The impact of ICAM-1, CCL2 and TGM2 gene polymorphisms on differentiation syndrome in acute promyelocytic leukemia

Background Although arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) are well-tolerated and effective treatments for Acute Promyelocytic Leukemia (APL), Differentiation Syndrome (DS) is a lethal side effect in some patients. The pathogenesis of DS is complex and not well understood; however, it is considered as an inflammatory response due to cytokines release of differentiated cells. Moreover, adhesion molecules that are widely expressed on the surface of differentiated cells and gene expression changes of transglutaminase2 (TGM2) are mechanisms involved in the development of DS. The purpose of this study was to assess the association of single nucleotide polymorphisms (SNP) of Intercellular Adhesion Molecule-1 (ICAM-1), chemokine (C-C motif) ligand 2 (CCL2) and TGM2 as inflammatory factors with differentiation syndrome susceptibility. Methods DNA was extracted from 133 APL patients and 100 normal controls. Assessment according to the PETHEMA criteria revealed that 13.5% of these patients experienced differentiation syndrome. Tetra-ARMS PCR and PCR-RFLP were done to amplify DNA fragments in APL patients with and without DS. Then DNA sequencing was done to validate the results. SNPStats, SPSS and Finch TV were used to analyze the results. Results A significant correlation was found between rs4811528 in the TGM2 gene and differentiation syndrome susceptibility (P = 0.002, 95% CI = 1.74–18.81, OR = 5.72) while rs5498 in ICAM-1, rs1024611 in CCL2, and rs7270785 in TGM2 genes showed no correlation with differentiation syndrome. The G allele of rs7270785 and rs4811528 showed a haplotypic association with differentiation syndrome (P = 0.03, 95% CI = 1.13–13.86, OR = 3.96). Conclusions AA genotype of the TGM2 SNP (rs4811528) may be a risk factor for development of DS in patients with APL following the use of ATRA/ATO.

COMT in major depression - UK candidate gene association study

Catechol-O-methyltransferase (COMT) has a central role in brain dopamine, noradrenalin and adrenalin signaling, and has been suggested to be involved in the pathogenesis and pharmacological treatment of affective disorders. The functional single nucleotide polymorphism (SNP) in exon 4 (Val158Met, rs4680) influences the COMT enzyme activity. The Val158Met polymorphism is a commonly studied variant in psychiatric genetics, and initial studies in schizophrenia and bipolar disorder presented evidence for association with the Met allele. In unipolar depression, while some of the investigations point at an association between the Met/Met genotype and others have found a link between the Val/Val genotype and depression, most of the studies cannot detect any difference in Val158Met allele frequency between depressed individuals and controls.In the present study, we further elucidated the impact of COMT polymorphisms including the Val158Met in MDD. We investigated 1,250 subjects with DSM-IV and/or ICD-10 diagnosis of major depression (MDD), and 1,589 control subjects from UK. A total of 24 SNPs spanning the COMT gene were successfully genotyped using the Illumina HumaHap610-Quad Beadchip (22 SNPs), SNPlex™ genotyping system (1 SNP), and Sequenom MassARRAY® iPLEX Gold (1 SNP). Statistical analyses were implemented using PASW Statistics18, FINETTI (http://ihg.gsf.de/cgi-bin/hw/hwa1.pl), UNPHASED version 3.0.10 program and Haploview 4.0 program.Neither single-marker nor haplotypic association was found with the functional Val158Met polymorphism or with any of the other SNPs genotyped. Our findings do not provide evidence that COMT plays a role in MDD or that this gene explains part of the genetic overlap with bipolar disorder.

Association of SRD5A2 Variants and Serum Androstane-3α,17β-Diol Glucuronide Concentration in Chinese Elderly Men

BACKGROUND Results of recent studies have demonstrated that genetic variants of the enzyme steroid 5α reductase type II (SRD5A2) are associated with serum concentrations of major androgen metabolites such as conjugates of androstane-3α,17β-diol-glucuronide (3α-diol-G). However, this association was not consistently found among different ethnic groups. Thus, we aimed to determine whether the association with SRD5A2 genetic variations exists in a cohort of healthy Chinese elderly men, by examining 2 metabolite conjugates: androstane-3α,l7β-diol-3-glucuronide (3α-diol-3G) and androstane-3α,17β-diol-17-glucuronide (3α-diol-17G). METHODS We used GC-MS and LC-MS to measure serum sex steroid concentrations, including testosterone and dihydrotestosterone, and 3α-diol-3G and 3α-diol-17G in 1182 Chinese elderly men age 65 and older. Genotyping of the 3 SRD5A2 tagSNPs [rs3731586, rs12470143, and rs523349 (V89L)] was performed by using melting-temperature–shift allele-specific PCR. RESULTS The well-described SRD5A2 missense variant rs523349 (V89L) was modestly associated with the 3α-diol-17G concentration (P = 0.040). On the other hand, SNP rs12470143 was found to be significantly correlated with 3α-diol-3G concentration (P = 0.021). Results of haplotype analysis suggested that the presence of an A-C-G haplotype leads to an increased 3α-diol-3G concentration, a finding consistent with results of single SNP analysis. CONCLUSIONS The genetic variation of SRD5A2 is associated with circulating 3α-diol-3G and 3α-diol-17G concentrations in Chinese elderly men. In addition, we showed that SRD5A2 haplotypic association, rather than a single SNP alone, might be a better predictor of the 3α-diol-G concentration. Thus, the effect of either the haplotype itself or of other ungenotyped SNPs in linkage disequilibrium with the haplotype is responsible for the interindividual variation of 3α-diol-G.

Association Analysis of Heat Shock Protein 70 Gene Polymorphisms in Schizophrenia

Objectives:This study investigated the association between an enlarged set of SNPs at Heat shock proteins (HSPs) 70 gene and schizophrenia.Methods:Two hundred and ninety four patients with schizophrenia and 287 controls were enrolled in the study. Genotypings of 5 SNPs of HSP70 were performed using pyrosequencing method.Results:Significant association was detected at rs2075799 (allele A, Chi suare =8.03, d.f.=1 p=0.0046), but not at rs2227956 (p=0.28), rs1043618 (p=0.88), rs562047 (p=0.47) or rs539689 (p=0.32). in fact, the rs2075799*G/A genotype was more represented in patients with schizophrenia than in controls (Chi-sq=8.23, d.f.=1, p=0.0041). Haplotype based associations were also detected (global p value 0.000003); the T-A-C-C-G haplotype was more prevalent among the patients (odds ratio, OR 5.95). Sliding windows analysis revealed a major contribution from rs2227956 and rs2075799 (global-p value 0.0075), with T-A haplotype significantly associated with schizophrenia. There was no evidence of an association between the clinical variables and schizophrenia across the genotypes.Conclusion:Our results raise the possibility that HSP70 gene (i.e., haplotypes of rs2075799) might be implicated in the development of schizophrenia, although limited by rare haplotypic association with the disease. Hence further studies from different ethnics should be performed to confirm these results.