Influence of dopamine receptor gene polymorphisms on circulating T lymphocytes: A pilot study in healthy subjects

Dopamine is a key transmitter in the neuroimmune network, acting through five dopaminergic receptors (DR): the D₁-like D₁ and D₅ and the D₂-like D₂, D₃ and D₄. Several DR gene variants exist and may affect DR expression and activity. We assessed total lymphocytes, CD3+, CD4+ and CD8+ T lymphocytes in peripheral blood of healthy subjects and their association with selected DR gene variants (DRD1 rs4532 and rs686, DRD5 rs6283, DRD2 rs1800497 and rs6277, DRD3 rs6280 and rs1800828, DRD4 rs747302 and 7 48-base pair VNTR). DRD1 rs4532 and rs686 and DRD5 rs6283 were associated with total lymphocytes, and with CD3+ and CD4+ (but not CD8+) T lymphocytes, while none of the D₂-like DR gene variants showed any association with lymphocyte counts. An arbitrary score based on the activity of D₁-like vs D₂-like DR correlated with total lymphocytes, CD3+ and CD4+ T cells (but not with CD8+ T cells). The association between D₁-like DR gene variants and lymphocyte count, and in particular with CD4+ (but not CD8+) T lymphocytes, may imply a functional prevalence of D₁-like over D₂-like DR in CD4+ T cells. This is the first study showing an influence of DR gene polymorphisms on lymphocyte count, and in particular on CD4+ T cells. Future studies should address the possible association between DR gene variants and the immune function in health and disease. The relevance of these findings for the immune effects of dopaminergic agents should be also carefully examined.     

Genetic determinants of chronic oxaliplatin‐induced peripheral neurotoxicity: a genome‐wide study replication and meta‐analysis

We aimed at validating the role of genetic variants identified by a recent genome‐wide association study (GWAS) as determinants of chronic oxaliplatin‐induced peripheral neurotoxicity (OXAIPN). Eight polymorphisms (rs10486003, rs2338, rs843748, rs797519, rs4936453, rs12023000, rs17140129, and rs6924717) were genotyped in a total of 150 colorectal cancer patients of Caucasian origin receiving oxaliplatin‐based chemotherapy. The severity grade of chronic OXAIPN was assessed by NCI‐CTC criteria and the clinical version of the Total Neuropathy Score^© (TNSc^©). None of the polymorphisms investigated was found associated with grade ≥ 2 chronic OXAIPN (NCI‐CTC criteria), while a nominal association emerged for ACYP2 rs843748 when using the TNSc^© scale (dominant model: odds ratio [OR]: 0.27, 95% confidence interval [CI]: 0.10–0.75, P = 0.008). In the combined analysis of this results with data of the two previously published studies which assessed chronic OXAIPN by NCI‐CTC criteria, evidence suggestive of association with chronic OXAIPN (NCI‐CTC criteria) was found for ACYP2 rs843748 (dominant model: OR: 2.40, 95%CI: 1.40–5.24, P = 0.027), which, however, did not remain significant after correction for multiple testing (threshold P‐value <0.00625). These findings suggest a minor role of the single nucleotide polymorphisms (SNPs) investigated as genetic determinants of chronic OXAIPN. These results also highlight the importance of replication studies with meta‐analysis for validation of GWAS findings.     

cyp2c19基因多态性、高水平FIB对氯吡格雷抗凝效应的相关性研究

目的研究冠心病患者中cyp2c19基因多态性、高水平纤维蛋白原(FIB)与氯吡格雷抗凝效应的关系。方法选取2015年5~11月正在服用氯吡格雷的冠心病患者611例,并对其cyp2c19基因特征和FIB水平进行分析。将患者分为cyp2c19基因纯合子强代谢型组(n=261)、杂合子强代谢型组(n=272)及弱代谢型组(n=78);611例冠心病患者中有408例患者检测凝血项,分为高水平FIB组(n=116)、正常水平FIB组(n=224)及低水平FIB组(n=68);再分为cyp2c19基因弱代谢型且高水平FIB组(n=24)、cyp2c19基因纯合子强代谢型且高水平FIB组(n=48),cyp2c19基因杂合子强代谢型且高水平FIB组(n=44),比较3组的凝血酶时间(TT)。结果 cyp2c19基因型别有*1/*1、*1/*2、*1/*3、*2/*2、*2/*3、*3/*3。经基因芯片检测发现,上述各型分别为261例(占42.7%)、235例(占38.4%)、37例(占6.0%)、60例(占9.8%)、17例(占2.9%)、1例(占0.2%)。cyp2c19*1、*2和*3等位基因频率分别为65.0%(794/1 222)、30.5%(373/1 222)和4.5%(55/1 222);纯合子强代谢型组占42.7%(n=261),杂合子强代谢型组占44.4%(n=272),弱代谢型组占12.9%(n=78)。高水平FIB组的TT水平与正常水平FIB组比较差异无统计学意义(P=0.400 8);无论是纯合子还是杂合子,cyp2c19基因强代谢型均比cyp2c19基因弱代谢型对氯吡格雷抗凝效应更敏感(P0.05)。结论高水平FIB对氯吡格雷抗凝效应并无显著影响;cyp2c19基因多态性对氯吡格雷的抗凝效应有显著影响,有助于临床指导用药,降低冠状动脉血栓发生率。     

No association between common Gly972Arg variant of the insulin receptor substrate-1 and polycystic ovary syndrome in Southern Chilean women

BACKGROUND: Previously studies have indicated that the insulin receptor substrate-1 (IRS-1) Gly972Arg (G972R) polymorphism is associated with polycystic ovary syndrome (PCOS). We examined the possible association between G972R common variant of the IRS-1 gene and PCOS in Southern Chilean women with PCOS and controls. METHODS: A total of 50 women with PCOS (29.1+/-8.1 yr) and 75 healthy women (29.3+/-9.3 yr) were included. Serum lipids, glucose and uric acid concentrations were determined by enzymatic-colorimetric methods. The G972R variant of the IRS-1 gene was detected by PCR-RFLP. RESULTS: Women with PCOS exhibited a higher concentrations of total testosterone, glucose, insulin, total cholesterol, triglycerides, LDL-C and uric acid, and lower HDL-C concentrations than controls (P<0.05). The presence of G972R polymorphism in PCOS and control women was not significantly different (16% vs. 6.6%, P=0.276). The OR for PCOS associated to 972R variant was 2.67 (95% CI: 0.82-8.69, P=NS). Moreover, neither association between G972R genotypes and metabolic parameters were observed in PCOS women or controls. CONCLUSION: Our data do not support an association between G972R variant of the IRS-1 with PCOS or its metabolic parameters in Southern Chilean women.     

探讨X^2检验结合FDR筛选致病SNPs位点的适用条件

目的在单核苷酸多态性（SNPs）数据中探讨不同模拟条件X^2检验结合错误发现率（FDR）筛选SNPs位点的适用条件。方法依据2009年2月发布HapMapm期美国犹他州北欧和西欧后裔人群22号染色体前5000个SNPs数据,采用HAPGEN2模拟病例对照数据,运用Haploview4．2筛选标签SNPs（TagSNPs）,比较不同模拟条件筛选致病SNPs的正确率。结果相对危险度（RR）获取方式无显著差异;3种遗传模型均表现正确率随RR值增大而增高,RR相同时,加性模型正确率最高,显性模型次之,隐性模型最低;加性模型RR〉2．2、显性模型RR〉4和隐性模型RR〉5时,正确率超过60％。结论X^2检验结合FDR在加性模型效果最佳,实际科研工作需依据目标疾病具体情况考虑是否适合X^2检验结合FDR方法。     

Clinical significance of human kallikrein 10 gene expression in colorectal cancer and gastric cancer

BACKGROUND AND AIM: Recent evidence suggests that the human kallikrein 10 (KLK10) gene is differentially regulated in endocrine-related tumors and has potential as diagnostic and/or prognostic marker; however, KLK10 expression has never been investigated in gastrointestinal cancers. The aims of this study were to demonstrate expression and single nucleotide polymorphisms of KLK10 in colorectal cancer (CRC) and gastric cancer (GC), and to correlate the relative KLK10 expression level with clinicopathological factors of CRC and GC. METHODS: Between March 2004 and January 2005, 63 patients with histologically confirmed CRC and 36 with GC were recruited into the study. Using quantitative real-time (qRT) RT-PCR and Western blot, KLK10 expression in tumor and non-tumor colorectal and gastric tissues was determined at the mRNA and protein levels. KLK10 protein was localized by immunohistochemistry. The KLK10 genomic DNA from 16 cases of paired normal/cancerous colorectal tissues was PCR-amplified and examined for single nucleotide polymorphisms by direct sequencing. RESULTS: KLK10 mRNA expression was detected by qRT in 61 of 63 (96.8%) CRC specimens and in all GC specimens. KLK10 expression was much higher in tumor tissue than in the corresponding normal mucosal tissue at the mRNA and protein levels (P<0.01). The KLK10 mRNA expression level significantly correlated with lymphatic invasion (P=0.034) and clinical stage of CRC (P=0.025). The KLK10 mRNA expression level significantly correlated with the depth of GC invasion (P=0.018), clinical stage (P=0.045), patient sex (P=0.027) and Lauren type of gastric cancer (P=0.028). No mutations or polymorphisms were detected in exon 1, 2 and 5 of KLK10 gene in CRC. Single nucleotide polymorphisms were identified in codon 50 of exon 3, GCC (alanine) to TCC (serine). The genetic changes of exon 4 were located at codon 106 [GGC (glysine) to GGA (glysine)], codon 112 [ACG (threonine) to ACC (threonine)], codon 141 [CTA (leucine) to CTG (leucine)], and codon 149 [CCG (proline) to CTG (leucine)]. All were identical in tumor and corresponding normal tissue DNA from the same individuals. CONCLUSION: KLK10 expression is up-regulated in CRC and GC and higher expression of KLK10 closely correlates with advanced disease stage, which predicts a poorer prognosis; however, further follow-up study is needed.     

Dicarbonyl Electrophiles Mediate Inflammation-Induced Gastrointestinal Carcinogenesis

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Lipoprotein lipase gene variants and progression of nephropathy in hypercholesterolaemic patients with type 2 diabetes

Objective. Recent prospective studies have identified hyperlipidaemia as an independent determinant of diabetic nephropathy. Lipoprotein lipase (LPL) is a key enzyme in the postprandial processing of triglycerides and VLDL. Among a number of common sequence variants of the LPL, HindIII has been associated with coronary heart disease and, more recently, with microalbuminuria in type 2 diabetes. We evaluated the progression of renal disease in hypercholesterolaemic type 2 diabetic patients in relation to this polymorphism. Design and subjects. We followed up for 4 years 65 consecutively enrolled microalbuminuric patients with type 2 diabetes; of whom 28 had hypercholesterolaemia (6.62 ± 0.9 mmol L^?1, group A) and 37 were normocholesterolaemic (4.68 ± 0.5 mmol L^?1, group B). Main outcome measures. After performing the genetic analyses, albumin excretion rate (AER) and estimated glomerular filtration rate (GFR), calculated by the simplified equation of the MDRD Study Group, were repeated every year. Results. In group A, AER increased more (?AER: 11 [38] vs. 4 [18] μg min^?1 per year in group B, P < 0.0001) while GFR declined faster (?3.5 ± 2.1 vs. ?2.0 ± 1.4 mL min^?1 per year, P < 0.02). Patients homozygous for the allele + of HindIII showed a significantly faster decline of GFR and a higher increase of AER (both P = 0.0001) even after adjustment for cholesterol levels and anthropometric variables. Conclusions. In hypercholesterolaemic type 2 diabetic patients with microalbuminuria, the renal disease has an accelerated course, particularly in those carrying the H₊/H₊ genotype of the HindIII polymorphism at the LPL locus.     

Role of +405C>G and +936C>T Polymorphisms of the Vascular Endothelial Growth Factor Gene and Risk of Esophageal Cancer in the Kashmiri Population

Background: The gene for the vascular endothelial growth factor (VEGF), which promotes angiogenesis andpermeability, is polymorphic. The aim of the present study was to evaluate the relationship between +936C>Tand +404C>G polymorphism of VEGF with risk of esophageal cancer in the Kashmiri population in India.Materials and Methods: 150 esophageal cancer patients and 150 unrelated healthy controls were genotyped fortwo VGEF SNPs (+405C/G, and +936C/T) using DNA extracted from prospectively collected blood samples bythe PCR-RFLP method. Results: For the VEGF +936C>T polymorphism a significant association of CT andcombined CT+TT genotypes was observed with increased risk of esophageal cancer (p=0.021; 0.024). For the+405C>G polymorphism we observed significantly increased frequency of GG genotype in cases as comparedto controls and also the +405 GG Genotype was observed to have a two fold risk(OR=2.7356; 95%CI=1.1409-6.5593; p=0.020). The combined genotypes of GG-CC and GG-CT of +405C>G and +936C>T were found tobe significantly associated with increased risk of esophageal cancer (p=0.0376; 0.0099). Conclusions: From theresults of the present study a significant association of +936C>T and +405C>G polymorphisms with increasedesophageal cancer risk exists in the Kashmiri population.