Gamal Ebid

Rationale for an international consortium to study inherited genetic susceptibility to childhood acute lymphoblastic leukemia.

Acute lymphoblastic leukemia is the major pediatric cancer in developed countries. To date most association studies of acute lymphoblastic leukemia have been based on the candidate gene approach and have evaluated a restricted number of polymorphisms. Such studies have served to highlight difficulties in conducting statistically and methodologically rigorous investigations into acute lymphoblastic leukemia risk. Recent genome-wide association studies of childhood acute lymphoblastic leukemia have provided robust evidence that common variation at four genetic loci confers a modest increase in risk. The accumulated experience to date and relative lack of success of initial efforts to identify novel acute lymphoblastic leukemia predisposition loci emphasize the need for alternative study designs and methods. The International Childhood Acute Lymphoblastic Leukaemia Genetics Consortium includes 12 research groups in Europe, Asia, the Middle East and the Americas engaged in studying the genetics of acute lymphoblastic leukemia. The initial goal of this consortium is to identify and characterize low-penetrance susceptibility variants for acute lymphoblastic leukemia through association-based analyses. Efforts to develop genome-wide association studies of acute lymphoblastic leukemia, in terms of both sample size and single nucleotide polymorphism coverage, and to increase the number of single nucleotide polymorphisms taken forward to large-scale replication should lead to the identification of additional novel risk variants for acute lymphoblastic leukemia. Ethnic differences in the risk of acute lymphoblastic leukemia are well recognized and thus in assessing the interplay between inherited and non-genetic risk factors, analyses using different population cohorts with different incidence rates are likely to be highly informative. Given that the frequency of many acute lymphoblastic leukemia subgroups is small, identifying differential effects will realistically only be possible through multi-center pooled analyses. Here, we review the rationale for identifying genetic risk variants for acute lymphoblastic leukemia and our proposed strategy for establishing the International Childhood Acute Lymphoblastic Leukaemia Genetics Consortium.

The impact of cytokine gene polymorphisms on the outcome of HLA matched sibling hematopoietic stem cell transplantation

HighlightsCytokines are mediators of immune responses including GVHD.Polymorphisms of cytokine genes result into high and low producer phenotypes.There is ethnic variation in high and low producer cytokines genotype/phenotype.This leads to variation in the contribution to GVHD in different populations. &NA; Graft‐versus‐host disease (GVHD) is the major complication of allogeneic hematopoietic stem cell transplantation (HSCT); cytokines are recognized as important mediators in its pathogenesis. In this study we investigated the role of cytokine gene polymorphisms on HSCT outcome. A total of 106 patient and 98 donors were genotyped by polymerase chain reaction sequence specific primers (PCR‐SSP) based assay for tumor necrosis factor‐&agr;−308 (TNF&agr; ‐308), interleukin (IL)‐6‐174, IL‐10‐1082, −819, −592, Interferon‐&ggr;+874 (IFN‐&ggr;+874), and transforming growth factor‐&bgr;1 (TGF‐&bgr;1) codon10 and 25 polymorphisms. Except one in each category, all patients and donors were TNF&agr; ‐308 high producers and the majority were IL‐6‐174 high producers (93.3% and 90.8% respectively); a pattern that would alleviate any potential biological impact. Patients IFN‐&ggr;+874 showed significant association with the development of chronic GVHD. Patients with IFN‐&ggr; +874 high producer showed an 8 folds likelihood to develop chronic GVHD as compared to those with IFN‐&ggr;+874 low producer predicted phenotype (95% CI: 1.59‐40.2, p = 0.01). Patients TGF&bgr;1‐codon 10 and 25 high/intermediate producers showed a lower incidence of acute GVHD though it did not achieve statistical significance (p = 0.065) on account of the low frequency of this genotype in our patients and donors (11.4 and 8.2% respectively). Other factors contributing to risk of GVHD included older age for both acute and chronic (p = 0.01 and 0.02 respectively) with age 24 as the best discriminating cutoff; CD34+ cell dose for chronic GVHD (p = 0.045) with a dose of 8 × 106/kg as the best discriminating cutoff; and conditioning regimen with Flu/Bu associated with the lowest incidence of acute GVHD (p = 0.003) and no impact on chronic GVHD. In conclusion the current study further indicates a potential role of some cytokine gene polymorphisms in the development of GVHD. The relative distribution of high and low producer genotypes in different ethnic groups contributes to their biological impact in different populations.