Higher Frequency Of TT Genotype Research Articles

Genetic Variants in Smoking-Related Genes in Two Smoking Cessation Programs: A Cross-Sectional Study.

Previous studies have identified variants in genes encoding proteins associated with the degree of addiction, smoking onset, and cessation. We aimed to describe thirty-one single nucleotide polymorphisms (SNPs) in seven candidate genomic regions spanning six genes associated with tobacco-smoking in a cross-sectional study from two different interventions for quitting smoking: (1) thirty-eight smokers were recruited via multimedia to participate in e-Decídete! program (e-Dec) and (2) ninety-four attended an institutional smoking cessation program on-site. SNPs genotyping was done by real-time PCR using TaqMan probes. The analysis of alleles and genotypes was carried out using the EpiInfo v7. on-site subjects had more years smoking and tobacco index than e-Dec smokers (p < 0.05, both); in CYP2A6 we found differences in the rs28399433 (p < 0.01), the e-Dec group had a higher frequency of TT genotype (0.78 vs. 0.35), and TG genotype frequency was higher in the on-site group (0.63 vs. 0.18), same as GG genotype (0.03 vs. 0.02). Moreover, three SNPs in NRXN1, two in CHRNA3, and two in CHRNA5 had differences in genotype frequencies (p < 0.01). Cigarettes per day were different (p < 0.05) in the metabolizer classification by CYP2A6 alleles. In conclusion, subjects attending a mobile smoking cessation intervention smoked fewer cigarettes per day, by fewer years, and by fewer cumulative pack-years. There were differences in the genotype frequencies of SNPs in genes related to nicotine metabolism and nicotine dependence. Slow metabolizers smoked more cigarettes per day than intermediate and normal metabolizers.

Relationship between onset of eclampsia and AGTR1 gene polymorphisms.

We aimed to study the correlations of angiotensin II receptor type 1 (AGTR1) gene polymorphisms with the occurrence and development of eclampsia. A total of 200 pregnant women with eclampsia admitted to our hospital from January 1, 2017 to September 30, 2019 were collected as observation group and 200 normal pregnant women during the same period were recruited in the control group. Genome sequencing was performed to detect the AGTR1 gene polymorphisms in the two groups. Expression level of AGTR1 in both groups was detected. The influences of AGTR1 on clinical data of pregnant women with eclampsia were analyzed. There were no significant differences in age (p=0.545), height (p=0.738), weight (p=0.695) and hypertension (p=0.372) between observation group and control group. However, significant differences were found in the distributions of alleles at AGTR1 rs1799870 (p=0.002) and AGTR1 rs52936049 (p=0.047) between groups. The frequencies of T allele at rs1799870 and rs52936044 in observation group were higher than those in the control group. In addition, the distributions of AGTR1 gene genotypes at rs1799870 (p=0.012), rs144520513 (p=0.008) and rs529360494 (p p =0.036) in observation group differed from those in control group. Observation group had higher frequencies of TT genotype at rs1799870, GG genotype at rs144520513 and TG genotype at rs529360494 than those in control group. Besides, the frequency of CGG haplotype (p=0.008) of AGTR1 gene in observation group was notably lower than that in the control group, while the frequency of TGT haplotype (p=0.012) of AGTR1 gene in the former was remarkably higher than that in the latter. Moreover, the linkage disequilibrium between rs529360494 and rs144520513 of AGTR1 gene was relatively high (D'=0.623). AGTR1 gene polymorphism rs529360494 showed an evident relationship with the expression of AGTR1 gene, and the expression of AGTR1 in pregnant women with eclampsia who carried TG genotype was markedly reduced (p<0.05). Furthermore, AGTR1 gene polymorphism rs1799870 was associated with prothrombin time (PT) in pregnant women with eclampsia (p=0.046), and PT in those carrying genotype TC was shorter. Rs144520513 was related to the levels of triglyceride (TG) (p<0.001) and low-density lipoprotein (LDL) (p<0.001) in pregnant women with eclampsia, and TG and LDL levels were significantly lower. AGTR1 gene polymorphisms are closely associated with the onset and progression of eclampsia.

Correlations of IL-6 and IL-10 gene polymorphisms with childhood acute lymphoblastic leukemia.

The aim of this study was to investigate the correlations between interleukin-6 (IL-6) and IL-10 gene polymorphisms with childhood acute lymphoblastic leukemia. Specimens were collected from 200 children with acute lymphoblastic leukemia (disease group) and 200 normal children (control group) in our hospital. DNA was extracted from peripheral blood nucleated cells in both groups to detect the gene polymorphisms rs2069830 and rs2069836 of IL-6, as well as rs3024489 and rs3024493 of IL-10. Then, the content of serum IL-6 and IL-10 was determined via enzyme-linked immunosorbent assay (ELISA). It was found that there were differences in the distribution of alleles of IL-6 gene polymorphism rs2069830 (p=0.000) and IL-10 gene polymorphism rs3024493 (p=0.007) between the disease group and control group. The frequency of T allele of IL-6 gene polymorphism rs2069830 was higher, while that of IL-10 gene polymorphism rs3024493 was lower in the disease group. Besides, the differences in the distribution of genotypes of IL-6 gene polymorphism rs2069830 (p=0.000) and IL-10 gene polymorphism rs3024493 (p=0.000) were also observed between the disease group and control group. Moreover, the disease group had higher frequencies of TT genotype of IL-6 gene polymorphism rs2069830 and TA genotype of IL-10 gene polymorphism rs3024493. The frequencies of dominant model of IL-6 gene polymorphism rs2069830 (p=0.048) and recessive model of IL-10 gene polymorphism rs3024493 (p=0.000) in the disease group were different from those in the control group. In addition, the frequency of CC + CT dominant model of IL-6 gene polymorphism rs2069830 was lower, and the frequency of TA + AA recessive model of IL-10 gene polymorphism rs3024493 was higher in the disease group. There were differences in haplotypes CG (p=0.001), CT (p=0.007), and TG (p=0.000) of IL-6 gene, as well as haplotypes AA (p=0.002) and AT (p=0.005) of IL-10 gene between disease group and control group. Furthermore, the content of IL-6 in the serum was associated with the genotypes of IL-6 gene polymorphism rs2069830 (p<0.05), whereas the children with acute lymphoblastic leukemia carrying CT genotype had remarkably higher content of serum IL-6. The genotypes of IL-6 gene polymorphism rs2069830 was notably related to white blood cell (WBC) (p=0.002), and the WBC level was higher in children with CT genotype. The genotypes of IL-10 gene polymorphism rs3024489 had prominent correlations with platelet (PLT) (p=0.043), and the children with AA genotype had a higher PLT level. In addition, the genotypes of IL-10 gene polymorphism rs3024493 were evidently correlated with hemoglobin, which was significantly higher in children carrying TA genotype. The gene polymorphisms of IL-6 and IL-10 are significantly correlated with the susceptibility to and pathogenesis of childhood acute lymphoblastic leukemia.

Impact of ABCB1 Gene (C3435T/A2677G) Polymorphic Sequence Variations on the Outcome of Patients with Chronic Myeloid Leukemia and Acute Lymphoblastic Leukemia in Kashmiri Population: A Case-Control Study.

Inherited polymorphic sequence variations in drug transport genes like ABCB1 impact a portion of patients with hematologic malignancies that show intrinsic or acquire resistance to treatment. Keeping in view inter-individual sensitivities for such drugs, we through this case-control study tested whether ABCB1 C3435T and G2677T polymorphisms have any influence on the risk and treatment response in patients with chronic myeloid leukemia (CML) and B-acute lymphoblastic leukemia (B-ALL). Genotyping for ABCB1 polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism in 100 CML and 80 B-ALL patients along with 100 age and gender matched healthy controls. ABCB1 C3435T and G2677T polymorphism showed no association with CML. Genotype distribution revealed significant higher frequency of TT genotype for both SNPs in B-ALL cases and associated with increased B-ALL risk (OR 2.5, p = 0.04 for 3435TT; OR 2.4, p = 0.04 for 2677TT). There was no significant difference in genotype frequency of 3435C > T and 2677G > T among resistant and responsive groups for the two leukemia types. Kaplan-Meier survival plots revealed significantly lower event free survival in CML and B-ALL patients that were carriers of 3435TT genotype (p < 0.05). Multivariate analysis considered 3435TT genotype as independent risk factor for imatinib resistance in CML cases (HR 6.24, p = 0.002) and increased relapse risk in B-ALL patients (HR 4.51, p = 0.03). The current study provides preliminary evidence of a significant association between variant TT genotype and increased B-ALL risk. Also, results suggest that ABCB1 3435TT genotype increases imatinib resistance in CML and influence therapeutic outcome in B-ALL.

Gene–environment interaction between APOA5 c.553G>T and pregnancy in hypertriglyceridemia-induced acute pancreatitis

The etiology of hypertriglyceridemia (HTG) and, consequently, HTG-induced acute pancreatitis (HTG-AP), is complex. Herein, we explore a possible gene-environment interaction between APOA5 c.553G>T (p.185Gly>Cys, rs2075291), a common variant associated with altered triglyceride levels, and pregnancy in HTG-AP. We enrolled 318 Chinese HTG-AP patients and divided them into 3 distinct groups: Group 1, male patients (n=183); Group 2, female patients whose disease was unrelated to pregnancy (n=105); and Group 3, female patients whose disease was related to pregnancy (n=30). APOA5 rs2075291 genotype status was determined by Sanger sequencing. A total of 362 healthy Han Chinese subjects were used as controls. Data on body mass index, peak triglyceride level, age of disease onset, episode number, and clinical severity of HTG-AP were collected from each patient. Multiple comparisons, between patient groups, between patient groups and controls, or within each patient group, were performed. A robust association of APOA5 rs2075291 with HTG-AP in general, and HTG-AP during pregnancy in particular, was demonstrated. The minor T allele showed a stronger association with Group 3 patients than with either Group 1 or Group 2 patients. This stronger association was due mainly to the much higher frequency of TT genotype in Group 3 patients (20%) than that (<6%) in Group 1 and Group 2 patients. Moreover, the TT genotype was associated with a significantly higher peak triglyceride level in Group 3 patients compared with the GG genotype. Our findings provide evidence for an interaction between APOA5 rs2075291 and pregnancy in HTG-AP.

TREX1 531C>T Polymorphism is Associated with High Proviral Load Levels in HTLV-1-Infected Persons.

Human T-lymphotropic virus type 1 (HTLV-1) deregulates the immune system and cell cycle, resulting in loss of immune tolerance and disease, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Three prime repair exonuclease 1 (TREX1) maintains innate immune tolerance of the host and host-cell permissiveness to retroviral infections. TREX1 polymorphisms may influence the course of infection and autoimmune manifestations. The influence of TREX1 531C/T polymorphism was investigated in HTLV-1 infection and development of symptoms among 151 persons infected with HTLV-1 (32 HAM/TSP, 19 rheumatologic manifestations, two dermatitis, five more than one diagnosis, two probable HAM/TSP, and 91 asymptomatic individuals) and 100 uninfected persons in the control group. Polymorphism genotyping and proviral load quantification were performed by real-time polymerase chain reaction (PCR) and antinuclear antibodies (ANAs) were screened by an indirect immunofluorescence assay. No statistically significant difference was found in polymorphism genotype and allele frequencies between the infected and control groups. HAM/TSP patients showed higher frequency of TT genotype than asymptomatic persons (p = 0.0339). Proviral load was significantly higher among individuals with CT/TT genotypes and CC genotype carriers had lower proviral load and higher levels of proinflammatory cytokines. ANAs were present only in the HAM/TSP group. TREX1 531C>T polymorphism seems to be associated with TREX-1 regulation and HTLV-1 infection.

PON1 gene polymorphisms in patients with chronic obstructive pulmonary disease

AimsChronic obstructive pulmonary disease (COPD) is characterised with oxidative stress. Paraoxonase 1 (PON1) is an enzyme, coded by PON1 gene, with distinctive antiatherogenic and antioxidative roles. We aimed to investigate...

Association between S100B gene polymorphisms and hand, foot and mouth disease caused by enterovirus 71 infection

To investigate the association between rs9722 polymorphisms in the S100B gene and hand, foot and mouth disease (HFMD) caused by enterovirus 71. A total of 124 HFMD children with enterovirus 71 infection were enrolled as subjects, and 56 healthy children were enrolled as control group. The rs9722 polymorphisms in the S100B gene were detected for both groups, and the serum level of S100B protein was measured for 74 HFMD children. The rs9722 locus of the S100B gene had three genotypes, CC, CT, and TT, and the genotype frequencies were in accordance with Hardy-Weinberg equilibrium. Compared with the control group, the HFMD group had significant increases in the frequencies of TT genotype and T allele (P<0.01). Children with severe HFMD caused by enterovirus 71 infection had significantly higher frequencies of TT genotype and T allele than those with moderate or mild HFMD (P<0.05). Compared with the cured patients, the patients with poor prognosis had significant increases in the frequencies of TT genotype and T allele in the rs9722 locus of the S100B gene (P<0.05). Among the 74 children with HFMD, the children with TT genotype had the highest serum level of S100B protein, and those with CC genotype had the lowest level (P<0.01). T allele in the rs9722 locus of the S100B gene might be a risk factor for severe HFMD caused by enterovirus 71 infection.

A genetic variant in CDKN2A/B gene is associated with the increased risk of breast cancer.

Breast cancer is among the leading cause of cancer-related-deaths in women, supporting the need for the identification of novel prognostic and predictive biomarkers. Recent studies have identified common genetic variants in a region on chromosome 9p21 associated with an increased risk of developing different cancers. Here, we explored the association of a genetic variant in CDKN2A/B, rs10811661, for the first time in 564 subjects with/without breast cancer. Genotyping was performed using TaqMan real time PCR method. The associations of this genetic variant with breast cancer risk and pathological information of patients were assessed. We observed that patients with breast cancer had a higher frequency of TT genotype (P<.001) than control group, which was associated with advanced TNM classification (P=.04) and larger tumor size (P=.014), as detected by the recessive genetic inheritance model. Moreover, the logistic regression under recessive genetic model revealed that breast cancer patients with TT had higher risk of breast cancer, compared to CC/CT genotypes (eg, OR=4.9, 95% CI:1.9-12, P=.001), after adjusted for potential confounders, age, BMI, and family history. We demonstrated that patients carrying the TT genotype for CDKN2A/B rs10811661 polymorphism had the increased risk of breast cancer susceptibility. However, further investigations are warranted in a larger and prospective setting to explore the value of this marker as a risk stratification marker in breast cancer.

Associations of P2Y12R gene polymorphisms with susceptibility to coronary heart disease and clinical efficacy of antiplatelet treatment with clopidogrel.

To investigate the correlations of three P2Y12 receptor (P2Y12R) gene polymorphisms (rs7428575 T>G, rs2046934 C>T, and rs3732759 A>G) with susceptibility to coronary artery disease (CHD) and clinical efficacy of clopidogrel treatment for CHD. From May 2014 to May 2015, 178 CHD patients (the case group) and 182 healthy controls (the control group) were selected from our hospital. The platelet-rich plasma (PRP) turbidimetry was used to measure the rate of adenosine diphosphate (ADP)-induced platelet aggregation before and after clopidogrel treatment. Clopidogrel-sensitive group was defined as a 10% or greater decrease in the rate of platelet aggregation after 10days of clopidogrel treatment, while clopidogrel-resistant group was defined as a <10% decrease. Genotyping was performed by denaturing high-performance liquid chromatography (DHPLC). A haplotype analysis of P2Y12R gene polymorphisms was performed using SHEsis software. There were significant differences in genotype and allele frequencies of rs2046934 C>T and rs3732759 A>G between the case and control groups (all P<.05). Haplotypes GTA and TTA were negatively associated with CHD risk (both P<.05), but haplotype TCA was positively associated with CHD risk (P=.005). CHD patients in the clopidogrel-sensitive group had higher frequencies of TT genotype of rs2046934 C>T and lower frequencies of GG genotype of rs3732759 A>G than those in the clopidogrel-resistant group (both P<.05). P2Y12R gene rs2046934 C>T and rs3732759 A>G polymorphisms might be associated with the risk of CHD and the efficacy of clopidogrel treatment for CHD.

The clinical features of patients with a Y93H variant of hepatitis C virus detected by a PCR invader assay.

Resistance-associated variants (RAVs) reduce the efficacy of interferon (IFN)-free therapy with asunaprevir and daclatasvir for patients infected with hepatitis C virus (HCV) genotype 1b. The characteristics of patients with an L31 or a Y93 variant in the nonstructural 5A region detected by a polymerase chain reaction invader assay were investigated. In total, 201 patients with HCV genotype 1b were examined for L31F/M/V variants or a Y93H variant by the polymerase chain reaction invader assay. L31M and Y93H variants were detected in 4.6 and 21.4 % of patients, respectively. Patients with an L31M variant had no significant characteristics. Patients with a Y93H variant had significantly higher HCV RNA levels (6.5 ± 0.5 log copies per milliliter vs 6.1 ± 0.7 log copies per milliliter, p = 0.0002), higher frequency of mutant type of the IFN-sensitivity-determining region (88.4 % vs 71.7 %, p = 0.0251), and higher frequency of TT genotype at rs8099917 of IL28B (91.7 % vs 54.3 %, p < 0.0001) than those with Y93 wild-type strains. Multivariate analysis identified HCV RNA levels [odds ratio (OR) 3.72, 95 % confidence interval (CI) 1.71-8.06, p = 0.0009] and TT genotype at rs8099917 (OR 7.45, 95 % CI 2.11-26.4, p = 0.0018) as factors associated with the presence of a Y93H variant. The presence of a Y93H variant was associated with higher HCV RNA levels and TT genotype at rs8099917 of IL28B. Thus, patients with a Y93H variant may be ideal candidates for IFN-based therapy rather than IFN-free therapy, although the high viral load of these patients may reduce the response rate of IFN-based therapy.

Polymorphism rs2239185 in vitamin D receptor gene is associated with severe community-acquired pneumonia of children in Chinese Han population: a case-control study.

Vitamin D receptor (VDR) is a potential candidate gene for community-acquired pneumonia (CAP). Examining the susceptibility VDR gene for CAP is essential for early intervention, prevention of related complications, and improvement of outcome. A case-control study was performed to examine the association between rs2239185 of VDR gene and CAP among children in Chinese Han population. Polymerase chain reaction and direct sequencing were used to genotype rs2239185 in 91 CAP children and 94 healthy children. For rs2239185, individuals with TT genotype showed a significantly higher risk of CAP than those with CC plus CT genotypes (P = 0.008). The occurrence of T allele of rs2239185 was significantly more frequent in CAP children than those in normal controls (P = 0.045).We found through stratification analysis that CAP children with systemic inflammatory response syndrome (SIRS), leukocyte count (WBC) >10 × 10(9)/L, C-reactive protein (CRP) >25 mg/L, procalcitonin (PCT) >2 ng/mL, and pediatric critical illness score <80 scores showed significantly higher frequency of TT genotype than those in normal controls (P = 0.0012, 0.0035, 0.0005, 0.0002, and 0.0021, respectively). TT genotype of rs2239185 in VDR gene might be one of the potential genetic risk factors for CAP, and T allele of rs2239185 might be associated with the susceptibility to CAP and the severity of CAP.

Association of transforming growth factor-Beta 1 promoter variant -509 c/t with bronchial asthma in South Indian population.

Transforming growth factor-beta 1 (TGF-β1) is a multifunctional cytokine that plays a pivotal role in airway remodeling observed in the asthmatic airways. C to T base substitution at -509 promoter position in the TGF-β1 gene leads to its increased expression which contributes to airway remodeling in bronchial asthma. We sought to evaluate the association of TGF-β1 -509 C/T promoter variant with clinical asthma and varying degrees of disease severity. Three hundred and eighty-two clinically diagnosed asthma patients and 410 healthy controls were enrolled for the study. Patients were classified into severity classes according to the Global Initiative for Asthma (GINA) guidelines. TGF-β1 -509 C/T genotyping was carried out by amplification refractory mutation system polymerase chain reaction (ARMS-PCR) technique. In the present study, we found significantly higher frequency of TT genotype in asthma patients compared to controls (for TT vs. CC, p = 0.020). In addition, a significant difference was observed in the frequency of C and T allele in patients and controls (for T vs. C, p = 0.029). The heterozygous "CT" genotype was higher in moderate and severe asthmatics compared to mild subset of patients (for mild vs. moderate, p = 0.037). However, there was no significant distribution and association of variant allele with the severity subsets.

Associations between Toll-like receptor 9 gene polymorphisms and systemic lupus erythematosus in Guangxi Zhuang and Han populations

Objective To assess the association between Toll-like receptor 9 (TLR9) gene single nucleotide polymorphisms (SNPs) and systemic lupus erythematosus (SLE) development in Guangxi Zhuang and Han populations,as well as the difference in TLR9 SNPs between the two populations.Methods Totally,41 SLE patients of Zhuang nationality and 56 of Han nationality,as well as 82 healthy checkup examinees of Zhuang nationality and 120 of Han nationality were enrolled in this study.Venous blood samples were obtained from all of these subjects and subjected to DNA extraction.The single nucleotide polymorphisms in TLR9 gene were detected by PCR-restriction fragment length polymorphism (PCR-RFLP) analysis followed by direct sequencing.Chi-square test and adjusted Chi-square test were conducted to assess the relationship between the genotype and allele frequencies of TLR9 SNPs and some clinical and laboratory parameters of patients with SLE,as well as the differences in genotype and allele frequencies of TLR9 SNPs between the two populations.Results The frequencies of CC,CT and TT genotypes of TLR9 SNP rs352140 were 42.9％,41.1％ and 16.1％ respectively in the patients of Han nationality,compared to 38.3％,55.8％ and 5.8％ in the healthy controls of Han nationality (all P ＜ 0.05),but no significant difference was observed in the frequency of C or T allele of the SNP rs352140 between the patients and controls of Han nationality (both P ＞ 0.05).There was no significant difference in the genotype or allele frequency of TLR9 SNP rs352140 between the patients and healthy controls of Zhuang nationality,or between the patients of Han nationality and Zhuang nationality (all P ＞ 0.05).The patients with anti-dsDNA antibodies showed a significantly higher frequency of TT genotype (P ＜ 0.05),but similar T allele frequency at TLR9 SNP rs352140 (P ＞ 0.05) compared with those without.The frequencies of both TT genotype and T allele of TLR9 SNP rs352140 were significantly increased in the patients with a SLE disease activity index (SLEDAI) ≥ 9 compared with those with a SLEDAI ＜ 9 (both P ＜ 0.05).There was no statistical difference in either the TT genotype or the T allele frequency at TLR9 SNP rs352140 between antinuclear antibody-positive and-negative patients with SLE (both P ＞ 0.05).Conclusions The TLR9 SNP rs352140 is correlated with several clinical and laboratory parameters of SLE,and might contribute to the susceptibility to SLE in Guangxi Han population. Key words: Lupus erythematosus, systemic; Toll-like receptor 9; Polymorphism, single nucleotide; Zhuang nationality; Han nationality

Polymorphism of CD44 Influences the Efficacy of CD34+ Cells Mobilization in Patients with Hematological Malignancies

In the last decade, peripheral blood was the main source of hematopoietic stem cells (HSC) for autologous and allogeneic transplantation. The exact mechanisms of HSC mobilization are still not clear and the efficacy of the procedure is hardly predictable. Ligand-receptor interactions of adhesion molecules, such as SDF1/CXCR4, VLA4/VCAM-1, or CD44/osteopontin, play an important role in homing of HSC in the hematopoietic niche. There is some evidence that disruption of the ligand-receptor complex leads to the egress of HSCs to the peripheral blood. The aim of the present study was the evaluation of constitutive polymorphism of genes encoding cytokines and receptors present in the HSC niche and their impact on the efficacy of mobilization of HSCs in patients with hematological malignancies. We enrolled 110 patients (60 females and 50 males) in the study. The median age of the patients was 55 (range, 22 to 69) years. The group consisted of patients with multiple myeloma (n = 74), non-Hodgkin lymphoma (n = 19), Hodgkin lymphoma (n = 15), or acute myeloid leukemia (n = 2). The mobilization procedures comprised chemotherapy and subsequent granulocyte-colony stimulating factor (G-CSF) at a dose of 10 μg/kg daily. The poor mobilizers group was defined according to Italian National Bone Marrow Transplant Registry criteria: patients with peak CD34+ in the peripheral blood < 20/μL or total yield < 2 × 106 CD34+ cells/kg body weight in maximum 3 aphereses. Genotyping was performed using standard PCR-based assays. The group of patients (N = 108) who achieved minimal threshold for collections (CD34+ at least 10/μL) proceeded to apheresis. The median total yield of CD34+ in this group was 5.6 × 106 cells/kg body weight, whereas the median number of cells collected during the first apheresis was 3.3 × 106 cells/kg body weight. Median number of days of G-CSF treatment before first apheresis was 10. Fifteen patients fulfilled the criteria for poor mobilizer. The group of poor mobilizers had higher frequency of TT genotype in rs13347 (CD44) gene (CC+ CT versus TT P = .047). Patients homozygous for T allele had a lower total yield of CD34+ cells/kg body weight than the group with allele C (median, 3.7 × 106/kg versus 5.8 × 106/kg; P = .019) and a lower number of CD34+ cells gathered during first apheresis (.95 × 106/kg versus 3.3 × 106/kg, P = .04). Multivariate logistic regression analysis revealed that the CD44 TT genotype was the only factor associated with 5-fold higher risk of poor mobilization (P = .037). Polymorphic variants of CXCR4 and VCAM-1 did not significantly influence the efficacy of HSCs mobilization in our group of patients. In conclusion, our results indicate that among investigated single nucleotide polymorphisms (SNPs), only CD44 rs13347 has an impact on the efficacy of HSCs mobilization in patients with hematologic malignancies. CD44 SNPs analysis may be helpful for predicting the poor mobilizers population who may benefit from newer modalities using adhesion molecules inhibitors.

The G516T CYP2B6 Germline Polymorphism Affects the Risk of Acute Myeloid Leukemia and Is Associated with Specific Chromosomal Abnormalities

The etiology of acute myeloid leukemia (AML) underlies the influence of genetic variants in candidate genes. The CYP2B6 enzyme detoxifies many genotoxic xenobiotics, protecting cells from oxidative damage. The CYP2B6 gene is subjected to a single-nucleotide polymorphism (G516T) with heterozygotes (GT) and homozygotes (TT) presenting decreased enzymatic activity. This case-control study aimed to investigate the association of CYP2B6 G516T polymorphism with the susceptibility of AML and its cytogenetic and clinical characteristics. Genotyping was performed on 619 AML patients and 430 healthy individuals using RCR-RFLP and a novel LightSNip assay. The major finding was a statistically higher frequency of the variant genotypes (GT and TT) in patients compared to the controls (GT:38.8% vs 29.8% and TT:9.3% vs 5.3% respectively) (p<0.001). More specifically, a significantly higher frequency of GT+TT genotypes in de novo AML patients (46.6%) and an immensely high frequency of TT in secondary AML (s-AML) (20.5%) were observed. The statistical analysis showed that the variant T allele was approximately 1.5-fold and 2.4-fold higher in de novo and s-AML respectively than controls. Concerning FAB subtypes, the T allele presented an almost 2-fold increased in AML-M2. Interestingly, a higher incidence of the TT genotype was observed in patients with abnormal karyotypes. In particular, positive correlations of the mutant allele were found in patients carrying specific chromosomal aberrations [-7/del(7q), -5/del(5q), +8, +21 or t(8;21)], complex or monosomal karyotypes. Finally, a strikingly higher frequency of TT genotype was also observed in patients stratified to the poor risk group. In conclusion, our results provide evidence for the involvement of the CYP2B6 polymorphism in AML susceptibility and suggest a possible role of the CYP2B6 genetic background on the development of specific chromosomal aberrations.

Abstract 17905: Aetiological Role of Folate Deficiency in Congenital Cardiovascular Malformation: Evidence From “Mendelian Randomisation” and Meta-Analysis

Background: The existence of a causal relationship between lower levels of plasma folate and congenital cardiovascular malformation (CVM) remains contentious. We undertook a genetic approach using the principles of “Mendelian randomization” to determine the causality of folate in CVM risk. Methods and Findings: We compared genotype frequencies at the methylene tetrahydrofolate reductase (MTHFR) C677T single nucleotide polymorphism (SNP) in 1186 CVM cases and 4168 controls. The TT genotype at MTHFR C677T is associated with lower plasma folate. Thus, if lower plasma folate had a causal effect on CVM risk, a higher frequency of TT genotype among CVM cases than among healthy controls would be anticipated. We placed our results in the context of a meta-analysis of all previously published studies of this question, which included a further 1883 cases and 3069 controls in 25 studies. We used random-effects models to meta-analyse the data. We conducted sensitivity analyses to examine folate fortification of flour as a potential source of heterogeneity. The primary genotyping data in 1186 cases and 4168 controls revealed a trend towards increased risk with the TT genotype, but this did not reach statistical significance (OR 1.15 [95% CI 0.94-1.40]). Combination of our primary data with previous studies, however, showed association in the complete dataset (OR 1.45 [95% CI 1.12-1.89]; p=0.005) comprising a total of 3069 CVM cases and 7271 controls. Studies conducted in countries without mandatory folate fortification showed an effect of C677T genotype on CVM risk (OR 1.63 [95% CI 1.19 - 2.25]) whereas studies conducted in countries with mandatory fortification did not (OR 0.96 [95% CI 0.64-1.44]). These odds ratios were significantly different from each other (p=0.032). Conclusions: We demonstrate genetic evidence in favour of a causal relationship between lower levels of plasma folate and CVM. Moreover, our results suggest that folate fortification abrogates the risk of CVM attributable to folate deficiency.

Association of pregnancy-associated plasma protein A polymorphism with preeclampsia — A pilot study

Objectives The aim of the study was to investigate genetic and biochemical background of PAPP-A (pregnancy-associated plasma protein A) in patients with risk pregnancies. Design and methods Five PAPP-A gene polymorphisms and PAPP-A maternal serum levels were studied together in 165 women in third trimester pregnancies complicated with threatening preterm labor (n = 98), preeclampsia (n = 35), intrauterine growth restriction (n = 34) and ICP (intrahepatic cholestasis of pregnancy) (n = 15). 114 healthy pregnant women served as controls. Results Preeclamptic patients had significantly higher frequency of TT genotype of Cys327Cys polymorphism compared to controls (p < 0.01). Patients with ICP had increased serum levels of PAPP-A compared to controls and correlation analysis showed significant relationship between PAPP-A and CRP (C-reactive protein) in the patients with intrauterine growth restriction (r = 0.49, p = 0.007). Conclusion Our study indicates the association of TT genotype of Cys327Cys polymorphism of the PAPP-A gene with preeclampsia. However, further study with larger groups of preeclamptic patients is needed to confirm our results.

Association Between Vascular Endothelial Growth Factor + 936 Genotype and Acute Respiratory Distress Syndrome in a Chinese Population

Acute respiratory distress syndrome (ARDS) is an often fatal condition for which a genetic predisposition is postulated, although no specific genes have been identified to date. Vascular endothelial growth factor (VEGF) is postulated to have a role in ARDS. The objective of this study is to explore whether the VEGF+936 genotype is associated with ARDS in a Chinese population. A hospital-based case-control study was conducted in 170 cases of ARDS and 170 controls. Polymerase chain reaction-restriction fragment length polymorphism analysis was performed to detect the VEGF+936 genotype. Patients with ARDS had a significantly higher frequency of TT genotype (odds ratio=3.85, 95% confidence interval=1.05, 14.06; p=0.04) than controls. The TT genotype was significantly associated with increased mortality from ARDS (odds ratio=5.72, 95% confidence interval=1.20, 27.33; p=0.03). This study suggests that the VEGF+936 TT genotype is a risk factor and may contribute to the prognosis of ARDS in the Chinese population. Further studies are needed to elucidate the mechanism of this association as well as to study its effects on larger populations.

131 Aetiological role of folate deficiency in congenital heart disease: evidence from Mendelian randomisation and meta-analysis

<h3>Background</h3> The existence of a causal relationship between lower levels of plasma folate and congenital heart disease (CHD) remains contentious. Randomised trials of this question are not possible, in view of the known protective effect of folate against neural tube defects (NTDs). Folate fortification of flour is known to reduce the incidence of NTDs, but it is not known whether there is any effect on CHD. Clarity regarding the relationship between folate and CHD could potentially inform the practice of folate fortification. We present a genetic approach using “Mendelian randomisation” to determining the causality of folate in CHD risk. <h3>Methods</h3> We compared genotype frequencies at the methylene tetrahydrofolate reductase (MTHFR) C677T single nucleotide polymorphism (SNP) in 1186 CHD cases and 4168 controls. The TT genotype at MTHFR C677T is known to be associated with lower activity of MTHFR and plasma folate, and higher levels of plasma homocysteine. The effect of TT genotype on plasma folate levels is greater in conditions of folate deficiency. Thus, if lower plasma folate had a causal effect on CHD risk, a higher frequency of TT genotype among CHD cases than among healthy controls would be anticipated, and this would be expected to be more marked in conditions of folate deficiency. We placed our results in the context of a meta-analysis of all previously published studies of this question (to September 2010), which together included 1883 cases and 3069 controls in 25 studies. Thus, the combined analyses included 3069 CHD cases and 7271 controls. We used random-effects models to combine the data. We conducted sensitivity analyses to examine folate fortification of flour as a potential source of heterogeneity. <h3>Results</h3> The primary genotyping data in 1186 cases and 4168 controls revealed a trend towards increased risk with the TT genotype, but this did not reach statistical significance (OR 1.15 (95% CI 0.94 to 1.40)). Combination of our primary data with previous studies, however, revealed association in the larger dataset (OR 1.45 (95% CI 1.12 to 1.89); p=0.005). The population attributable fraction for the TT genotype was 3% of CHD. There was no evidence of publication bias among the contributing studies. We discovered folate fortification status to be a significant source of heterogeneity. Studies conducted in countries with mandatory folate fortification showed no effect of C677T genotype on CHD risk (OR 0.96 (95% CI 0.64 to 1.44)), whereas studies conducted in countries without mandatory fortification showed a significant effect of genotype (OR 1.63 (95% CI 1.19 to 2.25)). These ORs were significantly different from each other (p=0.032). <h3>Conclusions</h3> We demonstrate genetic evidence in favour of a causal relationship between plasma folate and CHD. The absence of a genetic association in countries practicing folate fortification suggests that fortification largely abrogates the risk of CHD attributable to folate deficiency.