However, the heterogeneity in test results and the different approaches of assessing a single sperm parameter highlight the need for more research and the development of standardized protocols to assess the role of sperm factors affecting embryo quality.
86 citations
TL;DR: Level of JAK2V617F mutation burden was associated with myeloproliferative neoplasm progression rate, consistent with a biological continuum of increasing JAK 2V617f mutation burden across increasing severity of myeloplasm from no disease to primary myelofibrosis.
Abstract: Clinical significance of the JAK2V617F mutation in patients with a myeloproliferative neoplasm has been the target of intensive research in recent years. However, there is considerably uncertainty about prognosis in JAK2V617F positive individuals without overt signs of myeloproliferative disease. In this study, we tested the hypothesis that increased JAK2V617F somatic mutation burden is associated with myeloproliferative neoplasm progression rate in the general population. Among 49,488 individuals from the Copenhagen General Population Study, 63 (0.1%) tested positive for the JAK2V617F mutation in the time period 2003-2008. Of these, 48 were available for re-examination in 2012. Level of JAK2V617F mutation burden was associated with myeloproliferative neoplasm progression rate, consistent with a biological continuum of increasing JAK2V617F mutation burden across increasing severity of myeloproliferative neoplasm from no disease (n=8 at re-examination) through essential thrombocythemia (n=20) and polycythemia vera (n=13) to primary myelofibrosis (n=7). Among those diagnosed with a myeloproliferative neoplasm only at re-examination in 2012, in the preceding years JAK2V617F mutation burden increased by 0.55% per year, erythrocyte volume fraction increased by 1.19% per year, and erythrocyte mean corpuscular volume increased by 1.25% per year, while there was no change in platelet count or erythropoietin levels. Furthermore, we established a JAK2V617F mutation burden cut-off point of 2% indicative of disease versus no disease; however, individuals with a mutation burden below 2% may suffer from a latent form of myeloproliferative disease revealed by a slightly larger spleen and/or slightly higher lactic acid dehydrogenase concentration compared to controls. Of all 63 JAK2V617F positive individuals, 48 were eventually diagnosed with a myeloproliferative neoplasm.
75 citations
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TL;DR: BPA male exposure jeopardizes embryonic survival and development due to the transmission of a paternal damaged genome and of a hyper-acetylated histone profile, both alterations depending on the dose of the toxicant and the temporal window of exposure.
Abstract: Exposure to bisphenol A (BPA) has been related to male reproductive disorders. Since this endocrine disruptor also displays genotoxic and epigenotoxic effects, it likely alters the spermatogenesis, a process in which both hormones and chromatin remodeling play crucial roles. The hypothesis of this work is that BPA impairs early embryo development by modifying the spermatic genetic and epigenetic information. Zebrafish males were exposed to 100 and 2000 μg/L BPA during early spermatogenesis and during the whole process. Genotoxic and epigenotoxic effects on spermatozoa (comet assay and immunocytochemistry) as well as progeny development (mortality, DNA repairing activity, apoptosis and epigenetic profile) were evaluated. Exposure to 100 µg/L BPA during mitosis slightly increased sperm chromatin fragmentation, enhancing DNA repairing activity in embryos. The rest of treatments promoted high levels of sperm DNA damage, triggering apoptosis in early embryo and severely impairing survival. Regarding epigenetics, histone acetylation (H3K9Ac and H3K27Ac) was similarly enhanced in spermatozoa and embryos from males exposed to all the treatments. Therefore, BPA male exposure jeopardizes embryonic survival and development due to the transmission of a paternal damaged genome and of a hyper-acetylated histone profile, both alterations depending on the dose of the toxicant and the temporal window of exposure.
53 citations
References
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TL;DR: Host genetic variation may contribute to phenotypic diversity among myeloproliferative disorders, including in the presence of a shared disease allele.
148 citations
"Evaluation of the association betwe..." refers background in this paper
...It was suggested that the JAK2 46/1 haplotype brings genetic instability to the JAK2 gene, favoring the emergence of JAK2 acquired mutations, such as the JAK2 V617F and JAK2 exon 12 mutations (10-12,18)....
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...As mentioned above, one hypothesis is that a genetic instability brought by the presence of a specific inherited haplotype facilitated the emergence of an acquired JAK2 mutation (10-12,18)....
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...(10) studied the genetic factors that could contribute to the phenotypic diversity of cMPN....
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TL;DR: The ‘GGCC’ haplotype of J AK2 confers susceptibility to JAK2 exon 12 mutation-positive polycythemia vera.
Abstract: The ‘GGCC’ haplotype of JAK2 confers susceptibility to JAK2 exon 12 mutation-positive polycythemia vera
67 citations
TL;DR: The results indicate that the G allele, part of the JAK2 46/1 haplotype, contributes significantly to the occurrence ofJAK2 V617F-positive myeloproliferative neoplasms.
Abstract: Polycythemia vera, essential thrombocythemia, and primary myelofibrosis are myeloproliferative neoplasms, characterized in a majority of cases by a unique somatic point mutation, JAK2 V617F. Recently, it was shown that JAK2 V617F occurs more frequently on a specific JAK2 haplotype, named JAK2 46/1. We genotyped 149 myeloproliferative neoplasms patients (69 had polycythemia vera, 65 had essential thrombocythemia, and 15 had primary myelofibrosis) with a known JAK2 V617F mutational status and 150 controls for the JAK2 rs10974944 (C/G) single nucleotide polymorphism, in which the G allele tags the 46/1 haplotype. We found that the rs10974944 GG/CG genotypes were significantly enriched in patients compared to controls (p 50% compared to those with a mutant allele burden 50% in JAK2 V617F-positive myeloproliferative neoplasms patients.
26 citations
"Evaluation of the association betwe..." refers background or result in this paper
...In addition, a comparison of the JAK2 rs10974944 SNP genotype or allele frequencies between the JAK2 V617F positive and negative patients did not reveal a significant difference in contrast to what has been previously described (11,12,16)....
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...Recent reports have suggested that hereditary genetic factors, specifically the JAK2 haplotypes, can strongly contribute to the development of cMPN (11,12,16-18)....
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TL;DR: The results indicate that the C allele of JAK2 rs4495487, in addition to the 46/1 haplotype, contributes significantly to the occurrence of J AK2 V617F-positive and JAK1 V617f-negative MPNs in the Japanese population.
Abstract: Background
Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are myeloproliferative neoplasms (MPNs) characterized in most cases by a unique somatic mutation, JAK2 V617F. Recent studies revealed that JAK2 V617F occurs more frequently in a specific JAK2 haplotype, named JAK2 46/1 or GGCC haplotype, which is tagged by rs10974944 (C/G) and/or rs12343867 (T/C). This study examined the impact of single nucleotide polymorphisms (SNPs) of the JAK2 locus on MPNs in a Japanese population.
15 citations
"Evaluation of the association betwe..." refers background in this paper
...Recent studies evaluating this correlation among other populations have also confirmed the JAK2 46/1 haplotype as a predisposing factor across various ethnic groups (19-20)....
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TL;DR: A robust polymerase chain reaction – restriction fragment length polymorphism (PCR-RFLP) assay for studying this SNP is developed to serve as a rapid screening tool of the putative JAK2 V617F -predisposing haplotype.
Abstract: opment of JAK2 V617F -positive MPNs, we developed a robust polymerase chain reaction – restriction fragment length polymorphism (PCR-RFLP) assay for studying this SNP. This is meant to serve as a rapid screening tool of the putative JAK2 V617F -predisposing haplotype. Blood samples were collected from 30 volunteers, who presented for routine blood counts at the Haematology Clinic in Cluj-Napoca. Written consent was obtained from all participants. DNA was obtained from peripheral white blood cells, using a commercially available kit (Wizard DNA Purification Kit; Promega, Madison, Wisc., USA). The primers used for amplifying a fragment encompassing the JAK2 rs10974944 SNP (GenBank Accession number NT_008413) were designed using the online program Primer3 v.0.4.0 [11] . The primer sequences are as follows: Fw 5 -CAAGGGTCAACTGTAGTACATAA-3 and Rev 5 -CTGCTTGCTAGTGGGTGAAT-3 . The PCR reactions were set up in a 25 \u0002 l reaction volume, with the following composition: 12.5 \u0002 l 2 ! PCR MasterMix containing recombinant Taq-DNA polymerase 0.05 U/ l, MgCl 2 4 m M , dNTPs mix 0.4 m M each (Fermentas MBI, Vilnius, Lithuania), 10 pmoles of each forward and reverse primer, 1 l of 2 mg/ml BSA solution (Fermentas MBI) and 75 ng of genomic DNA. The amplification procedure was adapted on an Eppendorf thermocycler (MasPolycythemia vera, essential thrombocythemia and primary myelofibrosis are the 3 classical myeloproliferative neoplasms (MPNs), negative for the BCR-ABL fusion. Their molecular physiopathology remained obscure for decades, until several research groups reported in 2005 that a single somatic point mutation in the gene coding for Janus-kinase 2 ( JAK2 ), predicting a valine-to-phenylalanine substitution in position 617 ( JAK2 V617F ), characterize most of polycythemia vera and about half of essential thrombocythemia and primary myelofibrosis patients [1–5] . JAK2 V617F mutation leads to constitutive activation of the JAK-STAT signaling pathway and thus continuous proliferation of the myeloid precursors [1–5] . Further studies indicated, however, that this mutation might not be the primary molecular event in these diseases [6, 7] . Very recently, 3 independent research groups reported for the first time that the JAK2 V617F tends to occur, or could have a selective advantage, in a specific JAK2 haplotype [8–10] . The common point of the 3 reports was a single nucleotide polymorphism (SNP) within the JAK2 gene, called rs10974944, part of the putative JAK2 V617F predisposing haplotype, of which the C allele is the common allele, whereas the G allele is the variant. Based on the recent finding that the JAK2 rs10974944 SNP could be associated with predisposition to the develReceived: August 4, 2009 Accepted after revision: October 12, 2009 Published online: December 11, 2009
12 citations