Identification of a protective haplogenotype within CAPN10 gene influencing colorectal cancer susceptibility

BACKGROUND AND AIM: Colorectal cancer (CRC) is one of the most prevalent types of cancer affecting both men and women in developed countries. Clinical and molecular evidence suggests that there are multiple biochemical pathways involved in its susceptibility, pathogenesis and prognosis. Several studies have reported a significant association between the incidence of CRC and type 2 diabetes mellitus (T2DM). However, genes associated with both conditions are rare. METHOD: We have analyzed the CAPN10 gene, a T2DM locus, using UCSNP-43, -44, -19, and -63 markers, looking for differences between 371 CRC patients and 605 unrelated controls of Spanish origin. RESULTS: We found that UCSNP-44 allele C is swept out from cases (OR = 0.16, P = 0.005). Moreover, the frequency of 2111/2111 haplogenotype is also statistically lower than expected in CRC patients (P = 0.006). CONCLUSION: Taken together, our results indicate a recessive model for the effect of CAPN10 variant UCSNP-44 influencing the risk of CRC and suggest a novel genetic link between T2DM and colon carcinoma.     

Perspective: prostate cancer susceptibility genes

In many developed countries, prostate cancer is the most frequently diagnosed malignancy in men. The extent to which the marked racial/ethnic difference in its incidence rate is attributable to screening methods, environmental, hormonal, and/or genetic factors remains unknown. A positive family history is among the strongest epidemiological risk factors for prostate cancer. It is now well recognized that association of candidate genetic markers to this multifactorial malignancy is more difficult than the identification of susceptibility genes for some common cancers such as breast, ovary, and colon cancer. Several reasons may explain such a difficulty: 1) prostate cancer is diagnosed at a late age, thus often making it impossible to obtain DNA samples from living affected men for more than one generation; 2) the presence within high-risk pedigrees of phenocopies, associated with the lack of distinguishing features between hereditary and sporadic forms; and 3) the genetic heterogeneity of this complex disease along with the accompanying difficulty of developing appropriate statistical transmission models taking into account simultaneously multiple susceptibility genes, frequently showing moderate or low penetrance. Despite the localization of seven susceptibility loci, there has been limited confirmatory evidence of linkage for currently known candidate genes. Nonetheless, the discovery of the first prostate cancer susceptibility gene characterized by positional cloning, ELAC2 was achieved taking advantage of the Utah Family Resource. Moreover, common missense mutations in the ELAC2 gene were found to be significantly associated with an increased risk of diagnosis of prostate cancer in some studies. More recently, recombination map-ping and candidate gene analysis were used to map several genes, including the 2'-5'-oligoadenylate-dependent ribonuclease L (RNASEL) gene, to the critical region of HPC1. Two deleterious mutations in RNASEL segregate independently with the disease in two of the eight HPC1-linked families. Additional studies using larger cohorts are needed to fully evaluate the role of these two susceptibility genes in prostate cancer risk. Although a number of rare highly penetrant loci contribute to the Mendelian inheritance of prostate cancer, some of the familial risks may be due to shared environment and more specifically to common low-penetrance genetic variants. In this regard, it is not surprising that analyses of genes encoding key proteins involved in androgen biosynthesis and action, led to the observation of a significant association between a susceptibility to prostate cancer and common genetic variants, such as those found in 5alpha-reductase type 2 and AR genes.     

Associations between two single nucleotide polymorphisms of adiponectin gene and coronary artery diseases

Adiponectin, an adipocyte-secreted protein, is known to have anti-atherogenic, anti-inflammatory and anti-diabetic properties and its serum levels are decreased in obesity, type 2 diabetes, and coronary artery disease. Several studies have been performed to investigate the association of genetic variations in the adiponectin with obesity, insulin resistance, and type 2 diabetes, but few studies were performed in association with coronary artery disease. Therefore we examined the associations between two single nucleotide polymorphisms (SNPs), +45T>G and +276G>T of the adiponectin gene, and coronary artery diseases (CAD). One hundred and fifty six subjects (mean age 57.4 yrs) were enrolled in which coronary angiograms were performed due to chest pain. Genotypings were done for two SNPs in the adiponectin gene by Taqman polymerase chain reaction (PCR) method. The presence of CAD was defined as a >50% reduction of coronary artery diameter. Among 156 subjects, the allele frequencies were 0.683 for G allele and 0.317 for T allele in SNP +276G>T and 0.705 for T allele and 0.295 for G allele in SNP +45T>G. Both genotypes were in compliance with Hardy-Weinberg equilibrium. No association with the presence of CAD was observed for adiponectin gene SNP276 and SNP45 (p = 0.954, p = 0.843). Also, no significant association was observed between the severity of CAD and either SNPs (p = 0.571, p = 0.955). Our study showed that SNP +276G>T and +45T>G in adiponectin gene were not associated with the presence of CAD. Further studies will be necessary to confirm the role of SNP 276G>T and 45T>G in the development of CAD.     

Diabetes and cancer: A 2013 synopsis

Diabetes, in particular type 2 diabetes, and cancer are two diseases that appear to be associated. Numerous epidemiological studies indicate indeed that diabetes increases the incidence of several tumors. Chronic hyperglycemia and/or insulin resistance with compensatory hyperinsulinemia could account for the association. On the other hand, the interpretation of the link between diabetes and cancer could be influenced by therapeutical interferences. Considering all these data together, cancer should be considered as a “new potential complication” of diabetes and integrated in the follow-up of diabetic subjects.     

Diabetes mellitus: influences on cancer risk

Diabetes mellitus and cancer are common conditions, and their co‐diagnosis in the same individual is not infrequent. The relative risks associated with type 2 diabetes are greater than twofold for hepatic, pancreatic, and endometrial cancers. The relative risk is somewhat lower, at 1.2–1.5‐fold for colorectal, breast, and bladder cancers. In comparison, the relative risk of lung cancer is less than 1. The evidence for other malignancies (e.g. kidney, non‐Hodgkin lymphoma) is inconclusive, whereas prostatic cancer occurs less frequently in male patients with diabetes. The potential biologic links between the two diseases are incompletely understood. Evidence from observational studies suggests that some medications used to treat hyperglycemia are associated with either increased or reduced risk of cancer. Whereas anti‐diabetic drugs have a minor influence on cancer risk, drugs used to treat cancer may either cause diabetes or worsen pre‐existing diabetes. If hyperinsulinemia acts as a critical link between the observed increased cancer risk and type 2 diabetes, one would predict that patients with type 1 diabetes would have a different cancer risk pattern than patients with type 2 diabetes because the former patients are exposed to lower levels of exogenous administered insulin. Obtained results showed that patients with type 1 diabetes had elevated risks of cancers of the stomach, cervix, and endometrium. Type 1 diabetes is associated with a modest excess cancer risk overall and risks of specific cancers that differ from those associated with type 2 diabetes. Copyright © 2014 John Wiley & Sons, Ltd.     

Prevalence of variants in candidate genes for type 2 diabetes mellitus in The Netherlands: the Rotterdam study and the Hoorn study

We have analyzed the association of variants in the genes for amylin, insulin receptor, insulin receptor substrate-1 (IRS-1), and coagulation factor V with type 2 diabetes mellitus. Random samples of subjects with type 2 diabetes and controls were taken from two population-based studies, the Hoorn and Rotterdam studies, to reduce the risk of artifactual associations. No association was found for variants in the genes for amylin, IRS-1, and coagulation factor V, nor was there any evidence for epistatic interactions between these gene variants. A significant difference in the frequency of the Arg972 allele of the IRS-1 gene was observed between control subjects from Hoorn and Rotterdam (9.4% vs. 18.6%; P < 0.05). The insulin receptor Met985 variant was found at frequencies of 4.4% and 1.8%, respectively, in type 2 diabetic (n = 433) and normoglycemic patients (n = 799; P < 0.02). Inclusion of data from two other studies yielded a summarized odds ratio of 1.87 (95% confidence interval, 1.06-3.29; P = 0.03). We conclude that the association between the Met985 variant in the insulin receptor gene and type 2 diabetes, which we previously reported in the Rotterdam study, is supported by thejoint analysis with a second population-based study and other studies. The large regional differences in allele frequency of the Arg972 allele of IRS-1 gene makes genetic association studies of this gene less reliable.     

Association between genetic variation in the gene for insulin-like growth factor-I and low birthweight

Low birthweight is associated with later risk of type 2 diabetes and related disorders. We aimed to show that a polymorphism in the gene for insulin-like growth factor-I, which has proved to raise risk of type 2 diabetes and myocardial infarction, is associated with low birthweight. We recorded birthweight and obtained DNA for 463 adults. Individuals who did not have the wild-type allele of the polymorphism had a 215 g lower birthweight than those homozygous for this allele (95% CI -411 to -10). Our data lend support to the hypothesis that genetic variation affecting fetal growth could account for the association between low birthweight and susceptibility to diabetes and cardiovascular disease in later life.     

Allele frequencies of +874T-->A single nucleotide polymorphism at the first intron of interferon-gamma gene in a group of Italian centenarians.

Ageing is characterized by a pro-inflammatory status which could contribute to the onset of major age-related diseases such as cardiovascular diseases, neurodegeneration, osteoarthritis and osteoporosis, and diabetes. Thus, it can be hypothesized that genetic variations in pro- or anti-inflammatory cytokines might influence successful ageing and longevity. We have studied the distribution of +874T-->A interferon-gamma (IFN-gamma) polymorphisms in a large number of Italian centenarians to evaluate if the two alleles might be differently represented in people selected for longevity. DNA samples were obtained from 174 Italian centenarians (>99 years old, 142 women and 32 men) and from 248 <60-year-old control subjects (90 women and 158 men) matched for geographical distribution. Polymorphisms at +874 were identified by using amplification refractory mutational system methodology. The +874T allele was found less frequently in centenarian women than in centenarian men or in control women whereas no significant differences were observed in the distribution of the two alleles between male or female controls. Allele frequencies in centenarian men were not found significantly different from male controls. Possession of the +874A allele, known to be associated with low IFN-gamma production, significantly increases the possibility to achieve extended longevity, suggesting that the pro-inflammatory status characteristic of ageing may be detrimental for successful ageing. The datum that the allele was significantly increased in female but not male centenarians seems to strengthen the idea that gender may be a major variable in the biology of the ageing process. However, the present data add another piece of evidence to the complex puzzle of genetic and environmental factors involved in controlling life span expectancy in humans. Thus, studies on cytokine gene polymorphisms may promise to individuate a complex network of trans-interactive genes able to influence the type and strength of responses to environmental stressors and as a final result, thereby conditioning individual life expectancy.     

Association of LMNA 1908C/T polymorphism with cerebral vascular disease and diabetic nephropathy in Japanese men with type 2 diabetes

OBJECTIVE: The LMNA 1908C/T polymorphism has been reported to be associated with dyslipidaemia, metabolic syndrome, adipose tissue metabolism and obesity phenotypes, suggesting that this polymorphism presents an increased risk of atherosclerosis and vascular diseases. However, there have been no previous reports on the relationship between the LMNA 1908C/T polymorphism and vascular diseases. The aim of this study therefore was to investigate the association between the LMNA 1908C/T polymorphism and the prevalence of vascular disease in Japanese patients with type 2 diabetes. DESIGN: A cross-sectional, hospital-based study of diabetic complications with an LMNA gene background. PATIENTS: One hundred and sixty-six Japanese men with type 2 diabetes. Measurements LMNA 1908C/T polymorphism (by polymerase chain reaction restriction fragment length polymorphism, PCR-RFLP); diabetic retinopathy (by standard fundus photography); diabetic nephropathy (by urinary albumin excretion rate); diabetic neuropathy (by signs, symptoms and/or nerve conduction velocity); coronary heart disease (by symptoms of typical chest pain and/or history of myocardial infarction, and ischaemic electrocardiographic alteration and/or coronary artery bypass graft surgery); cerebral vascular disease (by ultrasonography, computed tomography and/or magnetic resonance imaging). RESULTS: Carriers of the LMNA 1908T allele manifested a significantly higher prevalence of diabetic nephropathy and cerebral vascular disease than carriers of the C allele. Multiple regression analysis showed that the LMNA 1908T allele tended to be associated with cerebral vascular disease, but was independent of age, hypertension, total cholesterol or triglyceride [odds ratio (OR) 7.03, P=0.0611]. Similarly, the LMNA 1908T allele showed a significant association with diabetic nephropathy, not independent of total cholesterol or triglyceride. CONCLUSIONS: The LMNA 1908C/T polymorphism plays an important role in the development of cerebral vascular disease and diabetic nephropathy in Japanese men with type 2 diabetes.     

The role of obesity and related metabolic disturbances in cancers of the colon, prostate, and pancreas

Recent evidence indicates that obesity and related metabolic abnormalities are associated with increased incidence or mortality for a number of cancers, including those of the colon, prostate, and pancreas. Obesity, physical inactivity, visceral adiposity, hyperglycemia, and hyperinsulinemia are relatively consistent risk factors for colon cancer and adenoma. Also, patients with type 2 diabetes mellitus have a higher risk of colon cancer. For prostate cancer, the relationship to obesity appears more complex. Obesity seems to contribute to a greater risk of aggressive or fatal prostate cancer but perhaps to a lower risk of nonaggressive prostate cancer. Furthermore, men with type 2 diabetes mellitus are at lower risk of developing prostate cancer. Long-standing type 2 diabetes increases the risk of pancreatic cancer by approximately 50%. Furthermore, over the past 6 years, a large number of cohort studies have reported positive associations between obesity and pancreatic cancer. Together with data from prediagnostic blood specimens showing positive associations between glucose levels and pancreatic cancer up to 25 years later, sufficient evidence now supports a strong role for diabetes and obesity in pancreatic cancer etiology. The mechanisms for these associations, however, remain speculative and deserve further study. Hyperinsulinemia may be important, but the role of oxidative stress initiated by hyperglycemia also deserves further attention.     

中国人醛糖还原酶基因5'端(AC)n多态性与2型糖尿病肾病相关性的meta分析

目的 对中国人醛糖还原酶基因5'端(AC)n多态性与2型糖尿病合并糖尿病肾病相关性的研究进行meta分析.方法 通过文献检索收集2007年4月以前发表的中国人醛糖还原酶基因5'端(AC)n多态性与2型糖尿病合并糖尿病肾病相关性的病例-对照研究,剔除不符合要求的文献,以漏斗图检验入选文献的发表偏倚,并根据各入选文献的同质性检验结果进行数据合并,计算总OR值,meta分析采用Review Manager 4.2版统计软件.结果 共8篇文献符合条件纳入研究,入选文献无明显发表偏倚,各文献同质性检验显示有关Z-2(χ2=18.20,P=0.01)、Z+2(χ2=35.30,P<0.01)等位基因分布情况的文献间均存在显著异质性.Z～2等位基因增加2型糖尿病肾病的易感性(OR=1.72,95%CI 1.25-2.36,P<0.01),Z+6等位基因对2型糖尿病患者肾脏具有保护作用(OR=0.66,95%17/0.45-0.98,P=0.04),Z+2等位基因对糖尿病肾病的易感性无影响(OR=0.73,95%CI 0.47-1.12,P=0.15).结论 醛糖还原酶基因5'端(AC)n多态性与中国人2型糖尿病合并糖尿病肾病易感性相关,Z-2等位基因可能是2型糖尿病患者糖尿病肾病的易感基因,Z+6等位基因可能对2型糖尿病患者肾脏具有保护作用.     

Prediction of genetic risk for hypertension

BACKGROUND: Although genetic epidemiological studies have suggested that several genetic variants increase the risk for hypertension, the genes that underlie genetic susceptibility to this condition remain to be identified definitively. Large-scale association studies that examine many gene polymorphisms simultaneously are required to predict genetic risk for hypertension. METHODS and RESULTS: The population of the present study comprised 1,940 unrelated Japanese individuals, including 1,067 subjects with hypertension (574 men, 493 women) and 873 controls (533 men, 340 women). The genotypes for 33 single nucleotide polymorphisms of 27 candidate genes were determined with a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay system. Multivariate logistic regression analysis with adjustment for age, body mass index, and the prevalence of smoking, diabetes mellitus, hypercholesterolemia, and hyperuricemia revealed that two polymorphisms (825C -> T in the G protein beta3 subunit gene and 190G -> A in the CC chemokine receptor 2 gene) were significantly associated with hypertension in men and that one polymorphism (-238G -> A in the tumor necrosis factor- alpha gene) was significantly associated with hypertension in women. CONCLUSION: These results suggest that two and one genes may be susceptibility loci for hypertension in Japanese men and women, respectively, and that genotyping of these polymorphisms may prove informative for prediction of the genetic risk for hypertension.     

Prostate cancer susceptibility genes: lessons learned and challenges posed

In most developed countries, prostate cancer is the most frequently diagnosed malignancy in men. The extent to which the marked racial/ethnic difference in its incidence rate is attributable to screening methods, environmental, hormonal and/or genetic factors remains unknown. A positive family history is among the strongest epidemiological risk factors for prostate cancer. It is now well recognized that the role of candidate genetic markers to this multifactorial malignancy is more difficult to identify than the identification of other cancer susceptibility genes. Indeed, despite the localization of several susceptibility loci, there has been limited success in identifying high-risk susceptibility genes analogous to BRCA1 or BRCA2 for breast and ovarian cancer. Nonetheless, three strong candidate susceptibility genes have been described, namely ELAC2 (chromosome 17p11/HPC2 region), 2'-5'-oligoadenylate-dependent ribonuclease L (RNASEL), a gene in the HPC1 region, and Macrophage Scavenger Receptor 1 (MSR1), a gene within a region of linkage on chromosome 8p. Additional studies using larger cohorts are needed to fully evaluate the role of these susceptibility genes in prostate cancer risk. It is also of interest to mention that a significant percentage of men with early-onset prostate cancer harbor germline mutation in the BRCA2 gene thus confirming its role as a high-risk prostate cancer susceptibility gene. Although initial segregation analyses supported the hypothesis that a number of rare highly penetrant loci contribute to the Mendelian inheritance of prostate cancer, current experimental evidence better supports the hypothesis that some of the familial risks may be due to inheritance of multiple moderate-risk genetic variants. In this regard, it is not surprising that analyses of genes encoding key proteins involved in androgen biosynthesis and action led to the observation of a significant association between a susceptibility to prostate cancer and common genetic variants in some of those genes.     

Ethnic differences in the frequency of ENPP1/PC1 121Q genetic variant in the Dallas Heart Study cohort

Genetic susceptibility modulates the impact of obesity on the risk for type 2 diabetes. One candidate gene predisposing to type 2 diabetes is ENPP1/PC1. A common polymorphism in this protein, K121Q, is associated with insulin resistance and increased susceptibility to type 2 diabetes in Caucasian, Afro-Caribbean, and South Asian populations. The goal of this study was to evaluate differences in the prevalence of the ENPP1 121Q variant in the Caucasian, African-American, and Hispanic populations in Dallas county and to establish a population-based estimate of gene variant prevalence for future investigations. We also evaluated the association between the ENPP1 121Q variant and diabetes. The Dallas Heart Study (DHS) is a multiethnic probability-based sample of the Dallas county population in which African-Americans were systematically oversampled so that the final sample was 50% African-Americans. We performed ENPP1/PC1 genotyping in 1038 non-Hispanic Whites (544 women, 494 men), 1815 African-Americans (1052 women and 763 men), and 597 Hispanics (347 women, 250 men). The frequency of ENPP1/PC1 K121Q was higher in both African-Americans (78.5%) and Hispanics (21.9%) than in the non-Hispanic White group (13.2%). The former two groups also have a higher prevalence of type 2 diabetes (African-Americans, 14.1%, and Hispanics, 11.7%) compared to non-Hispanic Whites (6.8%). Logistic regression analysis revealed significant interactions between the ENPP1 genotype, age, and body mass index within each ethnic group. After adjustment for these variables and their interactions, ENPP1 Q allele predicted diabetes when a recessive model was tested. Ethnic differences in ENPP1 121Q allele frequency may contribute to the increased susceptibility to type 2 diabetes observed in US minority groups.     

Genetically increased angiotensin I-converting enzyme level and renal complications in the diabetic mouse

Diabetic nephropathy is a major risk factor for end-stage renal disease and cardiovascular diseases and has a marked genetic component. A common variant (D allele) of the angiotensin I-converting enzyme (ACE) gene, determining higher enzyme levels, has been associated with diabetic nephropathy. To address causality underlying this association, we induced diabetes in mice having one, two, or three copies of the gene, normal blood pressure, and an enzyme level range (65-162% of wild type) comparable to that seen in humans. Twelve weeks later, the three-copy diabetic mice had increased blood pressures and overt proteinuria. Proteinuria was correlated to plasma ACE level in the three-copy diabetic mice. Thus, a modest genetic increase in ACE levels is sufficient to cause nephropathy in diabetic mice.     

2型糖尿病与肺癌

2型糖尿病与肺癌均是常见病及多发病,两者之间存在联系,2型糖尿病患者肿瘤的发病率升高,高血糖、胰岛素抵抗、免疫功能破坏、脂肪细胞因子等均与肺癌发病率增高有关。关注两者关系,这将为糖尿病患者肿瘤的预防及控制提供新的方向及途径。本文主要就2型糖尿病与肺癌的关系作一综述。     

Association between (AC)n dinucleotide repeat polymorphism at the 5'-end of the aldose reductase gene and diabetic nephropathy: a meta-analysis

Association between the (AC)(n) dinucleotide repeat polymorphism at the 5'-end of the aldose reductase gene and the occurrence of diabetic nephropathy was conducted. We examined eight studies consisting of ten Caucasian type 1 diabetes mellitus case-control comparisons and eight studies consisting of nine type 2 diabetes mellitus case-control comparisons, which were based on our inclusion criterion and available in the literature. The meta-analysis demonstrated a large heterogeneity among the studies on the type 1 diabetic subjects and a significant association was observed between the (AC)(n) dinucleotide repeat polymorphism at the 5'-end of the aldose reductase gene and diabetic nephropathy. The Z-2 allele appeared to be a genetic risk factor for susceptibility to diabetic nephropathy with a random effects odds ratio (OR) of 1.40 (95% confidence interval, CI (1.07, 1.84)). The Z+2 allele showed a protective effect on diabetic nephropathy with a random effects OR of 0.77 (95% CI (0.65, 0.91)). The meta-analysis, however, showed no association between the genetic polymorphism and diabetic nephropathy in type 2 diabetic subjects. Neither the risk Z-2 allele nor the protective Z+2 allele in type 1 diabetic subjects appeared to have an effect on nephropathy in type 2 diabetic subjects, while their fixed effects OR was 1.09 (95% CI (0.96, 1.22)) and 0.88 (95% CI (0.67, 1.15)) respectively. The current meta-analysis demonstrated a correlation between the (AC)(n) dinucleotide repeat polymorphism and the occurrence of diabetic nephropathy in Caucasian type 1 diabetic subjects in contrast to type 2 diabetic subject population in which such an association could not be demonstrated.     

NKX3.1基因rs1512268单核苷酸多态性与前列腺癌风险关系的初步研究

目的 探讨NKX3.1基因的常见变异rs1512268单核苷酸多态性与中国人前列腺癌发生的关系及相关危险因素的相互作用. 方法 选取122例前列腺癌患者和年龄匹配的105例男性(前列腺癌特异抗原＜4μg/L,且无前列腺癌家族史者)作为对照,采用聚合酶链反应-高分辨熔解曲线(PCR-HRM)技术结合测序验证法检测NKX3.1基因rs1512268单核苷酸多态性的分布. 结果 前列腺癌组中GG、AG和AA基因型分布分别为42例(33.4％)、66例(54.1％)和14例(11.5％);正常对照组中三种基因型分布分别为45例(42.9％)、51例(48.6％)和9例(8.6％);两组间基因型频率(x2=1.70,0.69,0.52)和等位基因频率(x2=1.575)的分布差异无统计学意义(P＞0.05).NKX3.1基因rs1512268单核苷酸多态性的不同基因型与前列腺癌患者的年龄、Gleason评分和PSA浓度以及临床分期等指标间均无相关性(P＞0.05). 结论 NKX3.1基因rs1512268单核苷酸多态性与中国人前列腺癌的发生无明显相关性,可能不是中国人前列腺癌发病的遗传危险因素.