Genetics Research
rs3788189
Population Frequencies12
African
T 0.38951G 0.61049TT 0.164338TG/GT 0.450345GG 0.385318pop=10,734
African American
T 0.39295G 0.60705TT 0.166346TG/GT 0.453215GG 0.380439pop=10,388
African Others
T 0.286G 0.714TT 0.104046TG/GT 0.364162GG 0.531792pop=346
Asian
T 0.447G 0.553TT 0.207071TG/GT 0.479798GG 0.313131pop=396
East Asian
T 0.425G 0.575TT 0.185714TG/GT 0.478571GG 0.335714pop=280
European
T 0.62965G 0.37035TT 0.424004TG/GT 0.411287GG 0.164709pop=22,646
Latin American 1
T 0.5138G 0.4862TT 0.280277TG/GT 0.467128GG 0.252595pop=1,156
Latin American 2
T 0.6001G 0.3999TT 0.36201TG/GT 0.476256GG 0.161734pop=2,906
Other
T 0.617G 0.383TT 0.426573TG/GT 0.379953GG 0.193473pop=858
Other Asian
T 0.5G 0.5TT 0.258621TG/GT 0.482759GG 0.258621pop=116
South Asian
T 0.542G 0.458TT 0.4TG/GT 0.283333GG 0.316667pop=120
Studies15
Unread Studies15 ▼
1
Lung cancer is the leading cause of cancer deaths worldwide. Pharmacogenomics plays an important role in tailoring cancer patients’ treatment. Pemetrexed is widely used in first- and second-line chemotherapy of non-small cell lung cancer (NSCLC); however, there is no available predictive biomarker for pemetrexed treatment. The present study aimed to investigate the role of polymorphisms in thymidylate synthase and SLC19A1 polymorphisms with clinical outcome in patients with advanced NSCLC treated in first-line with pemetrexed or pemetrexed plus cisplatin.
2
Pemetrexed is an approved first-line treatment for advanced non-squamous, non-small-cell lung cancer (NSCLC). The pharmacokinetics of pemetrexed is highly variable. Evidence of altered clinical response and toxicity of pemetrexed due to genetic polymorphisms in the folate pathway has generated interest to explore the pharmacogenetic effects on drug exposure and outcomes.
3
目的 探讨母亲还原叶酸载体(reduced folate carrier,RFC)基因多态性与子代先天性心脏病(congenital heart disease,CHD)的关系. 方法 采用基于医院的病例对照研究,以2017年11月至2020年3月于湖南省儿童医院心胸外科就诊的683例CHD婴儿的母亲为病例组,以同期在该院就诊并排除任何畸形的740例婴儿的母亲为对照组.使用调查问卷收集研究对象的暴露资料,并采集产妇5 mL静脉血用于基因多态性检测.采用多因素logistic回归分析RFC基因多态性及其单倍型与CHD的关联,并采用广义多因子降维法分析基因-基因间交互作用. 结果 多因素logistic回归显示,在控制混杂因素后,母亲RFC基因2个位点rs2236484(AG vs AA:OR=1.91,95%CI:1.45~2.51;GG vs AA:OR=1.96,95%CI:1.40~2.75)和rs2330183(CT vs CC:OR=1.39,95%CI:1.06~1.83)的多态性与子代CHD风险存在关联.母亲携带单倍型G-G(OR=1.21,95%CI:1.03~1.41)和T-G(OR=1.25,95%CI:1.07~1.46)显著增加子代CHD的风险.交互作用分析显示,RFC基因各位点在CHD发生中存在交互作用(P < 0.05). 结论 母亲RFC基因多态性及各位点间的交互作用与子代CHD的发生相关.
4
目的 探讨母亲还原叶酸载体 (reduced folate carrier, RFC) 基因多态性与子代先天性心脏病 (congenital heart disease, CHD) 的关系. 方法 采用基于医院的病例对照研究, 以 2017 年 11 月至 2020 年 3 月于湖南省儿童医院心胸外科就诊的 683 例 CHD 婴儿的母亲为病例组, 以同期在该院就诊并排除任何畸形的 740 例婴儿的母亲为对照组. 使用调查问卷收集研究对象的暴露资料, 并采集产妇 5 mL 静脉血用于基因多态性检测. 采用多因素 logistic 回归分析 RFC 基因多态性及其单倍型与 CHD 的关联, 并采用广义多因子降维法分析基因-基因间交互作用. 结果 多因素 logistic 回归显示, 在控制混杂因素后, 母亲 RFC 基因 2 个位点 rs2236484 (AG vs AA: OR= 1.91, 95% CI: 1.45~ 2.51; GG vs AA: OR= 1.96, 95% CI: 1.40~ 2.75) 和 rs2330183 (CT vs CC: OR= 1.39, 95% CI: 1.06~ 1.83) 的多态性与子代 CHD 风险存在关联. 母亲携带单倍型 GG (OR= 1.21, 95% CI: 1.03~ 1.41) 和 TG (OR= 1.25, 95% CI: 1.07~ 1.46) 显著增加子代 CHD 的风险. 交互作用分析显示, RFC 基因各位点在 CHD 发生中存在交互作用 (P< 0.05). 结论 母亲 RFC 基因多态性及各位点间的交互作用与子代 CHD 的发生相关.
5
Although it is generally recognized that genetic and environmental factors are associated with the risk of congenital heart disease (CHD), the mechanism remains largely uncertain. This study aimed to investigate the association of maternal folate use, the time when folate use was started, and polymorphisms of the reduced folate carrier (RFC1) gene with the risk of CHD in offspring of Chinese descent, which can help provide new insight into the etiology of folate-related birth defects. A case-control study of 683 mothers of CHD patients and 740 mothers of healthy children was performed. The present study showed that mothers who did not use folate were at a significantly increased risk of CHD (OR=2.04; 95% CI: 1.42-2.93). When compared with those who started using folate prior to conception, mothers who started using folate from the first trimester of pregnancy (OR=1.90; 95% CI: 1.43-2.54) or from the second trimester of pregnancy (OR=8.92; 95% CI: 4.20-18.97) had a significantly higher risk of CHD. Maternal RFC1 gene polymorphisms at rs2236484 (AG vs AA: OR=1.79 [95% CI: 1.33-2.39]; GG vs AA: OR=1.64 [95% CI: 1.15-2.35]) and rs2330183 (CT vs CC: OR=1.54 [95% CI: 1.14-2.09]) were also significantly associated with CHD risk. Additionally, the risk of CHD was significantly decreased among mothers who had variant genotypes but used folate when compared with those who had variant genotypes and did not use folate.Conclusion: In those of Chinese descent, maternal folate use and the time when use started are significantly associated with the risk of CHD in offspring. Furthermore, maternal folate supplementation may help to offset some of the risks of CHD in offspring due to maternal RFC1 genetic variants. What is Known: • Folate use could help prevent CHD, but the relationship between the time when folate use is started and CHD has not received sufficient attention. • Studies have assessed the associations of folate metabolism-related genes with CHD, but genes involved in cellular transportation of folate, such as the RFC1 gene, have not garnered enough attention. What is New: • In those of Chinese descents, the time when folate use is started is significantly associated with the risk of CHD in offspring. • Maternal RFC1 polymorphisms were significantly associated with the risk of CHD. • Folate supplementation may help to offset some risks of CHD due to RFC1 genetic variants.
6
En la etiología de las fisuras orofaciales no sindrómicas (FOFNS) el metabolismo de los folatos jugaría un importante rol, en donde se han reportado asociaciones con variantes hipofuncionales de genes de este metabolismo sumado a que el bajo consumo materno de esos micronutrientes es uno de los factores ambientales más importantes. Esta vitamina es crucial para la síntesis y metilación del ADN. En Chile, a pesar del aumento del consumo de folatos, no ha disminuido la tasa de FOFs. En el presente estudio se evaluó el riesgo de FOFNS en Chile asociado a niveles bajos de metilación global del ADN. Para ello se evaluaron 95 casos y 95 controles pareados por sexo y edad donde se cuantificó mediante pirosecuenciación los niveles de metilación de LINE-1 (marcador de metilación global del ADN) en células de la mucosa oral. Además, se evaluó la asociación de los niveles de metilación de LINE-1 con las variantes de los genes del metabolismo del folato MTHFR, SLC19A1 y TCN2. Los resultados muestran un aumento del riesgo de FOFNS asociado a hipometilación del ADN (p=0.008), pero este riesgo no se ve modificado por el genotipo de ninguna de las variantes de los tres genes analizados. En conclusión, nuestros hallazgos confirman la hipótesis sobre el aumento de la susceptibilidad a FOFNS cuando el DNA esta poco metilado, lo que podría afectar la expresión génica. Los resultados de interacción gen-metilación pueden ser efecto del modesto tamaño muestral utilizado.
7
The purpose of our study was to evaluate the efficacy of a combination of pralatrexate plus oxaliplatin in advanced esophagogastric cancer (EGC), analyze the impact of polymorphisms in folate metabolism pathway genes on toxicity and efficacy of pralatrexate, and to evaluate microRNA profile of tumor epithelium as a predictive biomarker. This was a two-stage trial with a safety lead in cohort and a primary endpoint of overall response rate (ORR). Patients received biweekly intravenous oxaliplatin (85 mg/m2) and pralatrexate (Dose level 1 [D1], 120 mg/m2; dose level-1 [D-1] 100 mg/m2). Single-nucleotide polymorphisms (SNP) in genes encoding proteins involved in pralatrexate metabolism were evaluated in germline DNA. microRNA profiling of the tumor epithelium was performed. ORR was 26%. Dose-limiting toxicities were observed in 2 of 4 patients at D1 and none at D-1. The T>C polymorphism in DHFR rs11951910 was significantly associated with lower progression-free survival (PFS; P ≤ 0.01), whereas the presence of the SLC19A1 rs2838957 G>A polymorphism was associated with improved PFS (P = 0.02). Presence of the GGH rs3780130 A>T and SLC19A1 rs1051266 G>A polymorphisms were significantly associated with better overall survival (OS; P = 0.01), whereas GGH rs7010484 T>C polymorphism was associated significantly with reduced OS (P = 0.04). There was no correlation between epithelial microRNA expression profile with disease progression or response. We conclude that the combination of oxaliplatin and pralatrexate is safe, is well tolerated, and has modest efficacy in advanced EGC. Pharmacogenomic analysis may be relevant to the use of pralatrexate in combination with platinum agents.
8
… -rs3788189 was also observed among women with high-intake (p-interaction = 0.01), with similar patterns found for the other four SLC19A1 SNPs that were in LD with rs3788189 (data …
9
Folate‐mediated one‐carbon metabolism plays critical roles in DNA synthesis, repair and DNA methylation. The impact of single nucleotide polymorphisms (SNPs) in folate‐metabolizing enzymes has been investigated in risk of breast cancer among European or Asian populations, but not among women of African ancestry. We conducted a comprehensive analysis of SNPs in eleven genes involved in one‐carbon metabolism and risk of breast cancer in 1,275 European‐American (EA) and 1,299 African‐American (AA) women who participated in the Women's Circle of Health Study. Allele frequencies varied significantly between EA and AA populations. A number of these SNPs, specifically in genes including MTR, MTRR, SHMT1, TYMS and SLC19A1, were associated with overall breast cancer risk, as well as risk by estrogen receptor (ER) status, in either EA or AA women. Associations appeared to be modified by dietary folate intake. Although single‐SNP associations were not statistically significant after correcting for multiple comparisons, polygenetic score analyses revealed significant associations with breast cancer risk. Per unit increase of the risk score was associated with a modest 19 to 50% increase in risk of breast cancer overall, ER positive or ER negative cancer (all p < 0.0005) in EAs or AAs. In summary, our data suggest that one‐carbon metabolizing gene polymorphisms could play a role in breast cancer and that may differ between EA and AA women.
10
Pathologic complete response (pCR) with neoadjuvant chemotherapy is associated with improved survival in many solid tumors. We evaluated pCR rate of cisplatin with pemetrexed in non–small-cell lung cancer. Methods: Patients with stages IB to IIIA non–small-cell lung cancer, Eastern Cooperative Oncology Group performance status 0 to 1 were enrolled in this single-arm phase II trial using two-stage design with 90% power to detect pCR rate of more than or equal to 10%. Pretreatment mediastinal lymph node biopsy was required. Patients received three cycles of cisplatin 75 mg/m2 with pemetrexed 500 mg/m2 (day 1 every 21 days) preoperatively and additional two cycles within 60 to 80 days after surgery. The primary end point was pCR. Polymorphisms in FPGS, GGH, SLC19A1, and TYMS genes were correlated with treatment outcomes. Results: Thirty-eight patients were enrolled, with median age of 62.5 years. Preoperatively, 26% had squamous histology, and 34% had biopsy-proven N2 involvement. R0 resection was achieved in 94% of the 34 patients who underwent surgery, and 54% had documented N2 clearance. There was no pCR seen. Median disease-free survival (DFS) and overall survival of these patients have not yet been reached in contrast to median of 13.8 and 24.2 months, respectively, in patients with persistent N2 disease (p = 0.3241 and p = 0.1022, respectively). There was a statistically significant association between DFS and postoperative tumor, node, metastasis stage (p = 0.0429), SLC19A1 rs3788189 TT genotype (p = 0.0821), and viable tumor defined as less than or equal to 10% of resected specimen (p = 0.026). Conclusion: The primary end point was not met. Patients with N2 clearance, less than or equal to 10% viable tumor in the resected specimen, and SLC19A1 rs3788189 TT genotype have favorable DFS outcomes.
11
Identification of polymorphisms that influence pemetrexed tolerability could lead to individualised treatment regimens and improve quality of life. Twenty-eight polymorphisms within eleven candidate genes were genotyped using the Illumina Human Exome v1.1 BeadChip and tested for their association with the clinical outcomes of non-small cell lung cancer and mesothelioma patients receiving pemetrexed/platinum doublet chemotherapy (n=136). GGH rs11545078 was associated with a reduced incidence of grade ⩾3 toxicity within the first four cycles of therapy (odds ratio (OR) 0.25, P=0.018), as well as reduced grade ⩾3 haematological toxicity (OR 0.13, P=0.048). DHFR rs1650697 conferred an increased risk of grade ⩾3 toxicity (OR 2.14, P=0.034). Furthermore, FOLR3 rs61734430 was associated with an increased likelihood of disease progression at mid-treatment radiological evaluation (OR 4.05, P=0.023). Polymorphisms within SLC19A1 (rs3788189, rs1051298 and rs914232) were associated with overall survival. This study confirms previous pharmacogenetic associations and identifies novel markers of pemetrexed toxicity.
12
Pemetrexed has been approved for first- and second-line treatment in patients with non-small cell lung cancer (NSCLC). Two studies have confirmed the role of polymorphisms (SNPs) ...
13
To correlate polymorphisms in genes involved in the transport, activation, and inactivation of pemetrexed with the outcome of patients with advanced non-small cell lung cancer (NSCLC) treated with pemetrexed.
14
To evaluate the efficacy and toxicity of pemetrexed combined with bevacizumab as second-line therapy for patients with advanced non-small-cell lung cancer (NSCLC) and to correlate allelic variants in pemetrexed-metabolizing genes with clinical outcome.
15
The International Adjuvant Lung Cancer Trial (IALT) demonstrated an absolute survival rate benefice of cisplatin based chemotherapy of 4% in surgically treated patients with non small cell lung carcinoma (NSCLC). To identify immunohistochemical biomarkers which correlate differently with survival in the chemotherapy and observation group (predictive analysis) we collected 867 paraffin blocks from 28 centers and made a histopathological review allowing selection of 783 tumors recorded as NSCLC with …
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