ABCB1 gene polymorphisms and haplotype analysis in colorectal cancer

Purpose  The aim of this study was to determine the significance of three most common single-nucleotide polymorphisms (SNPs) of ABCB1 gene in the development of colorectal cancer and to estimate the influence of these SNPs to surviving patients' treatment combination adjuvant therapy 5-fluorouracil/leucovorin. Haplotype structure of ABCB1 was analysed, and degree of linkage disequilibrium (LD) between SNPs of ABCB1 was estimated. Materials and methods  Tumour specimens of 95 patients with colorectal cancer and blood samples of 95 healthy cases were studied. Genotyping of ABCB1 gene was performed by automated sequencing or polymerase chain reaction-restriction fragment length polymorphism method. Comparison of frequencies of alleles/genotypes/haplotypes between the studied group (colorectal cancer samples) and the control group (blood samples) were analysed. These results were correlated with the surviving patients after treatment of adjuvant chemotherapy. Results  Significant differences in ABCB1 _1236C>T (p = 0.00043) and ABCB1 _2677G>T/A (p = 0.04) genotype distribution and T₁₂₃₆ allele distribution (CT₁₂₃₆ or TT₁₂₃₆ vs CC₁₂₃₆; p = 0.0499, OR = 0.55, Fi–Yule coefficient = 0.14) were found. A strong LD between ABCB1 _1236C>T and ABCB1 _2677G>T/A SNPs (D′ = 0.621, r ² = 0.318) was detected. All SNPs were located in one haplotype block. There were significant differences in haplotype distributions between colorectal cancer patients and healthy population (p = 0.03). Significant differences in survival probability of colorectal cancer patients' treatment chemotherapy according to allele of ABCB1 _3435C>T was observed. Survival probability of patients with wild-type C₃₄₃₅ allele were higher than among patients without this allele (p = 0.04572). Conclusions  These results suggested that three studied SNPs of ABCB1 were located in one haplotype block. Differences in ABCB1 _1236C>T and ABCB1 _2677G>T/A genotypes and T₁₂₃₆ allele distribution between investigated populations indicate significant impact of these SNPs on risk of development of colorectal cancer. Polymorphism ABCB1 _3435C>T may be a prediction marker of cancer chemotherapy effectiveness. Differences in haplotype distributions between colorectal cancer patients and healthy population suggested that other potential SNPs, especially in regulatory region of ABCB1 gene, may influence P-glycoprotein expression and function.     

Lack of association between tyrosine kinase 2 (TYK2) gene polymorphisms and susceptibility to SLE in a Japanese population

Tyrosine kinase 2 (TYK2) is a type I interferon (IFN) signaling pathway gene and was previously reported to be a risk factor for systemic lupus erythematosus (SLE) in Caucasian populations. In order to test for its genetic association with SLE in a Japanese population, TYK2 single nucleotide polymorphisms (SNPs), rs2304256, rs12720270 and rs280519, were genotyped. A case–control association study was performed in a total of 411 Japanese SLE patients and 467 healthy controls. Linkage disequilibrium (LD) among TYK2 SNPs was examined. According to the data from 94 healthy controls, non-synonymous rs2304256 resulting in Val → Phe substitution was revealed to be in a LD with rs12720270 and rs280519. Therefore, we further genotyped rs2304256 as a tag SNP in the full sample sets. As a result, no differences in genotype distribution and allelic frequencies of rs2304256 were found between SLE patients and healthy controls. In conclusion, TYK2 is not a genetic risk factor for SLE in a Japanese population. Our result suggests that there is an ethnic difference in the susceptibility genes for SLE.     

ITGA1 polymorphisms and haplotypes are associated with gastric cancer risk in a Korean population

AIM:To evaluate the association between the geneticpolymorphisms and haplotypes of the ITGA1 gene and the risk of gastric cancer.METHODS:The study subjects were 477 age-and sex-matched case-control pairs.Genotyping was performed for 15 single nucleotide polymorphisms(SNPs)in ITGA1.The associations between gastric cancer and these SNPs and haplotypes were analyzed with multivariate conditional logistic regression models.Multiple testing corrections were carried out following methodology for controlling the false discovery rate.Gene-based association tests were performed using the versatile gene-based association study(VEGAS)method.RESULTS:In the codominant model,the ORs for SNPs rs2432143(1.517;95%CI:1.144-2.011)and rs2447867(1.258;95%CI:1.051-1.505)were statistically significant.In the dominant model,polymorphisms of rs1862610 and rs2447867 were found to be significant risk factors,with ORs of 1.337(95%CI:1.029-1.737)and 1.412(95%CI:1.061-1.881),respectively.In the recessive model,only the rs2432143 polymorphism was significant(OR=1.559,95%CI:1.150-2.114).The C-C type of ITGA1 haplotype block 2 was a significant protective factor against gastric cancer in the both codominant model(OR=0.602,95%CI:0.212-0.709,P=0.021)and the dominant model(OR=0.653,95%CI:0.483-0.884).The ITGA1 gene showed a significant gene-based association with gastric cancer in the VEGAS test.In the dominant model,the A-T type of ITGA1 haplotype block 2 was a significant risk factor(OR=1.341,95%CI:1.034-1.741).SNP rs2447867 might be related to the severity of gastric epithelial injury due to inflammation and,thus,to the risk of developing gastric cancer.CONCLUSION:ITGA1 gene SNPs rs1862610,rs2432143,and rs2447867 and the ITGA1 haplotype block that includes SNPs rs1862610 and rs2432143 were significantly associated with gastric cancer.     

Dependency of phenprocoumon dosage on polymorphisms in the VKORC1 and CYP2C9 genes

Objectives Polymorphisms in the vitamin K epoxide–reductase-complex-1 (VKORC1) and the cytochrome-P450-isozyme (CYP2C9) genes account for therapeutic responses to vitamin K antagonists (VKA). This study aimed to investigate the prevalence of VKORC1 and CYP2C9 polymorphisms among patients under phenprocoumon and its influence on the VKA dosage. Methods Patients under phenprocoumon were screened for the polymorphisms −1639G > A and 3730G > A in the VKORC1 gene and 430C > T and 1075A > C in the CYP2C9 gene by means of a StripAssay. Baseline clinical and laboratory parameters were registered. Results Among 53 patients (28 females, mean age 72.5 years), VKORC1 polymorphisms were found in 34 [−1639G > A: homozygote (n = 11), heterozygote (n = 23)] and 28 [3730G > A: homozygote (n = 7), heterozygote (n = 21)] patients. Thirteen patients were compound heterozygote. CYP2C9 polymorphisms were found in 12 [430G > T: homozygote (n = 1), heterozygote (n = 11)] and 7 [1075A > C: homozygote (n = 0), heterozygote (n = 7)] patients. Seventeen patients had at least one VKORC1 and one CYP2C9 polymorphism. Mean phenprocoumon dosage per week to achieve therapeutic anticoagulation was lower (higher) in patients with than without the VKORC1 polymorphism −1639G > A (3730G > A) or the CYP2C9 polymorphisms. Despite the presence of VKORC1 or CYP2C9 polymorphisms, mean International Normalized Ratio was not significantly different between patients with and without polymorphisms. Conclusions Though VKORC1 and CYP2C9 polymorphisms influence the phenprocoumon dosage necessary to achieve therapeutic anticoagulation, anticoagulation is therapeutic if carefully monitored.     

Association of E-cadherin (CDH1) gene polymorphisms and gastric cancer risk

AIM:To investigate the associations between CDH1 gene polymorphisms and gastric cancer(GC) risk predisposition.METHODS:We analyzed four CDH1 polymorphisms(+54 T>C,-160 C>A,-616 G>C,-3159 T>C) in an Omani population,by extraction of genomic DNA from the peripheral blood of 192 patients with GC and 170 control participants and performed CDH1 genotyping using DNA sequencing.RESULTS:CDH1-160-AA genotype was associated with an increased risk of GC(OR = 3.6,95% CI:1.1-11.8)(P = 0.03).There was no significant asso...     

ADRB2基因多态性/单倍型与中国南方汉族人群支气管哮喘相关表型的关系

目的 研究中国南方汉族人群β2肾上腺素能受体(ADRB2)基因单核苷酸多态性/单倍型与支气管哮喘(简称哮喘)相关表型的相关性.方法 采用Taqman探针法对379例哮喘患者和435例健康对照者ADRB2基因6个位点(T-2387C、5'LC Arg19 Cys、Arg16Gly、Glu27Gln、Thr164Ile和C523A)进行基因分型,并确定其单倍型.采用酶联免疫吸附(enzyme linked immunosorbent assay,ELISA)法检测血清总IgE.结果 164位均为野生型纯合基因型,未检测到突变型等位基因,未纳入统计分析.T-2387C、5'LC Arg19 Cys、Arg16Gly、Glu27Gln和C523A基因型频率和单倍型频率在轻+中度哮喘组与重度哮喘组间分布差异均无统计学意义(x2分别为:2.45,4.12,0.43,5.81,0.44;2.39,0.80,1.42,0.20,P值均＞0.05),在夜间哮喘组与非夜间哮喘组间分布差异亦无统计学意义(x2分别为:0.77,1.51,1.68,1.51,1.03;1.05,0.45,1.01,0.40,P值均＞0.05).哮喘组血清总IgE[(83.95±67.35) μg/L]高于正常健康组[(66.12±61.27)μg/L)],各位点基因型间血清总IgE水平比较差异无统计学意义(x2或Z值分别为:1.88,-1.21,1.677,-1.17,1.93,P值均＞0.05),5个位点组成的4种纯合型单倍型间血清总IgE水平比较差异亦无统计学意义(x2为1.33,P＞0.05).同种基因型的哮喘患者血清总IgE水平与哮喘病情严重程度及夜间哮喘差异均无统计学意义(Z值分别为:-0.73,-0.06,-0.64,-1.35,-1.82,-1.15,-0.05,-1.15,-1.37,-1.78,-0.44,-0.01,-0.35;-1.48,-0.93,-0.45,-0.42,-0.48,-0.11,-0.09,-0.80,-0.27,-0.26,-0.30,-0.23,-1.03,P值均＞0.05).但将不同严重程度哮喘组分层分析发现,重度哮喘组Arg/Cys19+Cys/Cys19、Gln/Glu27+Glu/Glu27有更高的血清IgE水平.结论 ADRB2基因单核苷酸多态性/单倍型与哮喘严重程度、夜间哮喘无显著相关性,但-47、79位可能与重度哮喘患者血清总IgE有关.     

Associations of the CTLA-4 polymorphisms with type 1 diabetes in a Chilean population: Case-parent design

CTLA-4 plays a key role in T cells regulation. We analysed the CTLA-4 +49A/G and −318C/T polymorphisms in 178 cases of type 1 diabetes and their parents (534 individuals) from Santiago, Chile. A significant overall association with T1D (p = 0.028) was observed, possibly due to an overtransmission of the G–T haplotype.     

Association of adrenergic receptor gene polymorphisms in gallbladder cancer susceptibility in a North Indian population

Purpose

Gallbladder cancer (GBC), the most common gastrointestinal and biliary tract malignancy, often coincides with gallstone disease (GSD). The genetic variants of adrenergic receptor (ADR) have been previously reported to be associated with hypomotility disorder of cardiovascular system and GSD. Since GSD may function as GBC precursor, the present study aimed to investigate the association of common functional genetic variants of ADRA2A C-1291G, ADRβ3 T190C or Trp64Arg, and ADRβ1 C1165G or Arg389Gly with GBC and GSD susceptibility.

Methods

The present study included a total of 400 histologically confirmed GBC, 230 GSD, and 268 healthy controls. The ADRA2A C-1291G, ADRβ3 T190C, and ADRβ1 C1165G polymorphisms were determined by PCR–RFLP. Statistical analysis was performed by using SPSS version 16.

Results

ADRβ3 T190C polymorphism was significantly associated with increased risk of GBC (CT: Pcorr = 0.015, OR 2.87; CC: Pcorr = 0.038, OR 10.33; C allele: Pcorr = 0.014, OR 2.7; CT + CC: Pcorr = 0.017, OR 3.05). These associations existed even after gallstone and gender stratification. Similarly, ADRβ3 T190C polymorphism was also associated with GSD risk, though limited only to female GSD patients. In contrary, ADRA2A C-1291G conferred a marginally increased risk only in GSD patients. ADRβ1 C1165G polymorphism was not associated with GBC and GSD susceptibility when compared to controls.

Conclusion

ADRβ3 T190C polymorphism is significantly associated with GBC and GSD susceptibility. The ADRβ3 T190C may be involved in the pathophysiology of GBC by both gallstone-dependent pathway and by some other independent mechanisms.     

Association study of genetic polymorphisms of SLC2A10 gene and type 2 diabetes in the Taiwanese population

Aims/hypothesis The gene encoding solute carrier family 2, facilitated glucose transporter, member 10 (SLC2A10, previously known as glucose transporter 10 [GLUT10]) is a promising candidate gene for type 2 diabetes since it is highly expressed in liver and pancreas and is located on human chromosome region 20q12–q13.1, a region previously shown to harbour type 2 diabetes susceptibility genes. We investigated whether the SLC2A10 gene could be a type 2 diabetes susceptibility gene in the Taiwanese population.Subjects and methods Sequencing of SLC2A10 gene from 48 diabetic subjects detected short tandem repeat polymorphisms in the promoter region, but did not detect any other sequence variants or new single-nucleotide polymorphisms (SNPs) other than those already in the SNPper database () (30 June 2005).Results Using these genetic polymorphisms, we divided the SLC2A10 gene into four distinct linkage disequilibrium blocks and performed a case-control association study in a group of type 2 diabetes subjects (n=375) and normoglycaemic individuals (n=377). The HapD (A-G-T-C) haplotype in block 3, a rare haplotype, which consisted of four SNPs (rs3092412, rs2235491, rs2425904 and rs1059217), was modestly associated with type 2 diabetes with a haplotype score of −2.95567 (p=0.012 with the haplotype-specific test).Conclusions/interpretation Our results suggest that SLC2A10 genetic variations do not appear to be major determinants for type 2 diabetes susceptibility in the Taiwanese population.W. H. Lin and L. M. Chuang contributed equally to this work.     

Interleukin-23 receptor (IL-23R) gene polymorphisms in acquired aplastic anemia

Acquired aplastic anemia (AA) is a rare disease with a complex pathogenesis. In most cases, T cell-mediated immune destruction of hematopoietic cells results in peripheral blood pancytopenia and bone marrow hypoplasia. A subset of the heterodimeric interleukin-23 receptor gene (IL-23R) is significantly associated with autoimmune-mediated diseases. To examine whether IL-23R single nucleotide polymorphisms (SNPs) might contribute to AA, we selected three IL-23R SNPs with amino acid changes (rs11209026: p.Arg381Gln; rs41313262: p.Val362Ile; and rs11465797: p.Thr175Asn) and compared their frequencies in 279 AA patients and 184 ethnically matched healthy controls. The three SNP prevalences were similar between the AA patients and controls. The Arg381Gln variant, which has a strong protective effect against inflammatory bowel disease, showed no association with AA. Furthermore, IL-23 levels in sera were measured in the AA patients and in controls, and there were no significant differences among them. Our results indicate that these three IL-23R SNPs and serum IL-23 level have no apparent impact on susceptibility to AA.     

Genetic association of single nucleotide polymorphisms in endonuclease G-like 1 gene with type 2 diabetes in a Japanese population

Aims/hypothesis In order to identify type 2 diabetes disease susceptibility gene(s) in a Japanese population, we applied a region-wide case–control association test to the 20.4 Mb region between D3S1293 and D3S2319 on chromosome 3p24.3-22.1, supported by linkage to type 2 diabetes and its related traits in Japanese and multiple populations. Materials and methods We performed a two-stage association test using 1,762 Japanese persons with 485 gene-centric, evenly spaced, common single nucleotide polymorphism (SNP) markers with minor allele frequency >0.1. For mouse studies, total RNA was extracted from various organs of BKS.Cg-+Lepr ^db /+Lepr ^db and control mice, and from MIN6, NIH3T3 and C2C12 cell lines. Results We detected a landmark SNP375 (A/G) (rs2051211, p = 0.000046, odds ratio = 1.33, 95% CI 1.16–1.53) in intron 5 of the endonuclease G-like 1 (ENDOGL1) gene. Systematic dense SNPs approach identified a susceptibility linkage disequilibrium (LD) block of 116.5 kb by |D′|, an LD units map and a critical region of 2.1 kb by r ² in ENDOGL1. A haplotype-based association test showed that an at-risk haplotype is associated with disease status (p = 0.00001). The expression of ENDOGL1 was rather ubiquitous with relatively abundant expression in the brain and also in a pancreatic islet beta cell line. Mouse Endogl1 expression increased in pancreatic islets of hyperglycaemic BKS.Cg-+Lepr ^db /+Lepr ^db mice compared with that in control mice. Conclusions/interpretation Based on the population genetics, fine mapping of LD block and haplotype analysis, we conclude that ENDOGL1 is a candidate disease-susceptibility gene for type 2 diabetes in a Japanese population. Further analysis in a larger sample size is required to substantiate this conclusion. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

Functional assessment of compound mutations in the KCNQ1 and KCNH2 genes associated with long QT syndrome

BACKGROUND: Long QT syndrome (LQTS) is a cardiovascular disorder characterized by prolonged QTc time, syncope, or sudden death caused by torsades de pointes and ventricular fibrillation. We investigated the clinical and electrophysiologic phenotype of individual mutations and the compound mutations in a family in which different genotypes could be found. OBJECTIVES: The purpose of this study was to determine the impact of genotype-based diagnostic assessment in LQTS. METHODS: We used cascade screening and functional analyses to investigate the phenotype in a family with LQTS. The contributions of the compound mutations in the KCNQ1 and KCNH2 genes (KCNQ1 R591H, KCNH2 R328C) were analyzed by heterologous expression in Xenopus laevis oocytes using two-electrode voltage clamp and by confocal imaging. RESULTS: KCNH2 R328C did not show any functional phenotype whereas KCNQ1 R591H resulted in severe reduction of current. Neither wild-type nor mutant channels affected each other functionally in coexpression experiments. Therefore, a direct interaction between KCNQ1 and KCNH2 was ruled out under these conditions. CONCLUSION: Assessment of novel mutational findings in LQTS should include accurate genetic and functional analysis. Notably, appropriate studies are needed if two or more mutations in different genes are present in one proband. Our findings prompt reconsideration of the impact of compound mutations in LQTS families and reinforce the need for thorough functional evaluation of novel ion channel mutations before assignment of pathogenic status.     

N-Acetyltransferase 2 genetic polymorphisms and risk of colorectal cancer

AIM:To investigate the possible association between meat intake,cigarette smoking and N-acetyltransferase 2 (NAT2) genetic polymorphisms on colorectal cancer (CRC) risk.METHODS:Patients with CRC were matched for gender and age to healthy controls.Meat intake and cigarette smoking were assessed using a specific frequency questionnaire.DNA was extracted from peripheral blood and the genotypes of the polymorphism were assessed by polymerase chain reaction-restriction fragment length polymorphism.Five NAT2 alle...     

Low-density lipoprotein receptor-related protein-associated protein (LRPAP1) gene IVS5 insertion/deletion polymorphism is not a risk factor for gallstone disease in a Polish population

BACKGROUND: There is growing evidence that gallstone formation may be genetically determined. It was recently presented that a common polymorphism in the LRPAP1 gene might be associated with gallstone disease. AIM: Since reproducibility of data is important in genetic association studies, a case control study was designed to find out whether LRPAP1 gene polymorphism is associated with gallstone disease in a Polish population. SUBJECTS: Two hundred eighty-nine Polish Caucasian gallstone disease patients and 251 healthy controls participated in the study. METHODS: A 37-bp insertion/deletion polymorphism in intron 5 of LRPAP1 (rs11267919) was determined by means of polymerase chain reaction assay. RESULTS: The frequencies and distribution of the insertion/deletion alleles did not differ significantly between gallstone disease patients and controls. No significant gender-related differences in allele frequencies or distributions were noted. CONCLUSION: The LRPAP1 insertion/deletion polymorphism is not associated with gallstone disease in a Polish population.     

miRNA polymorphisms and risk of gastric cancer in Asian population

miRNAs are endogenous 19-to 25-nt noncoding RNAs that can negatively regulate gene expression by directly cleaving target mRNA or by inhibiting its translation.Recent studies have revealed that miRNA plays a significant role in gastric cancer development either as a tumor suppressor gene or oncogene.miRNA-singlenucleotide polymorphisms(SNPs),as a novel class of functional SNPs/polymorphisms,have been identified as candidate biomarkers for gastric cancer susceptibility.On the basis of recent data,the present review summarizes current knowledge of the functional effects of miRNA-SNPs and their importance as candidate gastric cancer biomarkers.Additionally,this review also includes a meta-analysis of the most frequently studied miRNA-SNPs in gastric cancer.     

The correlation of genetic instability of PINX1 gene to clinico-pathological features of gastric cancer in the Chinese population

Purpose  This project explored the influence of loss of heterozygosity (LOH) and microsatellite instability (MSI) of locus D8S277 to PINX1 expression of gastric cancer in Chinese people. Methods  LOH and MSI of locus D8S277 in 90 paraffin-embedded gastric carcinoma specimens were detected by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). Envision immunohistochemistry was used to assess the expression of PINX1. Results  The frequency of LOH was higher in cases with lymph node metastasis than those without (18.57 vs. 0.00%, P < 0.01), and was higher in the specimens that were at TNM stage III + IV than those at stage I + II (21.43 vs. 2.94%, P < 0.01). In terms of the frequency of MSI, it was lower in cases with lymph node metastasis than those without (10.00 vs. 30.00%,P < 0.05). The positive rate of PINX1 protein was higher in samples without lymph node metastasis than those with lymph node metastasis (80.00 vs. 50.00%, P < 0.01); and was higher in the cases at TNM stage I + II than those at stage III + IV; and was lower in the cases between 40 and 60 years old than those above 60 years old (43.75 vs. 65.52%, P < 0.05). Conclusion  LOH and MSI of PINX1 may play major role in tumor development and regulate it through different pathways. Because LOH plays a major role in negative expression of PINX1, it can be regarded as a sign of gastric cancer development and MSI may affect the prognosis and tumor turnover.     

New molecular marker for Trypanosoma (Duttonella) vivax identification

Trypanosoma vivax is a widespread hemoparasite in tropical areas and is pathogenic to ruminant domestic livestock as well as wild ruminants. The accurate identification of parasites in both hosts and vectors is crucial for epidemiological studies and disease control programs. We describe here the development of molecular markers specific for T. vivax identification. These markers were used to identify mouthpart infections in field-collected tsetse flies from Cameroon. The markers target the genomic sequence of a species-specific antigen from the bloodstream stages. No cross amplification with other trypanosome species was observed, which makes the markers a reliable tool to detect T. vivax infections, both in hosts and vectors. The PCR-amplified sequence contains a (CA)_n microsatellite repeat for which 11 different alleles were identified. This microsatellite, which showed high polymorphism, provides a suitable marker for population genetic studies.     

Haplotype analysis of signal peptide (insertion/deletion) and XbaI polymorphisms of the APOB gene in gallbladder cancer.

PURPOSE: The incidence of gallbladder cancer (GBC) is usually paralleled by the prevalence of gallstone disease, and genes of cholesterol metabolism have been implicated in gallstone disease. The XbaI and insertion/deletion (ins/del) polymorphism of Apolipoprotein B (APOB) appears to influence cholesterol homoeostasis and possibly risk for gallstone disease. We examined the effect of these polymorphisms individually as well as their haplotypes on GBC and gallstone patients in North Indian population. METHODS: The study comprises 123 consecutive cases of proven GBC, 172 cases of gallstone and 232 healthy subjects of similar age and sex. The genomic DNA was extracted from peripheral blood leucocytes and genotyping was performed using polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism. RESULTS: In a case-control study, APOB XbaI and ins/del polymorphisms were not significantly associated with risk of GBC. Using the expectation maximization algorithm, four haplotypes were obtained, and haplotype X(+),D was found to be significantly higher in GBC patients without stone in comparison with healthy subjects [odds ratio (OR) 2.9, 95% confidence interval 1.2-6.6 P=0.012]. CONCLUSIONS: The X(+),D haplotype of APOB is associated with increased risk for development of GBC and the risk is not modified in the presence of gallstones.     

VEGF gene polymorphisms and susceptibility to colorectal cancer disease in Italian population

Background  The vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen involved in the process of angiogenesis, a crucial phase in tumor growth and metastasis. We carried out a case–control study to evaluate whether polymorphisms of VEGF gene modulate the risk of developing colorectal cancer disease (CCD). Materials and methods  We evaluated VEGF −2578A/C, −460T/C, and +405C/G genotypes obtained from a series of 302 CCD patients and 115 controls from the Italian population using polymerase chain reaction restriction fragment length polymorphism assay. Results  Strong linkage disequilibrium (LD) was detected between −2578A/C and −460T/C (D′ = 0.97; CI = 0.93–1) and between −2578A/C and +405C/G (D′ = 0.97; CI = 0.98–1) in the case group. Complete LD was detected between −2578A/C and +405C/G and between −460T/C and +405C/G (D′ = 1; CI = 0.84–1; CI = 0.82–1, respectively) in the control group. A reduced risk for the disease was associated with −2578C/A and −2578C/C (odds ratio (OR) = 0.34, CI = 0.162–0.676 and OR = 0.38, CI = 0.181–0.775, respectively). A direct association was found for carriers of the VEGF −460C/C polymorphism (OR = 3.55; CI = 1.659–8.469). We identified a protective haplotype −2578A, −460T, and +405G (OR = 0.04; CI = 0.009–0.19) and two different high-risk haplotypes −2578A, −460C, and +405G (OR = 1.90; CI = 1.31–2.27) and −2578C, −460C, and +405C (OR = 9.62; CI = 1.3–70.87). Conclusions  The present study suggests that the VEGF gene polymorphisms may play a role in the development of colorectal cancer. Paolo Maltese and Emanuele Canestrari contributed equally to the study.