Insertion/Deletion Polymorphism on ACE Gene is Associated with Endothelial Dysfunction in Young Patients with Hypertension.

Endothelial dysfunction, insulin resistance (IR) and genetic predispositions are important risk factors of hypertension. Aim of our study was to test the hypothesis, whether insertion/deletion (I/D) polymorphism on the angiotensin converting enzyme (ACE) gene and M235T polymorphism on angiotesinogen gene (AGT) correlates with parameters of insulin sensitivity and plasminogen activator inhibitor (PAI-1) levels in newly diagnosed hypertensive patients as compared with normotensive controls. Blood pressure (BP), fasting plasma glucose, insulin, epinephrine, norepinephrine and PAI-1 concentrations were determined in 30 male patients with hypertension grade 1 (HT) and in 31 matched healthy subjects (NT). Insulin resistance was estimated using IR HOMA formula. Patients with HT had increased levels of PAI-1, norepinephrine, fasting plasma insulin levels, IR HOMA (p<0.001) compared to controls. Subjects (HT and NT) with DD and ID genotype had a significantly higher systolic BP (p<0.05) and PAI-1 compared to those with II genotype. Homozygous subjects 235T had a higher systolic BP and higher levels of epinephrine and norepinephrine than heterozygous or homozygous M235 (p<0.05). In conclusion, no association was found between M235T polymorphism and insulin resistance or PAI-1 levels, but results indicate relationship between I/D polymorphism of the ACE gene and plasma PAI-1 levels in the early stage of hypertension.     

Prevalence of the Angiotensin I Converting Enzyme Gene Insertion/Deletion Polymorphism in a Healthy Turkish Population

Angiotensin converting enzyme (ACE) plays an essential role in the renin–angiotensin system. It converts angiotensin I to angiotensin II and inactivates bradykinin and tachykinins. Numerous studies have been published investigating associations of the ACE gene I/D polymorphism with various pathophysiological conditions. We examined the prevalence of the ACE I/D polymorphism in a sample of healthy volunteers from western Turkey, including 1063 healthy Turkish controls. Analysis of the ACE I/D gene polymorphisms by polymerase chain reaction found frequencies of 16.1% for the II genotype, 47.7% for the ID genotype, and 36.2% for the DD genotype. The allele frequency was 39.9% for the I alleles and 60.1% for the D allele. This study demonstrates that the allele and genotype frequency values for the Turkish population are similar to previously published frequencies for Caucasian populations.     

A 45-bp Insertion/Deletion Polymorphism in Uncoupling Protein 2 is Not Associated with Obesity in a Chinese Population

The association of a 45-bp insertion/deletion (UCP2-45?bp I/D) polymorphism in uncoupling protein 2 with body mass index (BMI) remains controversial. A case-control study was conducted to examine the association in a Chinese population. The 1,526 subjects recruited in downtown Beijing and genotyped included 616 obese subjects with BMI >28 and 910 age- and gender-matched controls with BMI <24. The association of the polymorphisms with obesity was estimated using multivariate logistic regression in three models of inheritance. The odds ratios were 1.08 (95?% CI 0.846-1.368; P?=?0.551) in the dominant model, 0.931 (0.751-1.154; P?=?0.513) in the additive model, and 1.18 (0.550-2.550; P?=?0.666) in the recessive model. The overall comparison of the genotype distributions in obese and control subjects using the chi-square test yielded P?=?0.801. Our study demonstrated no association between UCP2-45?bp?I/D and BMI variation in the Chinese population.     

Associations of CFH Polymorphisms and CFHR1-CFHR3 Deletion with Blood Pressure and Hypertension in Chinese Population

Dysregulation of the complement system has been linked to pathogenesis of hypertension. However, whether genetic changes of complement factor H (CFH) and its related genes are associated with hypertension is unknown. We genotyped three SNPs in the CFH gene cluster that are closely linked to age-related macular degeneration, namely rs1061170 (Y402H), rs2274700 (A473A) and rs7542235 (CFHR1–3Δ), and tested for their associations with blood pressure and hypertension risk in a population-based cohort including 3,210 unrelated Chinese Hans (50–70 years of age) from Beijing and Shanghai. We found that rs2274700 (A473A) and rs7542235 (CFHR1–3Δ) were both significantly associated with diastolic blood pressure (DBP) (β = 0.632–1.431, P≤0.038) and systolic blood pressure (SBP) (β = 1.567–4.445, P≤0.008), and rs2274700 (A473A) was associated with hypertension risk (OR [95%CI]: 1.175 [1.005–1.373], P = 0.048). Notably, the associations of rs2274700 (A473A) with DBP (P = 2.1×10⁻³), SBP (P = 8×10⁻⁵) and hypertension risk (P = 7.9×10⁻³) were significant only in the individuals with low CRP levels (<2.0 mg/l), but not in those with CRP levels ≥2.0 mg/l (P≥0.0807) (P for interaction ≤0.0467). However, no significant association between rs1061170 (Y402H) and blood pressure or hypertension risk was observed (P≥0.259). In conclusion, our results suggest that genetic variations in CFH and its related genes may contribute to hypertension risk in Chinese Hans.     

Insertion/Deletion Polymorphism and Serum Activity of the Angiotensin-Converting Enzyme in Turkish Patients with Obstructive Sleep Apnea Syndrome

This study determined the allelic frequency and genotypic distribution of an angiotensin-converting enzyme (ACE) polymorphism and serum ACE activity in Turkish patients with obstructive sleep apnea syndrome (OSAS). A colorimetric assay measured serum ACE activity in 73 of 97 subjects. Frequencies for II, ID, and DD genotypes were 19.6, 53.6, and 26.8% in the OSAS group and 15, 38, and 47% in the control group, respectively (P = 0.02). The I allele frequency was higher in the OSAS group than in the healthy control group (P = 0.02). Carrying the I allele (II or ID genotypes) increased OSAS risk 2.41 times in the Turkish population. Mean ACE activity was significantly lower in patients with the II genotype than in the DD genotype (P = 0.011), and ACE activity was significantly lower in patients with severe OSAS than in those with mild OSAS (P = 0.006). Our results suggest that II and ID genotypes of the ACE gene increase the risk of developing OSAS in the Turkish population.     

Angiotensin-Converting Enzyme Gene Insertion/Deletion Polymorphism and Cardiometabolic Risk Factors: A Study Among Bhil Tribal Population from Two Environmental Settings

Studies have investigated the association between angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and cardiometabolic risk factors (CMRFs), however with varying results, which could be due to ethnicity differences. Therefore, the present study was conducted among Bhil tribal population (a mendelian population with the common gene pool and same sociocultural attributes), residing in two different environmental settings. The study attempts to understand the distribution and extent of association of ACE I/D gene polymorphism with cardiometabolic risk factors among Bhils from rural and urban settings. All the obesity and blood pressure variables were collected form 432 recruited subjects from both sexes aged 25–65 years and ACE I/D polymorphism was analysed on 299 subjects. Almost all the studied CMRFs were found to be significantly higher among urban Bhils. ACE gene was found to be polymorphic in the studied groups. DD genotype was found to pose more than threefold significant risk for low HDLC only in rural area. Estimate change analysis revealed an increasing D allele dose leads to more than one unit increase in Blood Pressure, and more than three units decrease in HDLC. The study highlights the differential effect of ACE I/D gene polymorphism in different environmental settings.     

A Functional Insertion/Deletion Polymorphism in the Proximal Promoter of CD3G Is Associated with Susceptibility for Hepatocellular Carcinoma in Chinese Population

Hepatocellular carcinoma (HCC) represents the most common primary malignancy of the liver with a worldwide increasing incidence. Although the risk factors for HCC are well characterized, the molecular mechanisms responsible for malignant transformation of hepatocytes are not well understood. In this study, a case-control study including 291 HCC patients and 294 healthy controls was conducted to investigate the association between HCC susceptibility and with a 4-bp insertion/deletion polymorphism (rs66465034) in the proximal promoter of CD3G. Logistic regression analysis showed that the heterozygote and the homozygote 4-bp ins/ins confer a significantly increased risk of HCC after controlling for other covariates (adjusted odds ratio [OR]=1.51, 95% confidence interval [C.I.] 1.01-2.27, p=0.040; OR=1.71, 95% C.I. 1.07-2.89, p=0.025, respectively). Carriage of the 4-bp insertion allele was associated with a greatly increased risk of developing the disease (OR=1.30, 95% C.I. 1.02-1.64, p=0.027). Moreover, hepatitis B virus (HBV) stratification analysis showed that the differences between cases and controls were more obvious in HBV-positive than in the HBV-negative population, suggesting a possible role of this polymorphism in the immune regulation during HBV infection. Further, luciferase-based transient transfection assays revealed that rs66465034 can affect promoter activity of CD3G, indicating its possible functional significance. Our data suggested that common genetic polymorphisms in CD3G may influence HCC risk in Chinese population. Considering the relative small sample size, replication in other populations with larger sample size and further functional analysis are required for fully understanding the roles of CD3G polymorphisms in predisposition for HCC.     

The Insertion/Deletion Polymorphism in the Angiotensin-converting Enzyme Gene and Hypoglycemia Awareness in Patients with Type 1 Diabetes.

Impaired hypoglycemia awareness affects approximately 25% of all patients with type 1 diabetes (T1DM). Duration of diabetes and tight glycemic control represent main risk factors of impaired hypoglycemia awareness. However, even among patients with good glycemic control and longstanding T1DM, awareness of hypoglycemia may be intact. Genetic factors might explain some of this remaining variability. Recently, the insertion/deletion ( I/ D) polymorphism in angiotensin converting enzyme gene ( ACE) was shown to be associated with significantly higher risk of hypoglycemic events in subjects with T1DM. Here, we studied the effects of genetic polymorphisms in the ACE on impaired hypoglycemia awareness in 231 Caucasian T1DM patients. Hypoglycemia awareness status was determined using standardized questionnaires (Clarke et al. and Edinburgh Hypoglycemia Scale). ACE I/ D genotype was determined by PCR amplification of the respective fragments from intron 16 of the ACE and size fractionation (I allele frequency=0.49; P=0.74 for Hardy-Weinberg equilibrium). In the logistic regression analysis, significant risk factors of impaired hypoglycemia awareness were duration of diabetes, C-peptide and HbA (1c) (all P<0.01). However, no significant effect of the I/ D polymorphism on impaired hypoglycemia awareness was observed with and without adjustment for age, diabetes duration, C-peptide and HbA (1c). Even though the study provides a relatively large dataset, it is possible that small differences may have been missed.     

Insertion/Deletion Polymorphism of the Serotonin Transporter Gene and Neuroticism as a Temperament Trait in Affective Patients and Healthy Individuals

Some studies associate the insertion/deletion polymorphism of the serotonin transporter (5-HTT) gene with anxiety-related personality traits in mentally healthy people, the short (s) allele being associated with a higher neuroticism score. The 5-HTT genotype and neuroticism score were established for 114 affective patients, 87 healthy relatives of endogenous psychosis patients, and for 156 mentally healthy people without familial psychiatric history. The effects of sex and age on the association between the two parameters was studied. Neuroticism proved to be not associated with the 5-HTT genotype.     

Association between the Insertion/Deletion Polymorphism of the Angiotensin-Converting Enzyme Gene and Angiopathy in Patients with Non-Insulin Dependent Diabetes Mellitus in Chuvash Republic

Insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) gene was analyzed in patients with non-insulin-dependent diabetes mellitus (NIDDM) and in the control group consisting of healthy subjects. The insertion allele (I) and genotype II were found to be associated with NIDDM. The frequencies of diabetic retinopathy and nephropathy in NIDDM patients were not associated with this polymorphism. However, an association was found between the DD genotype of the ACE gene and diabetic angiopathy in lower extremities.     

Macro- and Microelement Status in Animal and Human Hypertension: the Role of the ACE Gene I/D Polymorphism

Growth hormone (GH) and zinc (Zn) were evaluated for their potential to prevent radiation injury using a rat model of radiation-induced skin injury. Sprague–Dawley rats were divided into five groups: a control group not receiving Zn, GH, or irradiation: a radiation (RT) group receiving a single 30 Gy dose of gamma irradiation to the right hind legs; a radiation + GH group (RT + GH) receiving a single 30 Gy dose of gamma irradiation plus the subcutaneous administration of 0.01 IU kg d^?1 GH; a radiation + Zn group (RT + Zn) receiving a single 30 Gy dose plus 5 mg kg d^?1 Zn po; and a radiation + GH + Zn group (RT + GH + Zn) group receiving a single 30 Gy dose plus subcutaneous 0.01 IU kg d^?1 GH and 5 mg kg d^?1 Zn po. Acute skin reactions were assessed every 3 days by two radiation oncologists grouping. Light microscopic findings were assessed blindly by two pathologists. Groups receiving irradiation were associated with dermatitis as compared to the control group (P < 0.05). The severity of radiodermatitis in the RT + GH, RT + Zn, and RT + GH + Zn groups was significantly lower than that in the RT group (P < 0.05). Furthermore, radiodermatitis was observed earlier in the RT group than in the other treatment groups (P < 0.05). GH and Zn effectively prevented epidermal atrophy, dermal degeneration, and hair follicle atrophy. The highest level of protection against radiation dermatitis was observed in the combination group.     

The Relationship between Gene Polymorphism and CRP Level in a Chinese Han Population

We investigated the relationships among the +1444C/T polymorphism in the C-reactive protein (CRP) gene and the concentration of CRP and the risk of coronary heart disease. Using polymerase chain reaction-restriction fragment length polymorphism, we analyzed the frequency distribution of genotypes and alleles of the +1444C/T polymorphism in samples from 128 patients with coronary heart disease (coronary stenosis more than 50%) and 119 unrelated normal individuals. The plasma levels of CRP and lipids in the subjects were also measured. The frequencies of the genotypes were CC 89.1%, CT 10.9%, and TT 0% in patients and CC 89.9%, CT 10.1%, and TT 0% in controls. The frequency of allele C was 94.5% in patients and 95.0% in controls, and allele T was 5.5% in patients and 5.1% in controls. The distribution of genotypes and alleles in the Chinese Han population was significantly different from that of the Caucasian population. There were no significant differences between frequencies of genotype and allele of controls and those of patients (P>0.05), but in controls the concentrations of CRP in the CC genotype subgroup were significantly higher than those in the CT genotype subgroup (P<0.05). This suggests that the +1444C/T variant in the CRP gene influences the basal CRP level in normal people. These findings imply that there may eventually be a need to establish genotype-specific risk thresholds of the CRP level.     

绵羊ESR2基因组织表达及其多态性与产羔数关联分析

为了探究雌激素受体2 (Estrogen receptor 2, ESR2)基因在绵羊各组织的表达及其多态性与产羔数之间的关系,本研究利用半定量PCR和实时荧光定量PCR技术检测ESR2基因在不同繁殖力小尾寒羊群体组织中的相对表达量,同时采用Sequenom MassARRAY誖SNP技术对多羔品种绵羊(小尾寒羊,湖羊,策勒黑羊)和单羔品种绵羊(苏尼特羊,草原型藏羊,滩羊) ESR2基因g.73324006C>T位点进行检测,并与小尾寒羊产羔数进行关联分析。半定量PCR表明,ESR2基因在单、多羔小尾寒羊子宫中高表达,在其它组织中等或低丰度表达;单羔群体、多羔群体间荧光定量PCR表明,ESR2基因在单羔小尾寒羊垂体表达量显著高于多羔小尾寒羊(p<0.05);群体遗传学分析表明,g.73324006C>T在小尾寒羊群体中表现为低度多态(PIC<0.25),在滩羊群体中处于中度多态(0.25T在小尾寒羊群体处于哈代温伯格平衡状态(p>0.05);关联分析表明,g.73324006C>T位点多态性与小尾寒羊第一胎、第二胎、第三胎产羔数及平均产羔数均显著关联(p<0.05),CC型各胎产羔数均高于TC型。与FecB (A746G)基因组合后发现,GG-CC和AG-CC基因型母羊产羔数显著高于AA-TC、AA-CC、AG-TC基因型组合(p<0.05)。综上,ESR2与小尾寒羊产羔数密切相关,g.73324006C>T可作为绵羊产羔性状选育的潜在分子标记。     

中国及荷兰人群vWF基因内含子40多态性分析

本文调查了中国汉族及荷兰高加索群体中人类vWF基因内含子40 nt 31/2 215～2 380 区域 HUMFA 31(C) 遗传多态性的基因频率及基因型频率分布。并对两群体之间的分布以拟然比方法进行比较。对9个等位基因片段测序的结果表明, 在nt 31/2 234～2 265区域也有变异存在。提示该座位当被测等位基因DNA片段长度相同时,仍可能存在遗传差异。 Abstract　The allele frequencies and phenotype distribution of humanvWFgene intron 40 in the region of nt 31/2 215～2 380 (HUMFA 31(C)) were investigated in the population of the Netherlands and China. The data between two populations were compared by likelihood ratio test. Nine alleles were sequenced and the polymorphism of region of nt 31/2 234～2 265 was revealed.     

中国及荷兰人群vWF基因内含子40多态性分析

本文调查了中国汉族及荷兰高加索群体中人类ｖＷＦ基因内含子４０ｎｔ３１／２２１５～２３８０区域ＨＵＭＦＡ３１（Ｃ）遗传多态性的基因频率及基因型频率分布。并对两群体之间的分布以拟然比方法进行比较。对９个等位基因片段测序的结果表明,在ｎｔ３１／２２３４～２２６５区域也有变异存在。提示该座位当被测等位基因ＤＮＡ片段长度相同时,仍可能存在遗传差异。     

The Associations of LPIN1 Gene Expression in Adipose Tissue With Metabolic Phenotypes in the Chinese Population

The LPIN1 gene, encoding lipin‐1 protein, plays critical roles in adipocyte differentiation and lipid metabolism. This study aimed to analyze the association of LPIN1 mRNA levels in human adipose tissue with metabolic phenotypes. We also examined the association of LPIN1 genetic variation with type 2 diabetes and related metabolic phenotypes in the Chinese population. The relative LPIN1 mRNA levels were measured in abdominal visceral (VAT) and subcutaneous adipose tissue (SAT) obtained from 102 nondiabetic Chinese females. Seven single‐nucleotide polymorphisms (SNPs) spanning from the 5′‐upstream region to the 3′‐end of the LPIN1 gene were genotyped in 1,520 Chinese (760 type 2 diabetic cases and 760 controls). LPIN1 mRNA levels in VAT were negatively correlated with BMI (r = ?0.21, P = 0.03), body fat percentage (r = ?0.22, P = 0.02), plasma triglycerides levels (r = ?0.21, P = 0.03), and plasma leptin levels (r = ?0.63, P = 0.0002). LPIN1 mRNA levels were positively correlated with PPARG and ADIPOQ mRNA levels in both VAT and SAT. No single SNP of the LPIN1 gene was associated with type 2 diabetes in our population. One rare haplotype showed a significant association with type 2 diabetes (odds ratio (OR), 4.35; 95% confidence interval, 1.86–11.75; P = 4 × 10^?4). No SNP or haplotype of the LPIN1 gene was associated with quantitative metabolic traits in the nondiabetic subjects. The results confirmed the association of LPIN1 gene expression in adipose tissue with lower adiposity and favorable metabolic profiles in the Chinese population. However, the LPIN1 gene seemed not to be a major susceptibility gene for type 2 diabetes or related metabolic phenotypes in the Chinese population.     

Fine-Mapping Angiotensin-Converting Enzyme Gene: Separate QTLs Identified for Hypertension and for ACE Activity

Angiotensin-converting enzyme (ACE) has been implicated in multiple biological system, particularly cardiovascular diseases. However, findings associating ACE insertion/deletion polymorphism with hypertension or other related traits are inconsistent. Therefore, in a two-stage approach, we aimed to fine-map ACE in order to narrow-down the function-specific locations. We genotyped 31 single nucleotide polymorphisms (SNPs) of ACE from 1168 individuals from 305 young-onset (age ≤40) hypertension pedigrees, and found four linkage disequilibrium (LD) blocks. A tag-SNP, rs1800764 on LD block 2, upstream of and near the ACE promoter, was significantly associated with young-onset hypertension (p = 0.04). Tag-SNPs on all LD blocks were significantly associated with ACE activity (p-value: 10^–16 to <10^–33). The two regions most associated with ACE activity were found between exon13 and intron18 and between intron 20 and 3′UTR, as revealed by measured haplotype analysis. These two major QTLs of ACE activity and the moderate effect variant upstream of ACE promoter for young-onset hypertension were replicated by another independent association study with 842 subjects.     

Insertion/Deletion Polymorphism of the Angiotensin I-Converting Enzyme Gene and Its Relationship to Serum Free Amino Acid Levels in the Patients with Connective Tissue Dysplasias

An association between insertion/deletion polymorphism (IDP) of the Alu repeat in intron 16 of the angiotensin I-converting enzyme (ACE) gene and the serum free amino acid levels in the patients with connective tissue dysplasias was examined. Genotyping of 102 patients (25 II, 51 ID, and 26 DD) was performed using PCR. Serum free amino acids levels in these patients were determined by use of HPLC technique. A statistically significant increase of the leucine–isoleucine (P< 0.05) and phenylalanine (P < 0.01) levels in deletion homozygous patients (DD) relative insertion homozygous (II) patients was observed. The differences in respect of other amino acids were not detected. These findings point to the importance of registration of IDP in the ACE gene at dietary therapy of such patients, as well as in the individual choice of medical preparations containing the amino acids mentioned.     

E-钙粘蛋白基因启动子区域单核苷酸基因多态性(-347G→GA)和大肠癌遗传易感性的联系

目的:探讨E-钙粘蛋白基因(CDH1)启动子区域-347G→GA单核苷酸基因多态性(single nucleotide polymorphism,SNP)和中国地区散发大肠癌(colorectal cancer,CRC)人群遗传易感性的联系.方法:以中国地区大肠癌病人群为研究基础,同时建立无肿瘤家族史以及其它遗传性疾病史的正常对照组,进行病例对照研究,采用聚合酶链反应一限制性片段长度多态性技术(poly-merase chain reaction-restriction fragment length polymorphism,PCR-RFLP)行目的基因的多态性测定.结果:正常对照组和大肠癌组的目的基因型分布频率并无统计学差异(x2检验,P=0.246),而近端大肠癌患者中GA基因型(GA/GA杂合子和GA/GA纯合子)比例明显高于对照组(OR=1.773,95%CI=1.174-2.679,P=0.007),同时低分化大肠腺癌GA基因型比例也明显高于对照组(OR=2.623,95%CI=1.326-5.191,P=0.007).结论:CDHl启动子区域-347G→GA单核苷酸基因多态性中GA基因型可能增加近端大肠癌以及低分化腺癌的发病风险.