Polymorphic variants of folate metabolizing genes (C677T and A1298C <Emphasis Type="Italic">MTHFR</Emphasis> and C1420T SHMT1 and G1958A <Emphasis Type="Italic">MTHFD</Emphasis>) are not associated with the risk of breast cancer in the West Siberian Region of Russia

Breast cancer is one of the most widely distributed cancers in women. We investigated the role of allele variants in the folate metabolizing genes MTHFR (C677T and A1298C alleles), SHMT1 (C1420T allele), and MTHFD (G1258A allele) as a possible factor in predisposition to breast cancer. We determined allele and genotype frequencies of single nucleotide polymorphisms (SNPs) in the case (850 women with sporadic form of breast cancer) and control (810 healthy women) groups. None of the polymorphisms were significantly associated with breast cancer risk. To increase the statistical power of our study, we conducted a meta-analysis which included published genotype data and the results of our work. The meta-analysis revealed no significant association between the studied SNPs and breast cancer risks either.     

亚甲基四氢叶酸还原酶基因C677T、G1793A 单核苷酸多态性 与散发性乳腺癌易感性的关系

目的:研究亚甲基四氢叶酸还原酶(MTHFR)基因C677T、G1793A位点单核苷酸多态性与散发性乳腺癌易感性关系。方法:采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法,对200例乳腺癌患者及200例正常对照者MTHFR基因C677T、G1793A位点单核苷酸多态性进行分析,logistic回归分析不同基因型与乳腺癌风险的关系。结果:乳腺癌组MTHFR 677TT基因型频率为25.00%显著高于正常对照组的10.50%(X2=14.401,P=0.001),CT基因型频率为44.50%低于正常对照组的54.50%,CC基因型频率在乳腺癌组和正常对照组中无差别;MTHFR 1793GA基因型频率为18.50%显著高于正常对照者的8.50%(X2=8.563,P=0.003)。乳腺癌患者MTHFR 677T和1793A等位基因频率分别为47.25%、9.25%,显著高于对照组中的37.75%、4.25%。MTHFR 677TT基因型携带者罹患乳腺癌的风险是677CC基因型携带者的2.732倍(95%CI=1.418～5.051,P=0.001),MTHFR1793GA基因型携带者罹患乳腺癌的风险是1793GG基因型携带者的2.444倍(95%CI=1.325～4.505,P=0.003)。另外,乳腺癌组中MTHFR C677T基因多态性与肿瘤大小相关(x2=7.431,P=0.024,MTHFR G1793A基因多态性与淋巴结转移情况(x2=8.939,P=0.011)、癌组织学分级(x2=9.983,P=0.007)相关。结论:MTHFR C677T、G1793A基因多态性与散发性乳腺癌的易感性相关。     

亚甲基四氢叶酸还原酶基因C677T、G1793A单核苷酸多态性与散发性乳腺癌易感性的关系

目的：研究亚甲基四氢叶酸还原酶（MTHFR）基因C677T、G1793A位点单核苷酸多态性与散发性乳腺癌易感性关系。方法：采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法,对200例乳腺癌患者及200例正常对照者MTHFR基因C677T、G1793A位点单核苷酸多态性进行分析,logistic回归分析不同基因型与乳腺癌风险的关系。结果：乳腺癌组MTHFR 677TT基因型频率为25.00%显著高于正常对照组的10.50%（X2=14.401,P=0.001）,CT基因型频率为44.50%低于正常对照组的54.50%,CC基因型频率在乳腺癌组和正常对照组中无差别;MTHFR 1793GA基因型频率为18.50%显著高于正常对照者的8.50%（X2=8.563,P=0.003）。乳腺癌患者MTHFR 677T和1793A等位基因频率分别为47.25%、9.25%,显著高于对照组中的37.75%、4.25%。MTHFR 677TT基因型携带者罹患乳腺癌的风险是677CC基因型携带者的2.732倍（95%CI=1.418～5.051,P=0.001）,MTHFR1793GA基因型携带者罹患乳腺癌的风险是1793GG基因型携带者的2.444倍（95%CI=1.325～4.505,P=0.003）。另外,乳腺癌组中MTHFR C677T基因多态性与肿瘤大小相关（x2=7.431,P=0.024,MTHFR G1793A基因多态性与淋巴结转移情况（x2=8.939,P=0.011）、癌组织学分级（x2=9.983,P=0.007）相关。结论：MTHFR C677T、G1793A基因多态性与散发性乳腺癌的易感性相关。     

Correlation of polymorphism C3435T of the MDR-1 gene and the response of primary chemotherapy in women with locally advanced breast cancer

Primary chemotherapy is a useful strategy for the treatment of locally advanced breast cancer and therefore allows in vivo evaluation of the action of cytotoxic drugs and the possibility of accomplishing conservative breast surgeries, as well as the early treatment of metastasis. Mechanisms of resistance to the drugs include the action of protein associated with the efflux of drugs from the intracellular environment hindering their activity; one of the most studied proteins is P-glycoprotein codified by the MDR-1 gene. The presence of polymorphisms can determine different physiological actions of these proteins, intervening with the response of the drug's action. We evaluated the presence of single nucleotide polymorphism (SNP) C3435T of the MDR-1 gene and its correlation with the response to primary chemotherapy using the RECIST criteria. Forty-one Brazilian women with stages II and III breast cancer using the PCR-RFLP analysis were evaluated. Thirty-three patients with the SNP genotype (TT and CT) and eight patients with the wild genotype (CC) were found; there was no statistically significant correlation between the diverse genotypes and the clinical and pathological responses according to the Cramer correlation coefficient (V = 0.14). The parameters: nuclear and histological degree, and estrogens, progesterone and c-erb B2 receptors did not demonstrate a statistical correlation with the SNP C3435T. Patients with complete pathological response (12.5%) showed only the polymorphic genotype and not the wild genotype. The characteristics of miscegenation in our population could explain the absence of the characterization of a sub-group of individuals where the presence of the polymorphic genotype influenced the response to the primary chemotherapy.     

Risk of colorectal cancer associated with the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in the Kashmiri population

Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate metabolism and is involved in DNA synthesis, DNA repair and DNA methylation. The two common functional polymorphisms of MTHFR, 677 C→T and 1298 A→C, have been shown to impact various diseases, including cancer. The 677 C→T polymorphism has been widely investigated in different cancers and has been implicated as a risk factor for the development of various cancers. We investigated MTHFR C677T genotype frequency in colorectal cancer cases in the Kashmiri population and correlated this information with the known clinicopathological characters of colorectal cancer, in a case-control study. Eighty-six colorectal cancer cases were studied for MTHFR C677T polymorphism, compared to 160 controls taken from the general population, employing the PCR-RFLP technique. We found the frequency of the three different genotypes of MTHFR in our ethnic Kashmir population, i.e., CC, CT and TT, to be 68.6, 20.9 and 10.4% among colorectal cancer cases and 75.6, 16.9 and 7.5% among the general control population, respectively. There was a significant association between the MTHFR TT genotype and colorectal cancer in the higher age group. We conclude that the MTHFR C677T polymorphism slightly increases the risk for colorectal cancer development in our ethnic Kashmir population.     

CHOP T/C and C/T haplotypes contribute to early-onset type 2 diabetes in Italians

Type 2 diabetes (T2D) is characterized by impaired insulin secretion, insulin insensitivity and decreased beta-cell mass. Multiple genes contribute to T2D. The chromosome 12q13.1 region is in linkage to T2D in different populations, including our Italian dataset. CHOP is a candidate gene for the linkage, as it is located in the chromosome 12q13.1 region, and may contribute to T2D by increasing beta-cell apoptosis susceptibility and by impairing insulin sensitivity. Our goal was to identify any potential CHOP gene variants contributing to T2D in our Italian early-onset T2D families, which show linkage to the CHOP region. We directly sequenced the CHOP gene in 28 Italian probands of the linked T2D families and in 115 control subjects. We performed genotype and haplotype association tests with T2D of the identified single nucleotide polymorphisms (SNPs). We performed model-free and parametric association haplotype tests with T2D. We identified three SNPs [5'UTR-c.279T > C, 5'UTR-c.120A > G and + nt30C > T (F10F)] in CHOP. These SNPs are in complete linkage disequilibrium. The genotype association test showed an association trend with T2D of TT (F10F) and AG (-c.120A > G). The haplotype association test provided significant results for the haplotypes T/C (frequency = 0.33) and C/T (frequency = 0.01) (at 5'UTR-c.279T > C and + nt30C > T, respectively) under non-parametric analysis (P-value = 0.0000), recessive model (P-value = 0.0000) and additive model (P-value = 0.0014). Our data show that CHOP described haplotypes T/C and C/T, as an additive and as a homozygous variant, contribute significantly to T2D in our Italian early-onset group. We conclude that the CHOP T/C and C/T haplotype contributes to our T2D linkage signal on chromosome 12q13.1.     

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and susceptibility to gastric adenocarcinoma in an Italian population

Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the metabolism of folate, which provides a methyl donor for DNA methylation and deoxynucleoside synthesis. We performed a case-control study to explore the relationship between two common MTHFR polymorphisms (C677T and A1298C), their combination and interaction with environmental exposures, on gastric adenocarcinoma susceptibility and progression in an Italian population. One hundred and two cases and 254 hospital controls, matched by age and gender, were enrolled. Individuals carrying the MTHFR 677T allele showed an increased risk of gastric cancer (odds ratio (OR) 1.62, 95% confidence interval (CI) 0.98-2.67), particularly among ever smokers (OR 2.10, 95% CI 1.07-5.33) and, among 677 TT individuals, those with a low intake of fruit and vegetables (OR 2.18, 95% CI 1.05-4.54). The strongest effect, however, was noted for the MTHFR 677 TT genotype among the diffuse gastric cancer histotype (OR 2.92, 95% CI 1.12-7.60). No association was detected for the effect of MTHFR A1298C polymorphism. Survival analysis did not show any association between each polymorphism on the overall survival, although when the analysis was restricted to the first year of follow-up after the surgical intervention an improved survival was noted among MTHFR 677 CC subjects compared with the T allele carriers (p value for log-rank test 0.02). In conclusion, MTHFR 677 (any T genotype) appears to modulate an individual's susceptibility to gastric cancer, particularly when combined with cigarette smoking and among those with a low intake of fruit and vegetables. Our results also suggest that an aberrant DNA methylation pattern, through impaired folate metabolism, might play a key role in gastric carcinogenesis. A possible survival effect of the MTHFR C677T genotype in gastric cancer patients deserves further investigations with larger sample sizes.     

Lack of association between prohibitin 3' untranslated region C-->T polymorphism and breast cancer in a Turkish population

The 3' untranslated region (3'UTR) of the prohibitin gene has a positive effect on arresting cell proliferation between G1 and S phases and inhibits DNA synthesis. A C-to-T transition within this region creates a variant that alters mRNA function and has been shown to be associated with an increased breast cancer risk among young North Americans who are under 50 years and have at least one first-degree relative with breast cancer. We carried out a population-based case-control study to assess whether this association exists in Turkish women. We examined 106 breast cancer patients and 154 healthy controls by PCR and restriction fragment length polymorphism analysis. In the prohibitin 3'UTR, we did not detect a difference in CT/TT genotype frequency (p = 0.694; odds ratio [OR], 1.106; 95% confidence intervals [CI], 0.659-1.86) or in C/T allele frequency (p = 0.850; OR, 1.043; 95% CI, 0.667-1.62) between the all breast cancer patients and the controls. The results did not change in subgroups defined by age or family history. Hence our results do not lend support to the hypothesis that this polymorphism contributes to risk of breast cancer. The prohibitin T variant is not associated with the risk of breast cancer in Turkish women.     

No association between methylenetetrahydrofolate reductase C677T polymorphism and breast cancer

Methylenetetrahydrofolate reductase (MTHFR) is an enzyme (EC 1.5.1.20), that reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a carbon donor for the homocysteine to methionine conversion. MTHFR is a key enzyme that regulates folate metabolism which has an important role in DNA synthesis, DNA repair and methylation. The association between MTHFR C677T polymorphism and breast cancer has been investigated in several previous studies. Some researchers have shown an association between C677T polymorphism and breast cancer, but not all researchers found this association however. This study was designed to investigate, in the Turkish population, the association of MTHFR C677T polymorphism and breast cancer. Forty women patients with breast cancer and 68 healthy women were included in the study. MTHFR gene polymorphism was determined by the PCR-RFLP method. SPSS 10.0 for windows was used to determine statistical significance. No differences were observed in the distribution of MTHFR genotypes or allele frequencies in the cases versus the controls. It was found that the frequencies of MTHFR polymorphism were 55%, 40%, 5% for CC, CT, TT genotype in patients and 56%, 38%, 6% in healthy controls respectively. Furthermore, association was observed among family history, metastatic risk and MTHFR genotypes in patients. Our data fail to support a relationship between MTHFR C677T and the risk for breast cancer. It may be that there are ethnic differences in terms of this relationship.     

Quantitative assessment of the associations between MTHFR C677T and A1298C polymorphisms and risk of fractures: a meta-analysis

Many studies have investigated the associations between methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and risk of fractures, but the impact of MTHFR polymorphisms on fractures risk is unclear owing to the obvious inconsistence among those studies. This study aims to quantify the strength of association between MTHFR C677T and A1298C polymorphisms and risk of fractures. We searched the PubMed, Embase and Wanfang databases for articles relating the association between MTHFR C677T and A1298C polymorphisms and risk of fractures in humans. We estimated summary odds ratios (ORs) with their confidence intervals (CIs) to assess the associations. Meta-analyses suggested MTHFR C677T polymorphism was associated with increased risk of any site fractures (for T vs. C, OR = 1.17, 95 % CI 1.03–1.32; for TT vs. CC, OR = 1. 31, 95 % CI 1.11–1.54; for TT vs. CT, OR = 1.22, 95 % CI 1.04–1.43; for TT vs. CT/CC, OR = 1.31, 95 % CI 1.13–1.51). Besides, MTHFR A1298C polymorphism was also associated with increased risk of any site fractures. Subgroup meta-analyses suggested MTHFR C677T polymorphism was associated with increased risk of vertebral fractures under three genetic contrast modes (for TT vs. CC, OR = 1.43, 95 % CI 1.05–1.95; for TT vs. CT, OR = 1.36, 95 % CI 1.01–1.85; for TT vs. CT/CC, OR = 1.50, 95 % CI 1.17–1.91), but there was no association between MTHFR C677T polymorphism and risk of hip fractures and non-vertebral fractures (all P values were more than 0.05). Thus, individuals with homozygote genotype TT of MTHFR C677T have obviously increased risk of vertebral fractures compared those with heterozygote genotype CT or homozygote genotype CC. There is no association between MTHFR C677T polymorphism and risk of hip fractures and non-vertebral fractures.     

MTHFR C677T、A1298C基因多态性与老年单纯收缩期高血压患者Hcy、血脂水平的关系研究

摘要 目的：研究5,10-亚甲基四氢叶酸还原酶（MTHFR）C677T、A1298C基因多态性与老年单纯收缩期高血压（ISH）患者同型半胱氨酸（Hcy）、血脂水平的关系。方法：选取2019年3月至2021年3月期间中南大学湘雅医学院附属海口医院全科医学科收治的212例老年ISH患者作为ISH组,以同期体检无高血压老年人120例为对照组。检测两组MTHFR C677T、A1298C基因多态性。收集两组一般资料及血浆Hcy及血脂检查结果。观察MTHFR C677T、A1298C不同基因型的血浆Hcy、血脂水平差异。采用多因素Logistic回归分析老年ISH发生的影响因素。结果：相比于对照组,ISH组MTHFR C677T位点T等位基因频率较高,C等位基因频率较低;ISH组CC基因型频率较低,CT、TT基因型频率较高（P<0.05）。相比于对照组,ISH组A1298C位点C等位基因频率较高,A等位基因频率较低;ISH组A1298C位点AA基因型频率较低,CC、AC基因型频率较高（P<0.05）。MTHFR基因C677T位点不同基因型血浆Hcy、总胆固醇（TC）水平差异具有显著性（P<0.05）。MTHFR基因A1298C位点不同基因型血浆Hcy、TC水平明显差异具有显著性（P<0.05）。血浆Hcy、MTHFR C677T及A1298C基因多态性是老年ISH发生的影响因素（均P<0.05）。结论：MTHFR C677T、A1298C基因多态性与老年ISH患者血浆TC、Hcy水平有关,血浆Hcy、MTHFR C677T及A1298C基因多态性是老年ISH发生的影响因素。     

MTHFR C677T and A1298C gene polymorphisms and their relation to homocysteine level in Egyptian children with congenital heart diseases

Objective

To investigate the association of combined MTHFR C677T and A1298C gene polymorphisms with congenital heart diseases (CHD) in Egyptian children and their mothers and to determine their effect on homocysteine level in these children.

Material and methods

MTHFR C677T and A1298C polymorphisms were genotyped in 160 Egyptian children (80 patients with CHD and 80 healthy controls) and their mothers using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP), while, homocysteine (Hcy) level was measured optically by enzymatic method.

Results

We found that MTHFR 677TT genotype, T allele, 1298CC genotype, and C allele were associated with 2.61, 2.0, 2.91 and 1.99 fold increased risk of CHD in Egyptian children respectively. Furthermore, the frequencies of MTHFR 1298AC and CC genotypes and C allele significantly increased in mothers with CHD affected children. The homocysteine levels were significantly increased in MTHFR 677TT and 1298CC genotypes in children with CHD.

Conclusions

Our study demonstrated an association of MTHFR A1298C polymorphisms with CHD in Egyptian children and their mothers, while, MTHFR C677T polymorphisms were significantly associated with the risk of CHD in the children only. An association between combined MTHFR A1298C and C677T polymorphisms and CHD was recorded in the children and their mothers. Also, homocysteine levels were significantly increased with both MTHFR 677TT and 1298CC genotypes in Egyptian children with CHD.     

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and susceptibility to gastric adenocarcinoma in an Italian population

Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the metabolism of folate, which provides a methyl donor for DNA methylation and deoxynucleoside synthesis. We performed a case–control study to explore the relationship between two common MTHFR polymorphisms (C677T and A1298C), their combination and interaction with environmental exposures, on gastric adenocarcinoma susceptibility and progression in an Italian population. One hundred and two cases and 254 hospital controls, matched by age and gender, were enrolled. Individuals carrying the MTHFR 677T allele showed an increased risk of gastric cancer (odds ratio (OR) 1.62, 95% confidence interval (CI) 0.98–2.67), particularly among ever smokers (OR 2.10, 95% CI 1.07–5.33) and, among 677 TT individuals, those with a low intake of fruit and vegetables (OR 2.18, 95% CI 1.05–4.54). The strongest effect, however, was noted for the MTHFR 677 TT genotype among the diffuse gastric cancer histotype (OR 2.92, 95% CI 1.12–7.60). No association was detected for the effect of MTHFR A1298C polymorphism. Survival analysis did not show any association between each polymorphism on the overall survival, although when the analysis was restricted to the first year of follow-up after the surgical intervention an improved survival was noted among MTHFR 677 CC subjects compared with the T allele carriers (p value for log-rank test 0.02). In conclusion, MTHFR 677 (any T genotype) appears to modulate an individual's susceptibility to gastric cancer, particularly when combined with cigarette smoking and among those with a low intake of fruit and vegetables. Our results also suggest that an aberrant DNA methylation pattern, through impaired folate metabolism, might play a key role in gastric carcinogenesis. A possible survival effect of the MTHFR C677T genotype in gastric cancer patients deserves further investigations with larger sample sizes.     

MDR1 single nucleotide polymorphism C3435T in Turkish patients with non-small-cell lung cancer

We assessed whether single nucleotide polymorphisms (SNPs) in MDR1 gene C3435T predicted the outcome of platinum-based chemotherapies and survival in our non small cell lung cancer (NSCLC) patients. A total of 79 non-small cell lung cancer patients were enrolled to study. We determined the MDR1 C3435T single nucleotide gene polymorphisms. Median age was 60years: 91.7% male, 8.9% female. We found that CC, CT, TT genotype and T, C allele frequencies in lung cancer patients as 24.1%, 62%, 13.9% and 44.3%, 55.7%, respectively. Patients with CT genotype had a higher response rate (11.4%) than the other genotypes. However, this difference is not statistically significant (p=0.743). Cox regression analysis for overall survival showed that ECOG PS status 0 (HR PS 1 vs. 0, 5.68 p=0.002; HR of PS 2 vs. 0 is 21.579, p=0.001; HR of PS 3 vs. 0 is 35.35, p=0.001), stage ≤II (HR of stage III vs. I+II is 17.77; p=0.016, HR of stage IV vs. I+II is 26.97, p=0.006), and albumin level ≥3g/dl (HR of albumin <3g/dl vs. ≥3g/dl is 2.46, p=0.044) were the most important prognostic factors (also, time to progression was related to these factors). There was no significant association between the genotypes and clinicopathologic parameters; however, good performance status, early stage and ≥3g/dl albumin level were found to be the most important prognostic factors for overall survival and progression-free survival.     

HSP90, HSPA8, HIF-1 alpha and HSP70-2 polymorphisms in breast cancer: a case–control study

This case control study aims to investigate the role of HSP90 Gln488His (C?>?G), HSP70-2 P1/P2, HIF-1 alpha C1772T and HSPA8 intronic 1541–1542delGT polymorphisms as potential risk factors and/or prognostic markers for breast cancer. 113 consecutive incident cases of histologically confirmed ductal breast cancer and 124 healthy cases were recruited. The above mentioned polymorphisms were genotyped; multivariate logistic regression was performed. HSP90 GG (His/His) genotype was associated with elevated breast cancer risk. Similarly, the allele dose–response model pointed to increase in breast cancer risk per G allele. HSP70-2 P1/P2, HSPA8 intronic 1541–1542delGT and HIF-1 alpha polymorphisms were not associated with breast cancer risk, as evidenced by the dose–response allele models. The positive association between HSP90 G allele and breast cancer risk seemed to pertain to both premenopausal and postmenopausal women. With respect to survival analysis, none of the aforementioned polymorphisms was associated with either disease-free survival or overall survival. HSP90α Gln488His polymorphism seems to be a risk factor for breast cancer. On the other hand, our study did not point to excess risk conferred by HSPA8 1541–1542delGT, Hsp70-2 P1/P2 and HIF-1α C1772T.     

Evaluation of Toll-like receptors 3 (c.1377C/T) and 9 (G2848A) gene polymorphisms in cervical cancer susceptibility

Cervical cancer is emerging as a leading cause of morbidity and mortality in women worldwide. Toll-like Receptor (TLR) gene polymorphisms may contribute to subsequent inter-individual variability in cancer susceptibility. The present study aimed to identify the role of TLR 3 (c.1377C/T) [rs3775290] and TLR 9 (G2848A) [rs352140] gene polymorphisms in the risk of developing cervical cancer in North India. Peripheral blood samples were collected from 200 histopathologically confirmed cervical cancer patients from North India and 200 unrelated, cancer-free, age-matched healthy female controls of similar ethnicity. Genomic DNA was extracted using the salting-out method, and genotyped for TLR 3 and TLR 9 using polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP). Our data demonstrated a lack of association between TLR 3 (c.1377C/T) and TLR 9 (G2848A) gene polymorphisms and the risk of developing cervical cancer. TLR 3 CT + TT was marginally associated (P = 0.061; age-adjusted OR = 1.46; 95% CI = 0.98–2.16) with cervical cancer susceptibility. The AA genotype of TLR 9 showed borderline significance (P = 0.053) conferring a marginal increased risk (OR = 2.63, 95%CI = 0.99–7.01) for advanced cancer stages (III + IV). Further, TLR 3 and 9 polymorphisms did not have a significant role in modulation of risk due to tobacco usage in cervical cancer patients. Our study suggests only marginal role of TLR 3 and 9 gene polymorphisms in cervical cancer susceptibility in North India; however, future studies in ethnically diverse populations may provide a more comprehensive involvement of innate immunity in cervical cancer etiology in women worldwide.     

Lisinopril attenuates renal oxidative injury in l-NAME-induced hypertensive rats

Genetic factors related to cancer have been extensively studied and several polymorphisms have been associated to breast cancer. The FGFR4, MTHFR, and HFE genes have been associated with neoplastic diseases development. The current report outlines the analysis of the polymorphisms G388A (FGFR4), C677T (MTHFR), C282Y, and H63D (HFE) in Brazilian breast cancer patients. We studied 68 patients with invasive ductal and operable breast carcinoma and 85 women as a control group. The polymorphism frequencies in the breast cancer and control groups were analyzed, but no significant difference was observed by comparing the two groups. The presence of each polymorphism was analyzed according to the clinical features and markers already established as prognostic in the breast cancer group. The C677T, H63D, and G388A polymorphisms were not associated to histological grade, age of diagnosis, expression of HER2 receptor, or estrogen and progesterone receptor. The H63D polymorphism showed a significant association (P = 0.02) with the presence of p53 mutations, and C667T showed association to lymph node involvement (P = 0.05). Lymph node involvement, G388A polymorphism, and histological grade were independently associated to metastasis/death. Our data suggests that the polymorphisms G388A, C677T, and H63D are not useful in breast cancer diagnosis, but they may be significant additional prognostic markers related to breast cancer survival.     

Geographical Distribution of MTHFR C677T,A1298C and MTRR A66G Gene Polymorphisms in China: Findings from 15357 Adults of Han Nationality

Background

Methylenetetrahydrofolate reductase (MTHFR) C677T, A1298C and methionine synthase reductase (MTRR) A66G polymorphisms are important genetic determinants for homocysteine (Hcy) levels, and are associated with several disorders. These polymorphisms are heterogeneously distributed worldwide. Our objective was to explore the geographical distributions of these polymorphisms in China.

Methodologies

15357 healthy adults were recruited from 10 regions. Buccal samples were collected and genomic DNA was isolated. Genotyping was performed using the fluorogenic 5′-nuclease assay.

Principal Findings

The prevalence of the three polymorphisms among different populations from China varied significantly and showed apparent geographical gradients. For MTHFR C677T, the frequencies of the 677T allele and the 677TT genotype were significantly higher among northern populations and ranged from the lowest values (24.0% and 6.4%, respectively) in Hainan (southern) to the highest values (63.1% and 40.8%, respectively) in Shandong (northern). For MTHFR A1298C, the 1298C allele and the 1298CC genotype frequencies were significantly higher among southern populations and increased from low values (13.1% and 1.4%, respectively) in Shandong to high values (25.7% and 6.7%, respectively) in Hainan. For A66G, the 66G allele and the 66GG genotype frequencies increased from lower values (23.7% and 5.4%, respectively) in Shandong to higher values (29.2% and 8.6%, respectively) in Hainan. The overall frequency of the 677T allele, 677TT genotype, 1298C allele, 1298CC genotype, 66G allele and 66GG genotype in the Chinese Han population was 45.2%, 23.2%, 18.6%, 3.9%, 25.7%, and 6.6%, respectively. No gender differences were found in the prevalence of both the MTHFR C677T and MTRR A66G polymorphisms.

Conclusions

This study indicates that there are marked geographical variations in the prevalence of the three polymorphisms among Chinese Han populations. Our baseline data may be useful for future researches in related fields.     

Modifying effects of IL-6 polymorphisms on body size-associated breast cancer risk

Objective: The association between obesity and breast cancer risk is complex. We examined whether the association between body size and breast cancer risk is modified by interleukin‐6 (IL6) genotype. Methods and Procedures: Five polymorphisms in the IL‐6 gene (rs1800797/‐596A>G, rs1800796/‐572G>C, rs1800795/‐174G>C, rs2069832/IVS2G>A, and rs2069849 exon 5 C>T) were studied. We investigated IL6 genotypes and haplotypes with indicators of body size among non‐Hispanic white (NHW) and Hispanic/American Indian (AI) breast cancer cases and controls living in the Southwestern United States. Results: We observed lower mean levels of BMI among NHW women who carried one or two copies of the GGCAC haplotype (in order: rs1800797, rs1800796, rs1800795, rs2069832, and rs2069849; P trend 0.02). This haplotype, with an estimated frequency of 43% in NHW study controls, was considerably less common in Hispanic/AI controls (19%). We did not detect significant interactions between IL6 genotypes or haplotypes and BMI categorized as low/normal (<25), overweight (25 to <30), or obese (≥30) and breast cancer risk in either NHW or Hispanic/AI women. However, we detected consistent and significant interactions between waist‐to‐hip ratio (WHR) and IL6 rs1800795/‐174 G>C genotype for breast cancer risk. These associations were restricted to postmenopausal NHW women. Among women without recent hormone exposure, those with a WHR >0.9 and the rs1800795 GG genotype had a greater than threefold increased risk of breast cancer (odds ratios (ORs) 3.22, 95% confidence intervals (CIs) 1.27, 817) when compared with women with a WHR <0.8 and the rs1800795 GG genotype (P interaction 0.01). Discussion: These data suggest that IL‐6 genotypes may influence breast cancer risk in conjunction with central adiposity.