An intron 4 VNTR polymorphism of the endothelial nitric oxide synthase gene is associated with early‐onset colorectal cancer

Abstract

Endothelial-derived nitric oxide, which is produced by endothelial nitric oxide synthase (eNOS), may play an important role in colorectal carcinogenesis. However, the putative contribution of common eNOS genetic polymorphisms to colorectal cancer risk remains unknown. We genotyped 3 polymorphisms of eNOS (T-786C, G894T, and intron4b/a) in 727 colorectal adenocarcinoma cases and 736 age-and sex-matched healthy controls in Taiwan. Genotypes of the T-786C and G894T polymorphisms were determined by fluorescence polarization assays and the 27-bp variable number of tandem repeat (VNTR) polymorphism in intron 4 (intron4b/a) was analyzed by PCR. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Among younger participants ( 60 yrs), the intron4a variant genotype was associated with a significantly increased risk of colorectal cancer, compared with the intron4bb genotype (OR 5 1.60, 95% CI 5 1.04-2.46). In addition, those young individuals bearing a greater number of high-risk genotypes (OR > 1, i.e., CT1TT for T-786C, ba1aa for intron4b/a, and GG for G894T) of eNOS had a higher colorectal cancer risk (p trend 5 0.039). Compared with younger individuals without any putative high-risk genotypes, those with 3 high-risk genotypes had a significantly greater cancer risk (OR 5 1.89, 95% CI 5 1.04-3.43). Our results suggest that the eNOS intron4b/a polymorphism may contribute to early-onset colorectal cancer risk in the Taiwanese population. ' 2008 Wiley-Liss, Inc.Key words: colorectal cancer; endothelial nitric oxide synthase; polymorphisms; early-onset The free radical nitric oxide (NO) is synthesized during the conversion of L-arginine to L-citrulline by nitric oxide synthase (NOS) isoforms, i.e., endothelial (e), inducible (i) and neuronal (n) NOS. 1 NO has an impact on multiple physiologic and pathophysiologic processes, including vasodilatation, neuronal transmission, smooth muscle relaxation, immunity, and carcinogenesis. [2][3][4] Data with respect to the role of NO in tumor promotion or inhibition are conflicting. 4 Studies suggest that overproduction of NO can cause DNA damage and inhibit DNA repair 5 and that NO also promotes tumor angiogenesis and metastasis. 6 However, other studies suggest that NO may protect cells from DNA damage by upregulating p53, 7 poly(ADP-ribose) polymerase (PARP) 8 and DNA-dependent protein kinase (DNA-PK). 9 Moreover, NO may exert antitumor effects with the reduction of tumor cell adhesion to endothelium, 10 activation of antioxidant defenses 11 and induction of apoptosis. 12 Studies have demonstrated elevated NOS expression and activity in ovarian cancer, 13 breast cancer 14 and central nervous system tumors. 15 However, expression of NOS in colorectal cancer has not been extensively investigated and results are controversial. Chhatwal et al. 16 found aberrant expression of NOS activity in colonic polyps and carcinomas compared to normal mucosa. Three studies also found diminished expression of eNOS in colorectal tumor tissues, 17-19 whereas ...

Nitric Oxide Synthase 3 Gene Variants and Colorectal Cancer: a Meta-Analysis

“…However, although with the powerful statistical analysis, we could not discover any associations in the two loci (G894T/rs1799983, T-786C/rs2070744) and CRC risk or the tumor sites and pathologic stages. According to the recent studies, the significant corrections in these two NOS3 polymorphisms were confirmed even though the reverse opinions presented, (Yeh et al, 2009;Jang et al, 2013) which promoted us to study these concerned polymorphisms further. After seeking for the essential characteristics of NOS3 gene, we found that rs1799983 was the non-synonymous mutation with splicing (ESE or ESS) function.…”

“…When reading all the abstracts, we left over 9 papers with association of CRC risk and NOS3 gene involved (Conde et al, 2006;Ikeda et al, 2008;Funke et al, 2009a;Funke et al, 2009b;Yeh et al, 2009;Ho-Pun-Cheung et al, 2011;Kim et al, 2011;Arıkan et al, 2012;Jang et al, 2013), after excluding the articles that didn't satisfy our criteria. While reviewing all the papers, we removed 3 articles as follows: (1) two studies mainly described the radiotherapy and chemotherapy without raw data of genotypes in the CRC and control groups (Funke et al, 2009b;Ho-PunCheung et al, 2011); (2) although one study investigated the candidate genes polymorphism and CRC risk, there was no data about the each allele (Ikeda et al, 2008).…”

“…While reviewing all the papers, we removed 3 articles as follows: (1) two studies mainly described the radiotherapy and chemotherapy without raw data of genotypes in the CRC and control groups (Funke et al, 2009b;Ho-PunCheung et al, 2011); (2) although one study investigated the candidate genes polymorphism and CRC risk, there was no data about the each allele (Ikeda et al, 2008). Then, 6 articles with the eligible data met the inclusion criteria were included (three had the data of rs2070744 and five about the rs1799983) (Conde et al, 2006;Yeh et al, 2009;Funke et al, 2009a;Kim et al, 2011;Arıkan et al, 2012;Jang et al, 2013), in which one study only collected the CRC samples (Kim et al, 2011). The characteristics and H-W for the studies were showed in the Table 1.…”

“…The characteristics and H-W for the studies were showed in the Table 1. As for two subgroups about tumor sites and pathologic stages, five sets of data could be extracted for rs2070744 and six for the rs1799983 (Yeh et al, 2009;Kim et al, 2011;Arıkan et al, 2012;Jang et al, 2013). Within the eligible studies, 3 was involved with Caucasian populations (Conde et al, 2006;Funke et al, 2009a;Arıkan et al, 2012), the others investigated Asian patients (Yeh et al, 2009;Kim et al, 2011;Jang et al, 2013).…”

The Endothelial Nitric Oxide Synthase Gene Variants as a Risk Factor for Chronic Lymphocytic Leukemia

“…[34][35][36] In studies for cancer suspectibility, it was found that eNOS 4 a/b variant is associated with colorectal cancer, prostate cancer, whereas there was no significant association with bladder cancer and overall cancers. 4,7,10,37,38 In sub-group analysis based on ethnicity of meta analysis, it was reported that the eNOS 4 a/b variant was associated with an increased risk of cancer in Caucasians. 24 In our study, we found that the the eNOS intron 4 a/b variant wasn't significantly different between patients and controls.…”