Complement Receptor 1 (A3650G RsaI and Intron 27 HindIII) Polymorphisms and Risk of Gallbladder Cancer in North Indian Population

Decreased expression due to genetic variations in complement receptor 1 (CR1) on erythrocytes might result in reduced clearance of immune complexes, conferring interindividual variation for gallbladder cancer (GBC) susceptibility. We studied role of CR1 (A₃₆₅₀G RsaI and Intron 27 HindIII) polymorphisms in gallstone disease and GBC in north Indian population. Study included 185 GBC patients, 185 gallstone patients and 200 controls. Genotyping was done by PCR‐RFLP. Result showed GG genotype and G allele of CR1 A₃₆₅₀G RsaI were conferring significant risk for GBC [(P = 0.022; OR = 1.94; 95% CI = 1.1–3.4) and (P = 0.035; OR = 1.35; 95% CI = 1.0–3.8) respectively]. Also, comparison of GBC patients with gallstone patients showed increased risk for GBC in presence of GG genotype and G allele GBC (P = 0.048; OR = 1.74; 95% CI = 1.0–3.0) and (P = 0.027; OR = 1.39; 95% CI = 1.0–1.8) respectively. No association of CR1 A₃₆₅₀G RsaI polymorphism was observed when gallstone patients were compared with controls. CR1 Intron 27 HindIII polymorphism was not associated with GBC and gallstone susceptibility. Haplotype analysis showed increased risk of GBC in presence of G,L haplotype (P = 0.046; OR = 1.35: 95% CI = 1.0–1.8). Subgroup stratifications on basis of gender and gallstone status showed GG genotype of CR1 A₃₆₅₀G RsaI polymorphism imparted high risk for GBC in females (P = 0.043; OR = 1.99: 95% CI = 1.4–3.9). Also there was increased risk for GBC in presence as well as absence of gallstones (OR = 1.85 and 1.76 respectively), but it was not statistically significant. We conclude that CR1 A₃₆₅₀G RsaI polymorphism plays an important role in conferring genetic susceptibility to gallbladder cancer GBC in north Indian population.     

IL-1 gene polymorphisms and genetic susceptibility of gallbladder cancer in a north Indian population

Long-standing gallstones are generally present in 65-80% patients of gallbladder cancer (GBC). It has also been suggested that inflammation caused by gallstones may be involved in the development of GBC. Interleukin-1 receptor antagonist (IL-1RN) and interleukin-1 beta (IL-1B) are proinflammatory cytokine genes at the interleukin-1 locus, and polymorphisms of these genes have been associated with various inflammatory diseases. The aim of this study was to investigate whether polymorphism in the IL-1RN and IL-1B genes are associated with GBC patients with and without gallstones. Polymorphisms within the IL-1RN 86-base pair VNTR (variable number tandem repeat) and IL-1B (-511C --> T) were genotyped using polymerase chain reaction (PCR) and PCR restriction fragment length polymorphism in 166 healthy subjects and 124 GBC patients. The frequency of the IL-1RN, VNTR 2/2 genotype was significantly higher in GBC patients [P = 0.017; odds ratio (OR) = 3.25; 95% confidence interval (CI) = 1.23-8.58]. CC genotype and 'C' allele of the -511IL-1B C --> T polymorphism also showed high risk for GBC (P = 0.033; OR = 3.36; 95%CI = 1.52-7.43, P = 0.047, OR = 1.41; 95%CI = 1.00-1.98, respectively). The higher cancer risk due to the IL-1RN, 2/2 genotype was observed in GBC patients with or without stones (P = 0.038; OR = 3.58; 95%CI = 1.08-11.65, P = 0.035; OR = 3.33; 95%CI = 1.08-10.61). Risk due to the CC genotype of IL-1B, however, was confined to GBC patients harboring gallstones (P = 0.0003; OR = 6.92; 95%CI = 2.65-18.03). The haplotype 1/C of IL-1RN and IL-1B was found to confer a significantly enhanced risk of GBC in cancer patients with gallstones (P = 0.022; OR = 2.19; 95%CI = 1.12-4.27), while higher risk resulting from 2/C haplotype was of borderline significance (P = 0.061; OR = 3.04; 95%CI = 0.95-9.70). Individuals with 1/C and 2/C haplotypes of IL-1RN VNTR and -511IL-1B C --> T polymorphisms were more susceptible to develop GBC with gallstones compared to healthy controls in north India.     

Genetic susceptibility of epidermal growth factor +61A>G and transforming growth factor beta1 -509C>T gene polymorphisms with gallbladder cancer

Epidermal growth factor (EGF) and transforming growth factor beta1 (TGFbeta1) play important roles in tumor biology. Single nucleotide polymorphisms in EGF and TGFB1 genes alter the expression of these growth factors and influence the tumorigenesis process. The aim of our present study was to determine the association of EGF+61A>G (rs4444903) and TGFB1-509C>T (rs1800469) gene polymorphism with susceptibility to gallbladder cancer (GBC). The present case-control association study was carried out in 126 confirmed GBC patients and 190 healthy subjects. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism methods. The GG genotype of EGF+61A>G was significantly associated with GBC [p=0.012, odds ratio (OR)=2.22, 95% confidence interval (CI)=1.19-4.15] in comparison to healthy subjects. Analysis based on gender indicated risk due to GG genotype was limited to female GBC patients (p=0.003, OR=3.45, 95% CI=1.52-7.82). Upon stratification of GBC patients on the basis of the presence or absence of gallstones, the risk due to EGF polymorphism was not modulated by the status of gallstones. The TGFB1-509C>T polymorphism was not associated with GBC. Also, we did not find any association of this polymorphism when GBC patients were subdivided on the basis of gender. However, after stratification of GBC patients on the status of gallstones, we determined that the CT genotype of TGFB1 was associated with increased risk of GBC without gallstones (p value=0.030, OR=2.90, 95% CI=1.26-6.69). Furthermore, the combination of the GG genotype of EGF and the CT genotype of TGFB1 demonstrated synergistic increase in risk of GBC.In conclusion, the higher producing +61G allele of EGF and -509 CT genotype of TGFB1 synergistically increase the susceptibility of gallbladder cancer (p value=0.003). Further study in large samples size is required to confirm our findings.     

PDCD1 polymorphism amplifies the predisposing effect conferred by CTLA4 polymorphism in chronic hepatitis B virus infection

Programmed cell death 1 (PDCD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) both negatively regulate the T-cell response in chronic hepatitis B virus (HBV) infection. This study determined genotypes of PDCD1 -606 G/A and +8669 G/A and CTLA4 -318 C/T and +49 A/G polymorphisms in 172 chronic HBV patients and 145 healthy controls and analyzed the interaction between these polymorphisms of the 2 genes. The results indicated that carriage of the PDCD1 +8669 A allele was increased in HBV patients carrying the CTLA4 -318 CC genotype and carrying the CTLA4 +49 AA genotype compared with controls carrying the CTLA4 -318 CC genotype (80.2% vs 64.8%, p = 0.002, odds ratio [OR] = 2.202, 95% confidence interval [95% CI] = 1.326-3.656) and carrying the CTLA4 +49 AA genotype (18.6% vs 9.7%, p = 0.024, OR = 2.139, 95% CI = 1.093-4.187), respectively. More obviously, carriage of the PDCD1 +8669 AA genotype was significantly increased in HBV patients carrying the CTLA4 +49 AA genotype compared with controls carrying the same CTLA4 +49 genotype (14.0% vs 3.4%, p = 0.001, OR = 4.541, 95% CI = 1.686-12.230). These results suggest that the PDCD1 +8669 A allele and AA genotype may amplify the predisposing effect conferred by the CTLA4 polymorphism through PDCD1 and CTLA4 gene interaction in chronic HBV infection.     

Association between a T/C polymorphism in intron 2 of cholesterol 24S-hydroxylase gene and Alzheimer's disease in Chinese

A polymorphism (T/C) in intron 2 of the cholesterol 24-hydroxylase (CYP46) gene has recently been reported to be associated with the risk for late-onset Alzheimer's disease (LOAD). To investigate possible involvement of the CYP46 gene and apolipoprotein E (APOE) gene polymorphisms in the manifestation of LOAD, we analyzed 99 sporadic LOAD patients and 113 healthy controls of China. We found an obvious association between CYP46 TT genotype and LOAD (OR = 2.98, 95% CI 1.64-5.44, P < 0.001). A clear increase of the risk to develop LOAD was also observed in subjects carrying both the CYP46 TT genotype and the APOE epsilon4-allele (OR = 12.94, 95% CI 4.26-39.32, P < 0.001). Our data reveal that the polymorphism of CYP46 intron 2 is implicated in the susceptibility to LOAD and a strong synergistic interaction between CYP46 TT homozoygots and APOE epsilon4 carrier status on the risk of LOAD.     

A polymorphism in the CYP17 gene relates to the risk of recurrent pregnancy loss

The CYP17 gene encodes the enzyme cytochrome P450c17alpha, which mediates both 17alpha-hydroxylase and 17,20-lyase activity in the steroid biosynthesis pathway. A T-->C polymorphism in the 5' promoter region of CYP17 has been described. To examine the association between recurrent pregnancy loss (RPL) and a polymorphism in CYP17, a case-control study of 117 cases with RPL and 164 controls was conducted. This polymorphism was investigated by PCR/restriction fragment length polymorphism using DNA from peripheral lymphocytes. The T-->C transition in the variant allele (A2) creates a new recognition site for the restriction enzyme MspA1, which permits designation of the wildtype allele (A1) and A2. Women with the A2 allele of CYP17 had an increased risk of RPL [A1/A1 genotype (reference); A1/A2 genotype: odds ratio (OR), 1.68; 95% confidence interval (CI), 0.94-3.01; A2/A2 genotype: OR, 2.37; 95% CI, 1.16-4.83; P trend, 0.016]. Additionally, there was a similar tendency for the increased risk of primary RPL [A1/A1 genotype (reference); A1/A2 genotype: OR, 2.14; 95% CI, 1.14-4.01; A2/A2 genotype: OR, 2.50; 95% CI, 1.16-5.41; P trend, 0.015]. These results suggest that possession of the A2 variant of CYP17 may predispose to an increased risk of RPL with a gene dosage effect.     

Association between VEGF polymorphisms (936c/t, -460t/c and -634g/c) with haplotypes and coronary heart disease susceptibility

Aim: Our aim was to investigate the association between single nucleotide polymorphisms (SNPs) of vascular endothelial growth factor (VEGF) and coronary heart disease (CHD) susceptibility in Chinese Han population. Methods: 144 CHD patients and 150 healthy individuals were enrolled in the study. Three SNPs (936C/T, -460T/C and -634G/C) of VEGF were chose and then were genotyped with Sequenom time-of-flight mass spectrometry (TOFMS). Odds ratio (OR) with 95% confidence interval (CI) were used to evaluate the association of genotypes and haplotypes and CHD susceptibility. Results: The frequencies of -460T/C CC genotype (13.6%) was found higher in the case group than that of control group (6.7%), which indicated that CC genotype was a risk factor for CHD (OR=2.50, 95% CI=1.10-5.68). Correspondently, the C allele appeared to increase the risk of CHD (OR=1.54, 95% CI=1.07-2.22). For -634G/C polymorphism, the risk of the CC genotype carrier for CHD increased 2.24 fold compared to the wild genotype. Moreover, -634G/CC allele was significantly associated with CHD susceptibility (OR=1.65, 95% CI=1.15-2.36). In addition, +936C/T CT genotype and C allele appeared to be a genetic-susceptibility factors for CHD (OR=2.43, 95% CI=1.44-4.10; OR=1.95, 95% CI=1.26-3.02). The haplotype analysis showed that T-C-T, C-C-C and C-G-C haplotypes all could increase the risk for CHD (OR: 2.43, 2.77 and 2.33). Conclusion: we concluded VEGF polymorphisms were associated with CHD susceptibility. Moreover, the haplotypes of T-C-T, C-C-C and C-G-C all could increase the risk for CHD.     

A common polymorphism G-50T in cytochrome P450 2J2 gene is associated with increased risk of essential hypertension in a Russian population

The present study was designed to test whether common polymorphism G-50T within the promoter of human CYP2J2 gene is associated with increased risk of essential hypertension in a Russian population. We studied 576 unrelated subjects, including 295 patients with hypertension and 281 healthy subjects. Genotyping for polymorphism G-50T of the CYP2J2 gene was performed by polymerase chain reaction and restriction fragment length polymorphism techniques. The frequency of a -50T variant allele of CYP2J2 gene was significantly higher in patients with hypertension versus healthy controls (OR 4.03 95%CI 1.80-9.04 p=0.0004). The association of a -50GT genotype with hypertension remained significant after adjustment for age, gender and family history of hypertension by multivariate logistic regression (OR 4.78 95%CI 1.87-12.27 p=0.001). It has been found that OR for -50GT genotype x gender interaction (OR 4.48 95%CI 1.93-10.39 p=0.00048) was slightly higher than OR for -50GT genotype (OR 4.43 95%CI 1.91-10.29 p=0.00052), suggesting a weak effect of gender on the risk of hypertension in the heterozygous carriers of -50GT genotype. A family history of hypertension has no effect on the association between a -50GT genotype and hypertension. In present study we demonstrate for the first time that a CYP2J2*7 allele of the CYP2J2 gene is clearly associated with an increased risk of essential hypertension. Furthermore, this study highlights the importance of P-450 epoxygenase pathway of arachidonic acid metabolism in the pathogenesis of hypertensive disease.     

CYP17 genotype predicts serum hormone levels among pre-menopausal women

BACKGROUND: CYP17, which encodes cytochrome P450c17alpha, mediates both steroid 17alpha-hydroxylase and 17,20-lyase activities, and is essential for the production of glucocorticoids and sex steroids. There is evidence that a common polymorphism in CYP17 (T27C) is associated with estrogen levels, making it a potential marker of disease risk. METHODS: This is the first study to examine the relationship between CYP17 and estradiol (E2) using serum sampled exclusively from the early follicular phase of the menstrual cycle. We assessed the relationship between CYP17 and serum hormone levels, menstrual cycle length, bleed length, and age at menarche in 164 pre-menopausal women. RESULTS: Among women with body mass index (BMI) < or =25 kg/m2, those with the TC and CC genotypes had 19 and 42% higher E2 (P for trend 0.007) and 14 and 30% higher dehydroepiandrosterone sulphate respectively (P for trend 0.10) than women with the TT genotype. Androstenedione levels did not differ between genotypes. Among women with BMI >25 kg/m2, hormone levels did not differ by genotype. Women with the C allele were also more likely to have menstrual cycle lengths <27 days [odds ratio (OR) for TC=2.36, 95% confidence interval (CI)=1.24-4.52; OR for CC=5.59, 95% CI=1.53-20.43 compared to TT]. CYP17 genotype was not associated with menstrual bleed length or age at menarche. CONCLUSION: The CYP17 T27C polymorphism may be a marker of endocrine function.     

Predictive role of miR-146a rs2910164 (C>G), miR-149 rs2292832 (T>C), miR-196a2 rs11614913 (T>C) and miR-499 rs3746444 (T>C) in the development of hepatocellular carcinoma

We conducted a case-control study to evaluate the association of miR-146a rs2910164 (C>G), miR-149 rs2292832 (T>C), miR-196a2 rs11614913 (T>C) and miR-499 rs3746444 (T>C) polymorphisms with the risk of hepatocellular carcinoma. A total of 274 patients with HCC were collected between January 2013 and December 2014. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was taken to determine the polymorphism of miR-146a C>G, miR-149 T>C, miR-196a2 T>C and miR-499 T>C. By comparing with control groups, patients with HCC were more likely to be males (OR=2.01, 95% CI=1.38-2.95), have older age (OR=1.52, 95% CI=1.09-2.13), have a history of alcohol drinking (OR=2.09, 95% CI=1.49-2.93), and be infected with HBV (OR=32.98, 95% CI=19.70-55.46) and HCV (OR=56.26, 95% CI=23.28-152.98) infection. By conditional regression analysis, individuals carrying the TC and CC genotypes of miR-196a2 T>C were found to be associated with an elevated risk of HCC compared to the TT genotype, and the adjusted odds ratio were 1.50 (1.03-2.17) and 2.86 (1.60-5.16), respectively. Moreover, the TC+CC genotype was correlated with an increased risk of HCC (OR=1.69, 95% CI=1.19-2.41) compared to the wide-type genotype. In conclusion, our results suggested that miR-196a2 T>C polymorphism is associated with HCC risk in Chinese population.     

CCR5 Delta32 polymorphism: associated with gallbladder cancer susceptibility

Inflammation of gallbladder is an established risk factor for gallbladder cancer (GBC) pathogenesis. Chemokine receptors play crucial role in antitumour immunity and are involved in inflammation and pathogenesis of cancers. Present study was aimed to examine the role of CCR5 Δ32 polymorphism in conferring genetic susceptibility to GBC. Present case–control study included 144 proven GBC patients and 210 healthy controls. Genotyping was done by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) method. Statistically significant difference was observed in distribution of CCR5+/Δ32 genotype ( P  = 0.028) [odds ratio (OR) = 2.850; 95% confidence interval (CI) = 1.1–7.2] and CCR5 Δ32 allele ( P  = 0.012) (OR = 3.145, 95% CI = 1.2–7.7) in GBC patients which was conferring high risk. Stratification of GBC patients showed significant association of CCR5+/Δ32 genotype and CCR5 Δ32 allele with GBC patients with and without gallstones. Analysis based on age of onset and gender suggested significant association of CCR5 Δ32 allele with early onset (<50 years) of the disease but only marginal influence of gender in CCR5 Δ32 -mediated risk of cancer. Risk was further modulated by tobacco usage and significantly increased risk was observed in tobacco users with CCR5+/Δ32 genotype. In conclusion, CCR5+/Δ32 genotype and CCR5 Δ32 allele confer significant risk for GBC particularly in patients with early onset and tobacco usage. Role of CCR5+/Δ32 polymorphism in GBC susceptibility is independent of gallstone formation.     

Association between 8473T>C polymorphism in the cyclooxygenase-2 gene and the risk of nasopharyngeal carcinoma

Background: No studies have examined the relationship between COX-2 8473T>C polymorphism and the risk of nasopharyngeal carcinoma in Chinese population. Material and methods: 296 patients with nasopharyngeal carcinoma and 300 age and gender-matched healthy controls recruited were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Cancer risk associated with the genotypes was estimated as odds ratios (ORs) and 95% confidence intervals (95% CIs) using unconditioned logistic regression. Results: There was significant difference in the distribution of COX-2 8473T>C polymorphism genotype between nasopharyngeal carcinoma patients and healthy controls (P=0.027). When the TT genotype was used as the reference group, the CC genotype was associated with significantly decreased risk for nasopharyngeal carcinoma (adjusted OR=0.67, 95% CI=0.33-0.83; P=0.01). Under the recessive model of inheritance, the CC genotype was associated with significantly decreased risk for nasopharyngeal carcinoma (adjusted OR=0.43, 95% CI=0.37-0.81; P=0.007). Furthermore, the C allele was associated with significantly decreased risk for nasopharyngeal carcinoma (adjusted OR=0.48, 95% CI=0.39-0.85; P=0.009). Conclusion: These data suggested that COX-2 8473T>C polymorphism was associated with reduced risk of nasopharyngeal carcinoma.     

Exploration of 16 candidate genes identifies the association of IDE with Alzheimer's disease in Han Chinese

Alzheimer's disease (AD) has a complex pattern of inheritance and many genes have recently been reported to contribute to the disease susceptibility. We selected 106 SNPs within 16 candidate genes and performed a multistage association study using 4 sample sets consisting of 731 AD patients and 738 control subjects to identify genetic factors for AD in Han Chinese. A single nucleotide polymorphism (SNP) in the insulin degrading enzyme gene (IDE), rs3781239, showed a significant association with AD. The C allele increased the risk of AD 1.72-fold than the G allele (odds ratio [OR] = 1.72, 95% confidence interval [CI] = 1.17-2.53, p = 0.006) and CC carriers had a 4.89-fold higher risk for AD than that of the carriers with CG and GG genotypes (odds ratio = 4.89, 95% CI = 1.85-12.91, p = 0.001). Moreover, the CC genotype was significantly associated with earlier age at onset (p = 0.001, hazard ratio [HR] = 2.09, 95% CI = 1.38-3.18). Our data suggest that the polymorphism of IDE is associated with susceptibility to Alzheimer's disease in Han Chinese.     

Correlation between survivin genetic polymorphisms and lung cancer susceptibility

Aims: The purpose of the study was to analyze the relationship of survivin polymorphisms including -31G/C, -625G/C, 9194A/G and 9809T/C with the susceptibility to lung cancer. Methods: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to test the polymorphisms of -31G/C, -625G/C, 9194A/G and 9809T/C in 104 patients with lung cancer and 104 healthy controls. Then, linkage disequilibrium and haplotypes were analyzed by HaploView software. The differences of genotype, allele and haplotype frequencies in case and control group were assessed via chi-square test. Odds ratio (OR) with 95% CI were used to evaluate the correlation of survivin polymorphisms with lung cancer. Results: Genotype distribution of each polymorphism site in control group was in agreement with Hardy-Weinberg equilibrium (HWE) (P>0.05). The frequency of -31G/C CC genotype and C allele in case group were much higher than that of controls, respectively (CC: 33.6% vs. 22.1%; C: 57.2% vs. 46.6%) and CC genotype as well as C allele were appeared to be risk factors for lung cancer. Meanwhile, 9194A/G GG genotype could increase the risk for lung cancer (OR=2.86, 95% CI=1.14-7.20). The risk of G allele carriers for lung caner was higher than that of A allele (OR=1.63, 95% CI=1.08-2.47). The haplotypes analysis indicated that CGGC and GCAT were associated with the susceptibility to lung cancer (OR=2.79, 95% CI=1.58-4.92; OR=2.36, 95% CI=1.29-4.30). Conclusions: Survivin -31G/C and 9194A/G polymorphisms were associated with the risk of lung cancer. The CGGC and GCAT haplotypes carriers were more likely to develop lung cancer.     

Polymorphisms of CYP1A1 and GSTM1 genes and susceptibility to oral cancer

PURPOSE: Oral cancer is the fifth most common form of cancer in the world and comprises 6.5% of all cancer deaths. Since one of the major risk factors for oral cancer is tobacco use, we hypothesized that polymorphic genes coding for tobacco carcinogen-metabolizing enzymes may play a role in oral cancer susceptibility. MATERIALS AND METHODS: To investigate the association between polymorphisms of the CYP1A1 and GSTM1 genes and risks for oral squamous cell carcinoma (OSCC) in the Korean population, the prevalence of the CYP1A1 Mspl and GSTM1 null polymorphisms were examined in 72 patients with histologically confirmed primary OSCC, as well as in 221 healthy control subjects. RESULTS: A significant risk increase for oral cancer was observed among subjects with the homozygous CYP1A1 (m2/m2) genotype (OR=3.8, 95% CI=1.9-7.7), but not the GSTM1 null genotype (OR=0.7, 95% CI=0.4-1.3). Risk for oral cancer was significantly increased in subjects with the homozygous CYP1A1 (m2/m2)genotype, regardless of smoking history (smokers; OR=4.4; 95% CI=1.2-16.3; non- smokers OR=4.9; 95% CI=1.9-12.5). Using the potentially most protective genotype GSTM1 (+)/CYP1A1 [(m1/m1)+ (m1/m2)] as the reference group, an increased risk for oral cancer was observed among subjects with the GSTM1 (+)/ CYP1A1 (m2/m2) (OR= 2.0, 95% CI=0.8-5.2), and GSTM1 (-)/ CYP1A1 (m2/m2) (OR=4.9, 95% CI=1.5-15.5) genotypes (p < 0.009, (chi2 trend test). CONCLUSION: Our results suggest that individuals with a genotype of CYP1A1 (m2/m2) and GSTM1 (-) are highly susceptible for OSCC and that the CYP1A1 (m2/m2) genotype is closely associated with increased risk of OSCC in Koreans.     

APOE, ACT and CHRNA7 genes in the conversion from amnestic mild cognitive impairment to Alzheimer's disease

We have investigated whether the -86 C/T promoter polymorphism in CHRNA7 gene, the signal peptide polymorphism of the alpha1-antichymotripsin (ACT) gene or the APOE genotype are associated with an increased risk of mild cognitive impairment (MCI) or affect the risk of evolution to Alzheimer's disease (AD). We have followed up 89 patients with initial diagnoses of amnestic MCI for 49 months. Patients were separated into three groups: 27 subjects who remained with MCI, 40 that converted to AD before 20 months and 22 that converted to AD after. To assess the risk associated to each genotype a control group (n=90) without cognitive impairment was included. APOE4 allele was associated with an increased risk of MCI (OR: 6.04, 95% CI: 2.76-3.23; p<0.001) but did not have an effect on the probability of evolving AD. ACT or CHRNA7 genotypes were not associated with MCI but both appear to modify the risk of progression to dementia in opposing manners: ACT polymorphism increasing the risk to evolve to AD before 20 months (HR=2.03; 95% CI: 1-4.6; p=0.06) and CHRNA7 polymorphism protecting from evolution to dementia. Cox regression model demonstrated that ACT genotype confers a higher risk of rapid evolution to dementia than age or years of schooling. We conclude that APOE is a risk gene for amnestic MCI and that ACT and CHRNA7 may act in these patients as modifier genes for the time of progression to AD.     

Polymorphisms for chemical metabolizing genes and risk for cervical neoplasia

Infection with high-risk human papillomavirus (HPV) plays a major role in the etiology of cervical cancer (CC). However, most infected women do not develop cancer. Therefore, exposure to other carcinogenic agents may be a contributing risk factor for CC. We investigated the hypothesis that environmental exposure to cigarette smoke and inheritance of polymorphic chemical metabolizing genes (CYP2E1, GSTM1, and mEH) significantly increase the risk for neoplasia. We selected 76 cases with high-grade cervical neoplasia or with invasive CC and 75 matched healthy controls. The collected data support the well-established observation that infection with high-risk HPV is the major risk factor for CC (OR = 75; 95% CI = 26-220). In addition, our data show that women who smoked more than 15 "pack-year" had a significant 6.9-fold increase in risk (95% CI = 1.2-40.3) after adjustment for HPV infection. The CYP2E1 variant genotype did not significantly increase the risk for neoplasia. A significant increase in risk for neoplasia was observed for the low-activity mEH 113 His allele after adjustment for smoking (OR = 3.0; 95% CI = 1.4-6.3). The GSTM1 null genotype was associated with a significant 3.3-fold increased risk for neoplasia (95% CI = 1.0-11.8) compared to women who were GSTM1-positive after adjustment for smoking and HPV infection. Our study suggests that genetic differences in the metabolism of cigarette smoke, particularly GSTM1, may confer susceptibility to CC. Further studies using larger populations will be needed to confirm our observations and to validate data for disease prevention.     

Association of the IL‐10 receptor A536G (S138G) loss‐of‐function variant with multiple sclerosis in Tunisian patients

Interleukin‐10 (IL‐10), a potent anti‐inflammatory T‐cell cytokine, has been shown to be a regulatory cytokine that is associated with disease remission in multiple sclerosis (MS) and exerts its activity through its cognate cell surface receptor complex, IL‐10 receptor 1 (IL‐10R1) and IL‐10R2. The purpose of this study was to investigate the IL‐10R1 S138G loss‐of‐function polymorphism (A536G: rs3135932) for possible influence on susceptibility and outcome of MS in Tunisian patients. A total of 103 Tunisian MS patients and 160 control subjects were studied. Genomic DNA samples were extracted from leukocytes and used to investigate S138G polymorphism in IL‐10R1 gene by multiplex allele‐specific polymerase chain reaction. Associations between G allele [odds ratio (OR) = 5.57; 95% confidence intervals (CI) = 3.26–9.54; p = 10^?7], GG genotypes [OR = 10.41; 95% CI = 2.28–47.58; p = 0.0007] and AG genotype [OR = 4.14; 95% CI = 2.16–7.93; p = 0.000016] with the risk development of MS were found. In contrast, the AA genotype seemed to be associated with protection against MS [OR = 0.17; 95% CI = 0.09–0.30; p = 10^?7]. No association was found between S138G SNP and clinical features or disease activity of MS patients. In conclusion, our results suggest that S138G loss‐of‐function polymorphism of the IL‐10R1 may be important risk factor in increasing susceptibility to MS.