HER2 Ile655Val polymorphism is negatively associated with breast cancer susceptibility

Background

The HER2 (human epidermal growth factor receptor‐2) Ile655Val (rs1136201) genetic polymorphism can alter the receptor structure and its auto‐activation, which can modify the signal transduction and, consequently, the cell cycle regulation. For this reason, this polymorphism has been extensively investigated as a candidate marker for breast cancer (BC). In this context, the aim of this study was to evaluate the possible influence of HER2 Ile655Val in BC susceptibility and prognostic factors in a Brazilian population.

Methods

Polymorphism genotype was assessed through RFLP‐PCR in 107 BC patients with clinicopathological data available and in 150 women with no evidence of neoplasia and with no familial history of BC as control group. Association between this polymorphism and BC susceptibility and clinical parameters was evaluated through odds ratio (OR) and chi‐squared or Fisher's exact test, respectively.

Results

A significant negative association between valine allele and BC susceptibility in dominant model was found (OR 0.5; 95% CI 0.27‐0.93, P = .036). No significant association was found in relation to BC clinicopathological features (tumor size, lymph nodes commitment, histological grade, HER2 overexpression, hormonal receptors, p53, and Ki‐67).

Conclusion

Although this polymorphism did not demonstrate potential as a prognostic marker, it may be a suitable susceptibility marker for BC.

     

BDNF Val66Met polymorphism is associated with unstable angina

BackgroundBrain-derived neurotrophic factor (BDNF) is involved in the pathophysiology of coronary artery disease (CAD). The human BDNF Val66Met polymorphism has been shown to be associated with altered susceptibility to neuropsychiatric disorders. However it is unknown whether this polymorphism plays a role in cardiovascular disease.MethodsGenotyping of BDNF Val66Met polymorphism was carried out in 513 controls, 628 unstable angina pectoris (UAP) and 276 stable angina pectoris (SAP) patients. The plasma concentrations of BDNF and high-sensitivity C-reactive protein (hsCRP) were measured by ELISA. The general clinical data in patients and controls were obtained.ResultsThere was a significant association between genotype and allele frequency of the BDNF Val66Met polymorphism and UAP (all P < 0.05). Multivariate logistic regression analysis revealed that the BDNF_Met/Met genotype had a protective effect on the occurrence of UAP after controlling for known risk factors of CAD (OR 0.53, P = 0.005). Subjects with BDNF_Met/Met genotype also had decreased plasma hsCRP levels compared with the Val carriers (P < 0.01).ConclusionThe BDNF_Met/Met genotype has a protective effect on the occurrence of UAP, which might in part be due to the decreased plasma hsCRP level in BDNF_Met/Met carriers. To our knowledge, this is the first study that demonstrates the link between BDNF Val66Met polymorphism and CAD.     

The fecal metabolome is associated with gestational diabetes mellitus

Dysbiosis of gut microbiota has been linked to gestational diabetes mellitus (GDM), and grows as a resource for GDM biomarkers. However, the contributions of gut microbiota to GDM remain incompletely understood. Metabolites are key messengers in the interactions between gut microbiota and the host. Metabolomics is emerging as an essential tool in exploring the contributions of gut microbiota to diseases. In this study, we performed ¹H-NMR based metabolomics on the feces of 62 pregnant women, including 31 women with GDM, and 31 women as the non-diabetes (NDM) control. Using Principle Component Analysis (PCA) and Orthogonal Projection to Latent Structures Discrimination Analysis (OPLS-DA), we observed clear cluster separation of the fecal metabolome between women with GDM and the NDM control. We further applied several feature selection methods to find five fecal metabolites contributing to the cluster separation of the fecal metabolome. These five metabolites, namely dibutyl decanedioate, N-acetylgalactosamine-4-sulphate, homocysteine, l-malic acid, and butanone, were significantly correlated with the clinical indices of GDM. Metabolite enrichment and pathway analysis on the five metabolites suggested that the fecal citrate cycle and sulfur metabolism were correlated with GDM. The results of this study demonstrated that disorders in the fecal metabolome are associated with GDM.

Fecal metabolome could separate women with GDM from the non-diabetic control.     

Type 2 diabetes mellitus is associated with multiple cardiometabolic risk factors

The risk for cardiovascular disease (CVD) is multifactorial and includes such risk factors as diabetes, hypertension, smoking, and dyslipidemia. Thus, targeting the hyperglycemia in type 2 diabetes mellitus (DM) alone will not eliminate all of the excess cardiovascular risk; rather aggressive treatment is needed for all of the modifiable cardiometabolic risk factors. Therapeutic lifestyle change is considered primary therapy for hyperglycemia in type 2 DM. Currently, however, the focus in treatment is on preventing CVD rather than controlling glucose, lipid, or blood pressure (BP) levels. The American Diabetes Association guidelines identify low-density lipoprotein cholesterol as the first priority of lipid lowering, with optimal level set at <100 mg/dL (2.6 mmol/L). To reach the target BP level of <130/85 mm Hg, >65% of patients with DM and hypertension will require 2 or more different antihypertensive drugs. Strategies that combine thiazolidinediones and statins may have complementary effects on cardiovascular risk-factor profiles in type 2 DM, in addition to controlling glycemia. Despite the range of treatment options available, therapeutic agents that target new steps in the progression of CVD are needed, as patients with type 2 DM remain at increased risk and many do not achieve therapeutic targets with the drugs available.     

A prevalent amino acid polymorphism at codon 98 (Ala98Val) of the hepatocyte nuclear factor-1alpha is associated with maturity-onset diabetes of the young and younger age at onset of type 2 diabetes in Asian Indians

OBJECTIVE: Among Europeans, mutations in the hepatocyte nuclear factor-1alpha (HNF1alpha) gene are associated with the most common form of maturity-onset diabetes of the young (MODY)3. In Asian Indians, type 2 diabetes occurs earlier and often overlaps with MODY, but the genetics of the latter are unknown. The aim of this study was to estimate the prevalence of Ala98Val polymorphism of the HNF1alpha gene in different types of diabetes in Asian Indians. RESEARCH DESIGN AND METHODS: Genotyping of Ala98Val was done by the PCR-restriction fragment-length polymorphism method in the following groups: 1) MODY, defined as non-insulin-dependent diabetes (age at onset <25 years) and vertical transmission of diabetes through at least three generations (n = 122); 2) very-early-onset type 2 diabetes (age at onset <25 years) without family history (n = 23); 3) early-onset type 2 diabetes (age at onset between 26 and 40 years, n = 171); 4) late-onset type 2 diabetes (age at onset >40 years, n = 133); 5) type 1 diabetes (n = 150); and 6) normal glucose tolerance (n = 130). The frequency of the Val genotypes was compared in the diabetic and control groups. RESULTS: The frequency of the Val allele was significantly higher in MODY patients (P = 0.0013) compared with control groups. Furthermore, in the total group of patients with type 2-like diabetes (groups 1-4), the Val allele was associated with an earlier diagnosis of diabetes (P = 0.0002). CONCLUSIONS: Among Asian Indians, the Ala98Val polymorphism of HNF1alpha gene is associated with MODY and with earlier age at onset of type 2 diabetes.     

蛋白酪氨酸磷酸酶-1B基因多态性与2型糖尿病的相关性研究

目的 探讨蛋白酪氨酸磷酸酶—1B(protein tyrosine phosphastase-1B,PTP—1B)基因387位编码子Pro-Leu多态性与2型糖尿病(T2DM)的关系。方法 采用多聚酶联反应—限制性片段长度多态性(PCR—RFLP)的方法对湖北地区130例2型糖尿病患者及138例正常对照者PTP—1B基因387位编码子酶切位点进行研究。结果 2型糖尿病患者和正常对照者PTP—1B基因均以PP基因型为主，其频率分别为0．94和0．96；P等位基因频率分别为0．97和0．98，差异无统计学意义(P＞0．05)。2型糖尿病患者中PTP—1B基因P387L变异与体重指数(BMI)有关，但与空腹血糖、空腹胰岛素、总胆固醇、甘油三酯等临床变量不相关。结论 未发现PTP—1B基因387位Pro-Leu多态性与中国人2型糖尿病有关。     

早老素相关菱形样蛋白基因Leu262Val多态性与2型糖尿病及糖尿病肾病的相关性研究

目的 探讨早老素相关菱形样蛋白(PARL)基因Leu262Val多态性与2型糖尿病(T2DM)及糖尿病肾病(DN)的相关性.方法 运用聚合酶链反应一限制性片段长度多态性(PCR-RFLP)技术,在昆明地区汉族人中对278例T2DM患者[其中正常白蛋白尿(DN0)组102例,微量白蛋白尿(DN1)组91例,临床白蛋白尿(DN2)组85例]和113例健康对照者(NC)的PARL基因Leu262Val多态性进行检测,并比较分析各组间基因型频率和等位基因频率以及相关临床资料.结果 T2DM组和NC组间,DN组(DN1+DN2)、DN0组和NC组各组间基因型频率及等位基因频率均无统计学意义(P>0.05),二分类Logistic回归分析表明:在T2DM患者中,DM病程、收缩压(SBP)、甘油三酯(TG)和糖化血红蛋白百分比(HbA1c%)是DN发生的危险因素.结论 在昆明地区汉族人中PARL基因Leu262Val多态性可能与T2DM及DN的发生无相关性;DM病程、SBP、TG、HbA1c可能是DN的危险因素.     

Gestational diabetes mellitus is associated with increased C-reactive protein concentrations in the third but not second trimester

OBJECTIVE: Serum C-reactive protein (CRP) concentrations were measured longitudinally throughout pregnancy to test the hypothesis that CRP could relate more closely to glucose tolerance than to adiposity. METHODS: The CRP concentrations in pregnant women with normal glucose tolerance (NGT) and those with gestational diabetes mellitus (GDM) were measured at the same time as the oral glucose tolerance test (OGTT), at the 24th and 28th weeks of gestation and between the 37th and 38th weeks of gestation. RESULTS: At the end of the third trimester, women with GDM had significantly higher CRP levels than women with NGT [median (interquartile range), 9.7 mg L(-1) (5.4-16.0) and 5.7 mg L(-1) (5.1-7.2); P < 0.001, respectively], but at the time of the diagnostic OGTT no significant difference between the two groups was observed. This was owing to a significant increase of CRP in women with GDM between the time of the OGTT and the 37th-38th gestational weeks [median (interquartile range), 1.9 mg L(-1) (-2.2, 6.7); P = 0.01]; whereas, no change in CRP was found in women with NGT [median (interquartile range), -0.1 mg L(-1) (-2.4, 3.1); P = 0.76]. Multiple linear regression analysis showed only a significant independent influence of GDM (P < 0.001) on maternal CRP concentrations in the 37th-38th gestational weeks and a significant influence of body mass index (P < 0.007), but no influence of GDM at the time of the OGTT. CONCLUSION: These data suggest that in women with gestational diabetes the CRP concentration is primarily related to the degree of adiposity until the second trimester and that thereafter impaired glucose metabolism appears to be the predominant predictor of changes in CRP.     

Type 2 diabetes mellitus is associated with differential effects on plasma cholesteryl ester transfer protein and phospholipid transfer protein activities and concentrations

BACKGROUND: Human plasma contains two lipid transfer proteins, cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP), which are crucial in reverse cholesterol transport. METHODS: Plasma CETP and PLTP activity levels and concentrations in 16 type 2 diabetic patients and 16 matched healthy subjects were determined, and these data were correlated to clinical variables, including insulin sensitivity and lipid levels. RESULTS: Plasma triglycerides were higher (p<0.02) and high-density lipoprotein (HDL) cholesterol (p<0.02) was lower in diabetic patients. Plasma CETP activity and concentrations were not significantly different between diabetic and healthy subjects, but CETP specific activity was lower in diabetic patients (p<0.001). Multiple regression analysis showed that plasma CETP activity was positively related to CETP concentration (p=0.0001) and negatively to the diabetic state (p<0.002) or to HbA1c (p<0.02). PLTP activity (p<0.05) and specific activity were higher (p<0.05), whereas there was no difference in PLTP concentration between the two groups. There was no significant bivariate correlation between PLTP concentration and activity, in either healthy or diabetic subjects. Multiple regression analysis did disclose positive relationships of PLTP activity with PLTP concentration (p=0.0001), plasma triglycerides (p=0.0001) and waist/hip ratio (p=0.0001), but not with the diabetic state or HbA1c. CONCLUSIONS: Neither CETP nor PLTP activity was independently associated with insulin sensitivity. Specific CETP activity is decreased in type 2 diabetes mellitus. In contrast, specific PLTP activity is higher in diabetes, as a result of the association of plasma PLTP activity with plasma triglycerides and obesity. Measurement of both plasma lipid transfer protein activity and mass levels may thus provide extra information in diabetes mellitus.     

MICA polymorphism is associated with type 1 diabetes in the Korean population

OBJECTIVE: Recent studies have demonstrated that MICA (major histocompatibility complex class I chain-related genes) on the short arm of the chromosome 6 are associated with susceptibility to various autoimmune diseases in Caucasians. The aim of our study was to investigate the role of MICA in type 1 diabetes susceptibility independent of the HLA DR-DQ polymorphism in genetically distinct Koreans. RESEARCH DESIGN AND METHODS: A total of 119 patients selected from Korean Seoul type 1 diabetes registry and 134 nondiabetic unrelated control subjects were typed for exon 5 polymorphism of MICA in addition to HLA DR-DQ typing. A total of 52 simplex families of type 1 diabetes were also studied. RESULTS: The MICA microsatellite allele consisting of six repetitions of GCT/AGC (A6) was present at a significantly lower frequency in the diabetic patient group (Pc < 0.01; Pc = P value after Bonferroni correction) than in the control population. The MICA microsatellite allele consisting of four repetitions (A4) was present at a higher frequency in diabetic patients (P < 0.05). This deviated distribution was not changed even after controlling for the HLA DRB1-DQB1 haplotype. Transmission/disequilibrium test revealed significant deviation of transmission for alleles at the A6 polymorphism within the MICA gene (P < 0.05). CONCLUSIONS: We could assess that the MICA gene might be associated with type 1 diabetes transracially independent of the HLA gene.     

2型糖尿病大鼠骨骼肌解耦联蛋白3表达及罗格列酮的干预效应

目的：观察高脂饲养加佐菌链脲霉素（STZ）诱导2型糖尿病大鼠的骨骼肌解耦联蛋白3（UCP3）mRNA表达水平以及罗格列酮（RSG）的干预作用。方法：将8周龄雄性SD大鼠随机分为普通饲养组（NC组,n=15）,高脂饲养组（HF组,n=45）。8周后HF组内随机选出30只进行腹腔注射STZ。将血糖≥16.7mmol/L大鼠分成DMC组（n=14）和DMT组（n=14）,DMT组给予RSG灌胃进行干预治疗,NC组、HF组、DMC组给予等量生理盐水灌胃。8周后取空腹血糖、血脂并采用RT-PCR法测定骨骼肌中UCP3 mRNA含量。结果：HF组大鼠体重增加,血脂增高,血糖无明显增高。与NC组比较,HF组UCP3 mRNA表达量下降约25%（P﹤0.05）,DMC组表达量下降约35%（P﹤0.05）,DMT组表达量较DMC组增加约25%（P﹤0.05）。结论：RSG能明显增加2型糖尿病大鼠骨骼肌UCP3 mRNA表达,提示UCP3在2型糖尿病发展中有一定作用。[著者文摘]     

The Leu72Met polymorphism of the ghrelin gene is associated with a decreased risk for type 2 diabetes

BACKGROUND: Ghrelin is involved in several metabolic and cardiovascular processes. The Leu72Met polymorphism of its gene was associated with an increased risk of type 2 diabetes (DM2) in some, but not all studies. Its association with atherosclerosis is not known. METHODS: We investigated 420 Caucasian subjects with DM2 and 430 controls without diabetes (56.6% male, age 62+/-10 years). RESULTS: The Leu72Leu genotype frequencies were 89.76/84.65%, the Leu72Met 9.52/15.12% and the Met72Met 0.71/0.23% (P=0.029) in the DM2 and controls groups, respectively. In subjects with Met72+ genotypes the risk of DM2 was significantly decreased (univariate OR 0.63, 95% CI 0.42-0.95, P=0.026). In a logistic regression model, body mass index, hypertension and a positive family history for diabetes were predictors of diabetes while the polymorphism remained negatively associated with the disease (OR 0.62, 95% CI 0.40-0.97, P=0.036). After adjusting for known risk factors for atherosclerosis, the Met72+ variant was not associated with atherosclerotic disease (OR 1.41, 95% CI 0.78-2.54, P=0.25). Ghrelin concentrations were not associated with the polymorphism, DM2 or atherosclerotic disease. CONCLUSIONS: The Leu72Met polymorphism of the ghrelin gene is associated with a decreased risk for DM2. There is no association between the variant and atherosclerotic disease or ghrelin concentrations.     

Both youth and long-term vitamin D status is associated with risk of type 2 diabetes mellitus in adulthood: a cohort study

Objectives: To determine whether vitamin D status in childhood and adolescence (herein collectively referred to as youth) and the long-term status from youth to adulthood is associated with risk of developing type 2 diabetes mellitus (T2DM) and impaired fasting glucose (IFG) in adulthood.

Materials and methods: This was a 31-year follow-up study of 2300 participants aged 3–18 years. Multinomial logistic regression was used to assess the association of both (a) baseline 25-hydroxyvitamin D (25OHD) levels and (b) the mean of baseline and the latest follow-up 25OHD levels (continuous variable and quartiles) with incident T2DM and IFG (cut-off?=?5.6?mmol/L) in adult life.

Results: High serum 25OHD levels in youth and also mean values from youth to adulthood were associated with reduced risk of developing T2DM in adulthood (odds ratio, 95% confidence interval=?0.73, 0.57–0.95 and 0.65, 0.51–0.84, respectively, for each SD increment in 25OHD). Compared to Q1, a dose-dependent negative association was observed across other quartiles of youth 25OHD, while the strongest association was found in the Q3 for the mean 25OHD levels. Neither youth nor the mean 25OHD was associated with IFG.

Conclusions: High serum 25OHD levels in youth, and from child to adult life, were associated with a reduced risk of developing T2DM in adulthood.

• Key Messages

• High serum 25OHD levels in youth, and between youth and adulthood, were associated with a lower risk of T2DM in adulthood.

• Each SD (15.2?nmol/L) increment in youth serum 25OHD levels was associated with a 26% reduction in odds for T2DM, which was independent of a number of confounding variables and other risk factors for T2DM. A similar magnitude of association was observed for the long-term 25OHD levels between youth and adulthood.

• These findings suggest a potentially simple and cost-effective strategy for reducing adulthood risk of T2DM starting in an earlier stage of life – improving and maintaining vitamin D status throughout youth and early adulthood.

     

2型糖尿病患者对糖尿病的接受性及其影响因素

目的：了解2型糖尿病患者对糖尿病的接受性,并探讨影响其接受性的相关因素。方法：采用问卷调查法,对115例2型糖尿病患者的接受性进行调查。结果：2型糖尿病患者总体接受性水平为70.03±8.81,影响接受性的因素有性别、受教育水平和付费方式。结论：2型糖尿病患者的总体接受性仍需进一步提高,护理人员在临床实践中,应及时评估糖尿病患者的接受性,并应采用各种方法提高女性、无医疗保障和受教育水平较低的患者的接受性,以判断患者能否系统地接受健康教育,从而使患者能更好地进行自我管理。     

Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma2 (PPARgamma-2) gene is associated with greater insulin sensitivity and decreased risk of type 2 diabetes in an Iranian population.

BACKGROUND: The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma2 (PPARgamma-2) gene has been variably associated with insulin resistance, obesity and type 2 diabetes in several populations. However, this association has not been studied in Iranian subjects and we hypothesized that this variation might be associated with insulin resistance, type 2 diabetes and related metabolic traits in this population. METHODS: The Pro12Ala genotypes were determined by PCR-restriction fragment length polymorphism in 696 unrelated subjects including 412 non-diabetic controls and 284 type 2 diabetic patients. RESULTS: The frequency of the Ala allele was 9.4% and 5.9% in controls and type 2 diabetic subjects, respectively [adjusted odds ratio (OR) 0.457, p=0.005]. The Ala allele did not show a significant effect on anthropometric and biochemical parameters in the type 2 diabetic group, whereas in non-diabetic subjects, carriers of the Ala allele had significantly lower fasting insulin (p=0.007) and homeostasis model assessment of insulin resistance (HOMA-IR) (p=0.009) levels compared to Pro/Pro subjects. Multivariate logistic regression analysis showed that Pro12Ala polymorphism was an independent determinant of type 2 diabetes in this population. CONCLUSIONS: Our results for a sample of Iranian type 2 diabetes cases and controls provide evidence that the Pro/Ala genotype of the PPARgamma-2 gene is associated with insulin sensitivity and may also have protective role against type 2 diabetes.