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...     

Genetic polymorphisms of N-acetyltransferase 2 and colorectal cancer risk

AIM: To identify the distribution of N-acetyltrasferase 2 (NAT2) polymorphism in Hebei Han Chinese and the effects of the polymorphism on the development of colorectal cancer. METHODS: We performed a hospital-based case-control study of 237 healthy individuals and 83 colorectal cancer patients of Hebei Han Chinese. DMA was extracted from peripheral blood and cancer tissues. The genotypes of the polymorphisms were assessed by PCR-restriction fragment length polymorphism(RFLP). RESULTS: There were four NAT2 alleles of WT, Ml, M2, and M3 both in the healthy subjects and in the patients, and 10 genotypes of WT/WT, WT/M1, WT/M2, WT/M3, Ml/Ml, M1/M2, M1/M3, M2/M2, M2/M3, M3/M3. M2 allele was present in 15.61% of healthy subjects and 29.52% of patients (X2 = 15.31, P<0.0001), and M3 allele was present in 30.59% of healthy subjects and 16.87% of patients (X2 = 25.33, P<0.0001). There were more WT/M2 (X2 = 34.42,P<0.0001, odd ratio = 4.99,95%CI = 2.27-9.38) and less WT/M3 (x2 = 3.80, P= 0.03) in the patients than in the healthy subjects. In 70.3% of the patients, there was a difference in NAT2 genotype between their tumors and blood cells. Patients had more WT/M2 (X2 = 5.11, P= 0.02) and less M2/M3 (X2= 4.27, P= 0.039) in their blood cells than in the tumors. Furthermore, 53.8% (7/13) of M2/M3 in tumors were from WT/M2 of blood cells. CONCLUSION: There is a possible relationship between the NAT2 polymorphisms and colorectal cancer in Hebei Han Chinese. The genotype WT/M2 may be a risk factor for colorectal cancer.     

COX-2基因多态性与结直肠癌发病风险的关系研究

目的 探讨环氧合酶-2(COX-2)-765G＞C、-1195G＞A、8473T＞C基因多态性与结直肠癌(CRC)遗传易感性的关系,同时评估COX-2基因多态性与某些因素共同作用对CRC发病风险的影响.方法 采用病例对照研究方法,入选CRC患者130例及健康非肿瘤人群120例.PCR-RFLP方法检测病例组和对照组COX-2基因的3个多态基因型,结果采用非条件logistic回归分析,用比值比(OR)及95％可信区间(CI)评估研究因素对疾病危险度的作用.结果 病例组COX-2-765G＞C、-1195G＞A、8473T＞C基因型频率与对照组间的差异均无统计学意义.根据体重指数(BMI)将研究对象分层后,发现-765GG基因型与CRC发病风险的相关性具有统计学意义,与正常BMI(＜23)相比,携带-765GG基因型且超重或肥胖者(BMI≥23)患CRC风险增高(OR=2.024,95％CI:1.089～3.760,P=0.024).此外,还发现吸烟可增加患CRC的风险,与不吸烟人群相比,吸烟人群中的8473TT基因型携带者患CRC的风险明显增高(OR=1.938,95％CI:1.021～3.677,P=0.042).结论 虽然COX-2 765G＞C、-1195G＞A、8473T＞C基因多态性与CRC遗传易感性之间没有相关性,但是携带-765GG基因型的高BMI人群或携带8473TT基因型的吸烟人群的CRC发生风险显著增高.对COX-2基因多态性位点的检测将有助于预防CRC的发生.     

LBP and CD14 polymorphisms correlate with increased colorectal carcinoma risk in Han Chinese

AIM: To explore the associations of polymorphisms of lipopolysaccharide binding protein (LBP), cluster of differentiation 14 (CD14), toll-like receptor 4 (TLR-4), interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) with the colorectal carcinoma (CRC) risk in Han Chinese. METHODS: Polymorphisms of LBP (rs1739654, rs223 2596, rs2232618), CD14 (rs77083413, rs4914), TLR-4 (rs5030719), IL-6 (rs13306435) and TNF-α (rs35131721) were genotyped in 479 cases of sporadic colorectal carcinoma and 486 healthy contr...     

Toll-like receptor 4 polymorphisms in dengue virus-infected children

Differential viral recognition by cells bearing Toll-like receptor 4 (TLR4) polymorphisms Asp299Gly and Thr399Ile may influence susceptibility and severity of dengue virus infection. In central Java, Indonesia, we investigated 201 children with dengue hemorrhagic fever (DHF) and 179 healthy controls. Patients and controls were mostly ethnic Javanese. A nearly complete cosegregation of the two mutations was observed. The TLR4 299/399 genotype was found in five patients and four controls. Prevalence of the TLR4 299/399 genotype did not differ significantly between controls and DHF patients or between patients with different severities of DHF. Also, vascular leakage in patients with different TLR4 genotypes did not differ. Thus, the 299/399 TLR4 haplotype has only minor influence on susceptibility and severity of complicated dengue virus infection.     

脂联素受体在结直肠癌和结直肠腺瘤组织中表达

目的:检测脂联素受体1(adiponectin receptors1,R1)和R2在人结直肠癌组织、腺瘤组织、癌旁组织中的表达情况与临床病理特征的关系及3种组织中R1和R2的关联性.方法:采用免疫组织化学SP法检测51例新鲜结直肠癌组织,42例结直肠腺瘤组织,35例癌旁组织中脂联素受体R1和R2的表达.结果:免疫组织化学结果显示R1在人结直肠癌组织中表达高于腺瘤组织(P=0.047),结直肠癌组织中表达高于癌旁组织(P=0.002),腺瘤组织中的表达高于癌旁组织(P=0.042).R2在人结直肠癌组织中表达高于腺瘤组织(P=0.035),结直肠癌组织中表达高于癌旁组织(P=0.002),腺瘤组织中表达高于癌旁组织(P=0.046).在3种组织中,R1与R2的表达无关联性(P>0.05).在51例结直肠癌组织中脂联素受体表达与分化程度、淋巴结转移、TNM分期相关(均P<0.05),与性别、年龄、肿瘤大小、组织学类型无明显相关(P>0.05).结论:脂联素受体在人结直肠癌组织、腺瘤组织、癌旁组织中普遍表达,且在结直肠癌组织中的表达最高,腺瘤次之.脂联素受体表达与分化程度、淋巴结转移、TNM(tumor regional lymph node and metastasis)分期有关.脂联素受体有可能成为结直肠癌治疗的一个新靶点.     

Role of Toll-like receptors 2 and 4 in the induction of cyclooxygenase-2 in vascular smooth muscle

Bacteria stimulate macrophages as part of normal host defense. However, when this response is not limited, vascular smooth muscle may also be activated to express "vasoactive" genes (e.g., cyclooxygenase), leading to vascular collapse and septic shock. In macrophages, Toll-like receptors (TLRs) 4 and 2 transduce responses to Gram-negative and Gram-positive bacteria, respectively. However, the role of these TLRs in sensing bacteria in vascular smooth muscle is unclear. To address this question, we have cultured vascular smooth muscle cells from mice deficient in TLR4 (TLR4(-/-) mice), mice deficient in TLR2 (TLR2(-/-) mice), or control mice. Cells cultured from control or TLR2(-/-) mice, but not from TLR4(-/-) mice, expressed cyclooxygenase-2 and released increasing levels of prostaglandin E(2) after stimulation with whole Escherichia coli bacteria; the combination of IL-1beta plus TNF-alpha induced cyclooxygenase-2 in cells cultured from all three groups of animals. By contrast, Staphylococcus aureus affected cyclooxygenase-2 expression in two distinct ways. First, S. aureus induced a transient inhibition of cyclooxygenase-2 expression, which was overcome with time, and increased protein expression was noted. The effects of S. aureus on cyclooxygenase-2 expression were TLR2- and not TLR4-dependent. Thus, we show that Gram-positive and Gram-negative bacteria induce cyclooxygenase-2 in vascular smooth muscle with differing temporal profiles but with appropriate TLR2-versus-TLR4 signaling. These data have important implications for our understanding of the innate immune response in vascular cells and how it may impact vascular disease.     

Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease

Toll-like receptors (TLRs) play an important part in the innate immune recognition of invading microorganisms, initiating sufficient immune responses. Growing amounts of data suggest that the ability of certain individuals to respond properly to TLR ligands may be impaired by single nucleotide polymorphisms (SNPs) within TLR genes, resulting in an altered susceptibility to, or course of, infectious or inflammatory disease. Most studies have focused on two cosegregating SNPs-Asp299gly and Thr399Ile-within the gene encoding TLR4, the receptor for bacterial lipopolysaccharide. These SNPs are present in approximately 10% of white individuals, and have been found to be positively correlated with several infectious diseases. However, these SNPs seem to protect from atherosclerosis and related diseases, which is reviewed in this article also. Meanwhile, SNPs of genes encoding other TLRs-eg, TLR2, which recognises a wide variety of microbial ligands-have been reported, and preliminary studies indicate an impact on susceptibility to infectious and inflammatory diseases as well. This review summarises and discusses the results obtained, and draws conclusions from these data.     

CYP2C19 polymorphisms in patients with gastric and colorectal carcinoma

Background It has been reported that up to 80% of human cancer arise as a consequence of environmental exposure and host susceptibility factors. Environmental carcinogens are predominantly metabolized by the cytochrome P450 (CYP) superfamily of drug-or xenobiotic-metabolizing enzymes. Genetic variations in these enzymes affect individuals' susceptibility to carcinogens. Aim of the study The aim of this study was to evaluate the relationship between CYP2C19 polymorphism and susceptibility to these cancers by means of CYP2C19 genotyping among Turkish subjects. Methods DNA of subjects were isolated from leukocytes by high pure template preparation kit (Roche Diagnostics, GmbH, Mannheim, Germany) and genotypes were detected by LightCycler CYP2C19 Mutation Detection Kit by real-time PCR with LightCycler instrument (Roche Diagnostics, cat. no. 3113914). Results Being male was associated with a 3.5-fold (OR: 4.27, CI: 2.27–8.05) and 4.27-fold (OR: 3.50, CI: 1.948–6.301) risk for colorectal and gastric carcinoma, respectively. The CYP2C19 ^* 3 heterozygote genotype was not found in either gastric or colorectal carcinoma patients. Although the frequency of CYP2C19^*2 heterozygote genotype is high in patients with gastric and colorectal carcinoma, it is not significantly associated with cancer (OR: 1.79, CI: 0.829–3.865 and OR: 1.998, CI: 0.961–4.154, respectively). Conclusion Although the frequency of CYP2C19 ^* 2 heterozygote genotype is high in our patients with gastric and colorectal carcinoma, there is no the relationship between CYP2C19 polymorphism and susceptibility to these cancer.     

Genetic polymorphisms in the cyclooxygenase-1 and cyclooxygenase-2 genes and risk of colorectal adenoma

Purpose  Cyclooxygenase (COX) enzymes, COX1 and COX2, are key in converting arachidonic acid (AA) into prostaglandins that have been associated with colorectal carcinogenesis. The aim of our study was to investigate associations of polymorphisms in COX genes, alone and in interaction with exposures known to be related to inflammation and AA metabolism, with risk of colorectal adenomas. Materials and methods  In a community-, colonoscopy-based case–control study with 162 incident, sporadic colorectal adenoma cases and 211 controls, we investigated associations of two promoter polymorphisms (−842 A  > G in COX1 and −765 G > C in COX2) and two polymorphisms in the 3′-UTR of COX2 (8473 T > C and 9850 A > G) with risk of adenomas. Multiple logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) of colorectal adenoma after adjusting for potential confounders. Results  Overall, there was no evidence for an association between any of the four polymorphisms and colorectal adenomas. However, we found a statistically significant interaction between the COX2 8473 T > C polymorphism and nonsteroidal anti-inflammatory drug (NSAIDs) use (P _interaction = 0.03): The greatest reduced risk was observed for individuals with the 8473 C variant allele who also regularly used NSAIDs (OR = 0.35, 95% CI 0.16–0.75). Conclusion  These results suggest that the C allele of COX2 8473 T > C polymorphism may interact with NSAIDs to reduce risk for colorectal adenoma.     

Integrin alpha-2 and beta-3 gene polymorphisms and colorectal cancer risk

Background and aims  Integrins such as α₂β₁, α_IIbβ₃, and α_vβ₃ have been suggested as key players for cancer development and progression. Several polymorphisms affecting these molecules, two in integrin α₂ (ITGA2 807C>T and 1648G>A) and one in β₃ (ITGB3 176T>C), influence their levels, structure, and possibly their function. To analyze the role of ITGA2 and ITGB3 polymorphisms for colorectal cancer risk and clinical presentation, we performed a case–control study. Materials and methods  Four hundred thirty-three colorectal cancer patients and 433 healthy sex- and age-matched control subjects were investigated. ITGA2 and ITGB3 polymorphisms were determined by 5′-nuclease assays. Results/findings  The ITGA2 807C>T polymorphism was associated with reduced colorectal cancer risk. In a codominant model, the odds ratio for each additional 807-T allele for colorectal cancer was 0.77 (95% confidence interval 0.64–0.94; p = 0.011). The ITGA2 1648G> and the ITGB3 176T>C polymorphism were not associated with colorectal cancer. None of the three polymorphisms investigated was associated with tumor size, histological grade, presence of primary lymph node metastases, tumor stage, or age at diagnosis. Interpretation/conclusion  We conclude that the ITGA2 807C>T polymorphism may be associated with reduced colorectal cancer risk. Armin Gerger and Günter Hofmann contributed equally to this work.     

Increased levels of ligands of Toll-like receptors 2 and 4 in type 1 diabetes

Aims/hypothesis  Type 1 diabetes is a proinflammatory state characterised by increased levels of circulating biomarkers of inflammation and monocyte activity. We have shown increased Toll-like receptor 2 (TLR2) and TLR4 expression and signalling in monocytes from type 1 diabetic patients. Several endogenous ligands of TLR2 and TLR4 have been identified; however, there is a paucity of data on levels of these endogenous ligands in diabetes. Thus, the aim of this study was to examine circulating levels of exogenous/endogenous ligands of TLR2 and TLR4 in type 1 diabetic patients and to compare these with the levels in matched healthy controls. Methods  Healthy controls (n = 37) and type 1 diabetic patients (n = 34) were recruited, and a fasting blood sample was obtained. Circulating levels of endotoxin, heat-shock protein 60 (Hsp60), high-mobility group box 1 (HMGB1) and growth arrest-specific 6 (GAS6) proteins were assessed by ELISA, and TLR2 and TLR4 expression was determined by flow cytometry. Results  Levels of the classical TLR4 ligand, endotoxin, were significantly elevated in type 1 diabetic patients compared with those in matched controls. Hsp60 and HMGB1 concentrations were also significantly increased in the patients (p < 0.01 and p < 0.001, respectively). No significant differences were observed in GAS6. Conclusions/interpretation  We report the novel observation that levels of ligands of TLR2 and TLR4 are significantly elevated in type 1 diabetes, and this, in concert with hyperglycaemia, accounts for the increase in TLR2 and TLR4 activity, underscoring the proinflammatory state of type 1 diabetes.     

乙型肝炎病毒转染及脂多糖刺激对HepG2细胞Toll样受体2和4表达的影响

目的探讨乙型肝炎病毒(HBV)转染对HepG2细胞表面Toll样受体(TLR)表达的影响及脂多糖(LPS)加重HBV转染致肝细胞损伤是否存在直接作用,进一步探讨乙型肝炎发病及重型化的发生机制。方法以不同浓度的LPS刺激HepG2细胞、HepG2．2．15细胞(转染HBV全基因组的HepG2细胞),并以免疫细胞化学方法检测HepG2细胞及HepG2．2．15细胞表面TLR 2、4蛋白质表达情况,以逆转录聚合酶链反应(RT-PCR)检测TLR2、4 mRNA表达情况,用Abbot试剂检测HepG2．2．15细胞HgsAg和HgeAg表达情况,用流式细胞仪观察细胞生长周期及细胞凋亡情况。结果HepG2、HepG2．2．15细胞膜上均有TLR2、4蛋白质表达,免疫细胞化学染色在未加LPS及各浓度LPS刺激细胞均可见细胞膜有棕褐色着色,且随着LPS浓度增加,其着色强度增加;对0mg/L及10mg/L LPS诱导HepG2、HepG2．2．15细胞RNA进行RT-PCR扩增,其产物行10g/L琼脂糖凝胶电泳均可见特异性条带,且10mg/L LPS诱导细胞TLR2和TLR4与分子量标准品的吸光度值比值明显高于0mg/L LPS诱导细胞扩增产物,分别为306．63±6．18对519．84±9．15和700．54±13．56对1116．62±37．67,F值分别为740．58和426．07,P值分别为0．01和0．02;流式细胞仪检测细胞周期发现HepG2绌胞及未经LPS诱导的HepG2．2．15未发生凋亡,各浓度LPS诱导的HepG2．2．15细胞均有细胞凋亡发生,且细胞凋亡率随着LPS浓度增加上升。结论LPS可能通过其与肝细胞膜上的TLR结合,而参与HBV转染后肝细胞损害及肝脏炎症重型化的发病机制。     

Retinol binding protein 4 primes the NLRP3 inflammasome by signaling through Toll-like receptors 2 and 4

Adipose tissue (AT) inflammation contributes to systemic insulin resistance. In obesity and type 2 diabetes (T2D), retinol binding protein 4 (RBP4), the major retinol carrier in serum, is elevated in AT and has proinflammatory effects which are mediated partially through Toll-like receptor 4 (TLR4). We now show that RBP4 primes the NLRP3 inflammasome for interleukin-1β (IL1β) release, in a glucose-dependent manner, through the TLR4/MD2 receptor complex and TLR2. This impairs insulin signaling in adipocytes. IL1β is elevated in perigonadal white AT (PGWAT) of chow-fed RBP4-overexpressing mice and in serum and PGWAT of high-fat diet-fed RBP4-overexpressing mice vs. wild-type mice. Holo- or apo-RBP4 injection in wild-type mice causes insulin resistance and elevates PGWAT inflammatory markers, including IL1β. TLR4 inhibition in RBP4-overexpressing mice reduces PGWAT inflammation, including IL1β levels and improves insulin sensitivity. Thus, the proinflammatory effects of RBP4 require NLRP3-inflammasome priming. These studies may provide approaches to reduce AT inflammation and insulin resistance in obesity and diabetes.

The incidence of type 2 diabetes (T2D) continues to increase worldwide and constitutes a major global health threat (1). Insulin resistance in muscle, adipose tissue (AT), and liver is a hallmark of T2D, which is associated with low-grade chronic inflammation, characterized by increased serum cytokine levels and a proinflammatory immune profile in AT (2–4). Pattern recognition receptors including Toll-like receptors (TLRs) sense pathogenic microbial components (pathogen-associated molecular patterns, PAMPs) and also host-derived damage-associated molecular patterns (DAMPs), which results in nonpathogen-initiated inflammation often referred to as “sterile inflammation” (5). In obesity, TLR2 and TLR4 are implicated in inflammation-induced insulin resistance in AT, and genetic deletion of TLR2 or TLR4 in mice results in improved insulin sensitivity (6, 7). In obese, insulin-resistant humans, TLR2 and TLR4 expression and activation are increased in AT compared to healthy controls (8) and some evidence suggests that people taking an antiinflammatory agent (abatacept, also known as CTLA4-Ig) which blocks antigen presentation, may have improved insulin sensitivity (9, 10). TLR2 and TLR4 signal through the adaptor proteins myeloid differentiation primary response gene 88 (MyD88) and TIR-domain-containing adaptor-inducing IFN (TRIF) to activate proinflammatory signaling cascades including nuclear factor kappa B (NFκB) and c-Jun N-terminal kinase (JNK) (5, 11). This results in AT immune cell migration, activation, and cytokine secretion which augments insulin resistance in adipocytes (12). Thus, TLR2 and TLR4 contribute to AT inflammation and insulin resistance and their targeting may provide treatment strategies for T2D.Retinol binding protein 4 (RBP4), the major serum retinol transporter, is secreted by the liver and AT (13, 14). Serum RBP4 levels are elevated in obese, insulin-resistant mice and humans (15, 16). Genetic and pharmacological elevation of RBP4 induces insulin resistance in wild-type (WT) mice (16, 17) and reducing RBP4 levels improves insulin sensitivity (16, 18). In humans, RBP4 levels are elevated with prediabetes and correlate positively with many metabolic syndrome-related components, including increased waist/hip ratio, intraabdominal fat mass, dyslipidemia, hypertension, and cardiovascular disease in large epidemiological studies (15, 19–21). A gain-of-function polymorphism in the RBP4 promoter which increases adipose RBP4 expression is associated with an 80% increased risk of T2D in humans (19, 22).Inflammation is critical for RBP4-induced insulin resistance which is partially mediated through TLR4 (17, 18, 23). RBP4 induces insulin resistance in adipocytes indirectly by increasing proinflammatory cytokine secretion from macrophages (23). Insulin resistance and AT inflammation have been observed in two mouse models of RBP4 overexpression. Mice overexpressing RBP4 driven by a muscle-specific promoter (RBP4-Ox) have elevated serum and perigonadal white adipose tissue (PGWAT) RBP4 protein levels and PGWAT inflammation (17). Elevated AT RBP4 in these mice activates antigen presentation through the JNK pathway which results in proinflammatory CD4 T cell proliferation and Th1 polarization (17). Mice overexpressing RBP4 selectively in adipocytes also have AT inflammation and glucose intolerance even on a chow diet (14). Transfer of RBP4-activated dendritic cells into normal mice is sufficient to cause AT inflammation and insulin resistance (17). Interestingly, overexpression of RBP4 selectively in hepatocytes has been reported not to cause elevated circulating RBP4 levels and is not associated with insulin resistance (24) even though hepatocytes are thought to be the major site for RBP4 secretion (25). Adipocytes can contribute to circulating RBP4 levels especially in obesity (14). Taken together, these data suggest that RBP4 in AT may be an obesity and insulin-resistance-related damage-associated molecule pattern.Activation of PAMP and DAMP receptors in immune cells leads to the assembly of inflammasomes, which are multiprotein complexes that cleave and activate interleukin-1 beta (IL1β) and interleukin-18 (IL18) (26). The nucleotide-binding domain and leucine-rich repeat containing protein 3 (NLRP3) inflammasome plays a role in the pathogenesis of obesity, type 1 diabetes, type 2 diabetes, and metabolic syndrome (26–28). NLRP3 knockout (KO) protects against insulin resistance in mice (27). NLRP3 activation requires a two-step process. The first “priming” occurs in response to TLR-mediated activation of the NFκB pathway resulting in expression of pro-IL1β (26). The second “activating” step directly induces inflammasome assembly which recruits and cleaves procaspase-1 to its active form caspase-1 (26). Caspase-1 mediates the cleavage of pro-IL1β resulting in IL1β release (26). The NLRP3 inflammasome can be activated by metabolites which are elevated in obesity and insulin resistance, such as palmitate (29). While an ever-expanding list of several metabolites is known to provide the second signal in inflammasome activation, there is a paucity of data on the endogenous proteins and metabolites that provide the first priming signal in obesity and T2D. Here we show that RBP4 is an endogenous NLRP3-inflammasome priming agent and we investigate its upstream signaling pathways.Our data show that elevating RBP4 levels by RBP4 injection in WT mice or genetically induced RBP4 overexpression markedly elevates adipose IL1β expression, which leads to PGWAT inflammation and insulin resistance. IL1β is elevated in PGWAT of chow-fed RBP4-Ox mice and in serum and PGWAT of HFD-fed RBP4-Ox mice compared to WT mice. The RBP4-mediated proinflammatory effects are mediated specifically through TLR2 and a TLR4/MD2 receptor complex, which does not require the other adaptor proteins LPS-binding protein and CD14. The activation of macrophages by RBP4 through TLR2 and TLR4/MD2 requires signaling through the downstream pathways MyD88 and TRIF. TLR4 inhibition in RBP4-Ox reduces IL1β levels in PGWAT and improves insulin sensitivity. The RBP4-mediated increase in IL1β release from macrophages is glucose dependent. Thus, targeting the NLRP3 inflammasome or the upstream activating receptors or pathways may provide therapeutic avenues to ameliorate RBP4-mediated insulin resistance and T2D.     

Cyclooxygenase-2 polymorphisms and the risk of esophageal adeno- or squamous cell carcinoma

AIM： TO determine whether -1195 A→G and/or -765 G→C polymorphisms in Cyclooxygenase-2 CCOX-2） may have a risk modifying effect on the development of esophageal carcinoma in a Dutch Caucasian population. METHODS： Two study groups were recruited, 252 patients with esophageal carcinoma and 240 healthy controls, matched for race, age, gender and recruiting area. DNA was isolated from whole blood and used for genotyping. PCR products were digested with restriction enzymes and products were analyzed by agarose gel electrophoresis. Odds ratios （OR） and 95% confidence intervals （CI） were estimated. RESULTS： The distribution of the -1195A→G polymorphism was significantly different in esophageal cancer patients compared to controls. The -1195 GG genotype resulted in a higher risk of developing esophageal adenocarcinoma （OR = 3.85, 95% CI： 1.45-10.3） compared with the -1195AA genotype as a reference. The -765 G→C genotype distribution was not different between the two groups. The GG/ GG haplotype was present more often in esophageal adenocarcinoma patients than in controls （OR = 3.45, 95% CI： 1.24-9.58; with AG/AG as a reference）. The same trends were observed in patients with squamous cell carcinomas, however, the results did not reach statistical significance. CONCLUSION： Presence of the COX-2 -1195 GG genotype and of the GG/GG haplotype may result in a higher risk of developing esophageal carcinoma.