Association of the level of heteroplasmy of the 15059G>A mutation in the MT-CYB mitochondrial gene with essential hypertension

AIM: To examine whether the heteroplasmy level for 15059G>A mutation in the mitochondrial genome might be associated with essential hypertension. METHODS: This cross-sectional study involved 196 unrelated participants randomly selected from general population (90 males and 106 females) who underwent a regular medical check-up at the Institute for Ath-erosclerosis Research (Moscow, Russia). One hundred and twenty of them (61%) had essential hypertension, and 76 (39%) were apparently healthy normotensive persons. The level of heteroplasmy for 15059G>A mutation occurring in the coding region of cytochrome b gene (MT-CYB) of mtDNA isolated from the blood leukocytes, was quantified using DNA pyrosequencing method. RESULTS: The 15059G>A heteroplasmy level ranged between 4% and 83%, with a median level of 31%. Between the upper and lower quartiles of 15059G>A heteroplasmy distribution, significant differences were observed for patients’ age, systolic blood pressure, and triglyceride levels. 15059G>A heteroplasmy correlated both with age (r = 0.331, P < 0.001) and the presence of hypertension (r = 0.228, P = 0.002). Regression analysis revealed that the age explains 12% variability of 15059G>A heteroplasmy, and hypertension independently explains more 5% variability. The 15059G>A heteroplasmy exceeding 31% was found to be significantly associated with a higher risk of essential hypertension (odds ratio 2.76; P (Fisher) 0.019]. The study participants with high 15059G>A heteroplasmy level were found to have significantly higher age (P < 0.001) and the prevalence of essential hypertension (P = 0.033), as compared to those with low 15059G>A heteroplasmy level. These observations suggested a positive correlation between the level of 15059G>A heteroplasmy and essential hypertension. CONCLUSION: This study provides the evidence of association of mtDNA 15059G>A mutation heteroplasmy with essential hypertension.     

The heteroplasmic m.14709T>C mutation in the tRNAGlu gene in two Tunisian families with mitochondrial diabetes

Diabetes mellitus (DM) is a heterogeneous disorder characterized by the presence of chronic hyperglycemia. Genetic factors play an important role in the development of this disorder, and several studies reported mutations in nuclear genes implicated in the insulin function. Besides, DM can be maternally transmitted in some families, possibly due to the maternal mitochondrial inheritance. In fact, mitochondrial genes may be plausible causative agents for diabetes, since mitochondrial oxidative phosphorylation plays an important role in glucose-stimulated insulin secretion from beta cells.Materials and MethodsIn this report, we screened two Tunisian families with mitochondrial diabetes for the m.3243A>G and the m.14709T>C mutations, respectively, in the tRNA^Leu(UUR) and the tRNA^Glu genes.ResultsThe polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) and the sequence-specific primers by polymerase chain reaction (SSP-PCR) analysis in the leucocytes and the buccal mucosa in the members of the two families showed the absence of the m.3243A>G mutation and the presence of the heteroplasmic m.14709T>C mutation in the tRNA^Glu gene in the two tested tissues.ConclusionsWe conclude that the m.14709T>C mutation in the tRNA^Glu gene could be a cause of mitochondrial diabetes in Tunisian affected families. In addition, the heteroplasmic loads correlated with the severity and the onset of mitochondrial diabetes in one family but not in the other, suggesting the presence of environmental factors or nuclear modifier genes.     

A heteroplasmic mitochondrial DNA 3310 mutation in the ND1 gene in a patient with type 2 diabetes, hypertrophic cardiomyopathy, and mental retardation.

A mentally retarded 57-year-old Japanese man with maternally-inherited type 2 diabetes was found to have hypertrophic cardiomyopathy (HCM) that was associated with pathological changes in the myocardial mitochondria. The mitochondrial DNA (mtDNA) of this patient was examined and a C3310 T mutation was found in the ND1 gene, which resulted in the substitution of serine for proline. The normal 3310 mtDNA band could not be detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in mtDNA from his myocardium, pancreas, cerebral tissue, skeletal muscle, and lymphocytes. However two clones sequenced from his pancreatic tissue did not show this C3310 T mutation while forty-eight did. Mitochondria isolated from the lymphocytes of his two sisters also had this mutation. mtDNA point mutations in the ND1 gene region reported thus far have been mostly homoplasmic. However, the C3310 T point mutation that was found in this patient was heteroplasmic, which is a high level of mutation and may represent the pathogenic gene that was responsible for causing mitochondrial disease.     

家族性2型糖尿病线粒体基因突变发生率及其临床意义

目的探讨家族性2型糖尿病（T2DM）线粒体基因tRNA^Leu（UUR）mt3243A→G突变发生率及突变家系成员病情演变与临床特征。方法采用PCR／ApaI酶切法对66个家族性T2DM的家系成员共计518人进行突变筛查,并随访3年,观察其临床特点及胰岛B细胞功能变化。结果共发现突变阳性12例,其中3例为已确诊的T2DM患者,1例为糖耐量减低（IGT）患者,8例为糖耐量正常（NGT）者。随访3年后突变阳性者的耳聋症状加重,BMI、HOMA—IR下降,部分成员出现了白蛋白尿,2例演变为DM,3例进展为IGT,其中一例突变阳性者新生一女也为该基因突变阳性。结论家族性T2DM患者中线粒体基因突变发生率约为2．7％,且突变患者的临床表现呈一定的异质性;线粒体基因突变阳性的NGT者是糖尿病高危人群,易演变为IGT或DM,而IGT者易进展为DM。     

Screening for the Gly40Ser mutation in the glucagon receptor gene among patients with type 2 diabetes or essential hypertension in Taiwan

As a major counterregulatory hormone of insulin, glucagon plays an important role in regulating glucose homeostasis through its binding to the glucagon receptor. Recently a missense mutation in the glucagon-receptor gene (Gly40Ser) was found to be associated with type 2 diabetes in France and Sardinia, with a frequency as high as 4.6% and 8.3%, respectively. This mutation was also found to be associated with essential hypertension in the white population with a frequency of 5.4%. To investigate the role of this mutation in the pathogenesis of type 2 diabetes and essential hypertension in Taiwanese population, we screened 121 normal controls, 213 unrelated subjects with type 2 diabetes, and 107 unrelated subjects with essential hypertension by use of polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP). None of the Taiwanese subjects recruited in the study had this receptor mutation. Our results demonstrate a strong genetic heterogeneity among the ethnic group and suggest that the Gly40Ser mutation of the glucagon receptor gene plays little role, if any, in the pathogenesis of type 2 diabetes and essential hypertension in the Taiwanese population.     

线粒体转运RNA基因突变与原发性高血压的相关研究

目的探究线粒体转运RNA(tRNA)基因突变与母系遗传原发性高血压(EH)的关联性。方法依据EH诊断和母系遗传判别标准,筛选2015年1月至2018年12月解放军总医院心血管内科收治的母系遗传EH患者17例(A组)、非母系遗传EH患者65例(B组)。选取同期来院进行健康体检的正常对照人群33名(C组)。对全线粒体DNA(mtDNA)进行测序并与线粒体基因文库MitoMap的修正剑桥序列进行比对,分析3组受试者线粒体tRNA基因突变率差异及其与母系遗传EH发生的关系。应用SPSS 19.0软件对数据进行分析。结果纳入人群中母系遗传EH占总EH 20.7%(17/82)。mtDNA序列对比分析发现,与C组(0.04%)比较,A组(0.28%,P=0.024)及B组(0.12%,P=0.046)患者线粒体tRNA基因总变异率明显升高,但A与B组间比较差异无统计学意义(P=0.076)。对A组患者进一步分析显示,仅有1个线粒体tRNA基因位点突变的先证者A06、A11和A13所在3个家系分别发生mtDNA A5823G、mtDNA T4386C与mtDNA C15910T突变,三个家系母系成员EH发病率分别为53.8%(7/13)、87.5%(7/8)和75.0%(9/12),发病率均较高,提示这3个位点突变可能与母系遗传EH发生密切关联。另外,mtDNA 5597缺失在A组(4例,23.5%)、B组(14例,21.5%)和C组(1例,3.0%)均出现。与C组比较,A组(P=0.002)与B组(P=0.002)患者mtDNA 5597缺失率均显著升高,但A组与B组间比较差异无统计学意义(P=0.127)。结论 mtDNA A5823G、mtDNA T4386C与mtDNA C15910T突变与母系遗传EH有较好的关联性,但mtDNA 5597缺失与母系遗传EH关系不大。     

线粒体基因ND1 3316 G→A突变与2型糖尿病的关系

256例2型糖尿病和140例健康对照者研究显示,线粒体基因ND13316 G→A突变在中国北部2型糖尿病人群中的发生率约为3.52%,突变对T2DM的发生有一定风险性,但不是主要的易感基因.     

老年原发性高血压合并2型糖尿病及漏诊分析

目的　 探讨老年原发性高血压合并 2型糖尿病 ( 2DM )的发病情况及漏诊原因分析。　 方法 　对2 18例老年原发性高血压患者进行空腹血糖检查和标准口服葡萄糖耐量试验 ,比较 2DM重筛选方法及相关因素。　 结果 　 ( 1) 2 18例老年原发性高血压 6 4例伴有 2DM ,漏诊率 34 37%。 ( 2 )空腹血糖 (FPG)≥ 7 8mmol·L-1时敏感性和特异性分别为 6 5 6 2 %和 99 12 % ;FPG≥ 7 0mmol·L-1时敏感性和特异性分别为 91 32 %和 94 5 2 %。　 结论　老年原发性高血压患者同时伴糖尿病较常见的FPG≥ 7 8mmol·L-1时作为敏感指标 ,老年DM易漏诊     

内皮型一氧化氮合酶基因多态性与原发性高血压、2型糖尿病的关系

目的：探讨内皮型一氧化氮合酶（eNOS)基因27bp数目可变的串联重复序列（VNTR）多态性与中国汉族人原发性高血压（EH），2型糖尿病（DM)关系。方法：（1）聚合酶链反应（PCR）－琼脂糖凝胶电泳检测基因型。（2）硝酸盐还原酶法测定空腹血清一氧化氮代谢物（NOx)水平。（3）放免法检测葡萄糖耐量试验时血清免疫活性胰岛素（IRI），C肽（CP)。结果：（1）EH组，2型DM组a等位基因频率显著高于对照组（0．109和0．051；0．129对0．051，P均＜0．05）。2型DM组aa ab基因型频率显著高于对照组（0．224对0．103，P＜0．05）。（2）对照组内aa ab基因型空腹血清NOx明显低于bb基因型（P＜0．05）。（3）EH组aa ab基因型空腹，糖负荷后血清IRI，CP均高于bb基因型，其中部分时点差异有显著性（P＜0．01或P＜0．05）。2型DM组aa ab基因型间各个点血清IRI，CP变化方向不一致。（4）EH组内aa ab基因型HOMA－IR显著高于bb基因组（P＜0．05）。结论：eNOS 基因27bpVNTR多态性与中国汉族人EH及2型DM发生有关,a等位基因可能通过减少内皮基础NO释放参与EH发病，通过胰岛素抵抗机制参与EH和2型DM的发病。     

线粒体tRNALeu(UUR)基因点突变与1型糖尿病

目的　线粒体ｔ Ｒ Ｎ Ａ Ｌｅｕ（ Ｕ Ｕ Ｒ） 基因３２４３ 位点 Ａ→ Ｇ 突变是糖尿病的致病基因之一。本研究是为了了解该基因的突变在中国１ 型糖尿病患者中的情况以及与自身免疫导致１ 型糖尿病有无关联。方法　对１１６ 例随机收集的１ 型糖尿病患者用聚合酶链反应限制性内切酶消化作该点突变的筛选；８２ 例患者同时进行了谷氨酸脱羧酶（ Ｇ Ａ Ｄ） 抗体的测定。结果　发现１ 例该点突变（０ ．８６ ％ ） ，４８ 例 Ｇ Ａ Ｄ 抗体阳性（５８ ．５ ％ ） 。线粒体ｔ Ｒ Ｎ Ａ Ｌｅｕ（ Ｕ Ｕ Ｒ） 基因突变携带者 Ｇ Ａ Ｄ 抗体阴性，其家系成员糖尿病有不同的发病方式，但均表现为胰岛素缺乏。结论　线粒体ｔ Ｒ Ｎ Ａ Ｌｅｕ（ Ｕ Ｕ Ｒ） 基因异常所致糖尿病表现为胰岛素缺乏可能与自身免疫胰岛炎无关，而是一种独特的糖尿病亚型。     

Association of RETN gene polymorphism at +299 G>A with type 2 diabetes mellitus: a meta-analysis

International Journal of Diabetes in Developing Countries - Resistin (RETN) protein plays an important role in the regulation of energy, glucose, and lipid homeostasis and maintenance of fasting...     

Angiotensin II type 2 receptor gene polymorphisms and cardioprotective role in essential hypertension

Angiotensin II type 2 receptor (AT2R) has been proved to be involved in a cardioprotective role, but only a few studies have addressed the association of AT2R-genotype with this role. Whether the AT2R genotype is associated with hypertension is controversial. The aim of the study was to explore the information of single-nucleotide polymorphisms (SNPs) of the AT2R gene in Cantonese, an essential subpopulation of Chinese, and study the association of SNPs in the AT2R gene with hypertension, and to detect the genotypes that indicate a cardioprotective role. Two hundred and sixty-two patients with essential hypertension and 75 normotensive subjects were enrolled for a case-control study. All of the subjects were Cantonese. Sixteen individuals were chosen to sequence the AT2R gene and 16 SNPs were acquired. G/T rs5193 and G/A rs5194 were two SNPs in the 3′ untranslated region which were focused on the association of the AT2R-genotype and phonotype. Polymerase chain reaction was performed to amplify the fragment spanning the two SNPs. Genotype and haplotype were identified by dot blot hybridization. Four haplotypes in males (G-G, G-A, T-A, T-G) and eight haplotype combinations in females (G-G/G-G, G-A/G-A, G-G/G-A, G-G/T-A, G-G/T-G, T-A/T-A, T-G/T-G, and T-A/T-G) were detected. G-G and G-A haplotype were predominant, while T-A and T-G were rare in Cantonese. None of these was associated with hypertension. T-A carriers with essential hypertension indicated lower levels of left ventricular mass (LVM) and left ventricular hypertrophy index (LVHI). The levels of LVM and LVHI were still significantly lower in T-A carriers with hypertension adjusted for age or body mass index for men and women separately. No episodes of coronary heart disease and heart failure were detected in T-A carriers with hypertension. Haplotypes of G/T rs5193-G/A rs5194 are not associated with essential hypertension. Among these haplotypes, T-A may be implicated in a cardioprotective role to protect hypertense subjects from left ventricular hypertrophy.     

血管紧张素Ⅱ的2型受体基因多态性与男性原发性高血压相关性研究

目的 :探讨我国男性原发性高血压 (EH)患者及其危险分层与血管紧张素Ⅱ的 2型受体 (AT2 R)基因C312 3A多态性的关系。方法 :①随机选取 85例男性EH患者 ,另选 4 5例男性正常人作为对照。②用聚合酶链式反应 (PCR) /限制性内切酶AluI酶解检测AT2 R基因的C312 3A多态性。③根据心血管绝对危险水平分层把患者分为低中危、高危和极高危者。结果 :高危和极高危者的AT2 R基因的A等位基因频率均明显高于低中危者 (P <0 .0 5 ) ,但AT2 R基因的A和C等位基因频率与正常对照组间的差别却无统计学意义 (P >0 .0 5 )。结论 :AT2 R的C312 3A基因多态性与男性EH发病无关 ,但突变的A等位基因与EH患者的靶器官损害及并存的临床情况有密切关系     

ApoB基因突变与老年2型糖尿病及其心血管并发症的关系

目的 探索ＡｐｏＢ基因突变与老年２型糖尿病及其心血管并发症的关系。方法 采用ＰＣＲ的限制性内切酶ＭＳＰＩ酶切的方法对５５例老年２型糖尿病伴心绞痛、心肌梗死患者进行ＡｐｏＢ１００基因突变检测。结果 ３２例２型糖尿病伴心绞痛患者中基因水平有改变者为５例,２２例２型糖尿病心肌梗死患者基因水平改变者为４例。结论 老年２例糖尿病伴心绞痛、心肌梗死患者中,部分患者病因与其基因水平碱基突变有关。     

同型半胱氨酸水平、MTHFR基因突变与原发性高血压的病例对照研究

目的:探讨升高的同型半胱氨酸水平、MTHFR基因突变与原发性高血压的关系.方法:从上海一个社区中随机选取127例35～75岁的原发性高血压病人和170例正常血压者.采用聚合酶链反应-限制性片段长度多态性分析MTHFR基因多态性.使用高效液相色谱结合电化学方法检测血清中同型半胱氨酸总浓度,使用放射免疫法同时测定血清中叶酸和B12浓度.结果:调整年龄和性别后,病例和对照组同型半胱氨酸水平分别为10.56 μmol /L 和 10.34 μmol/L,差异无显著性 (P=0.63).在未服降压药的对象中同型半胱氨酸浓度与收缩压和舒张压亦无关联.该人群MTHFR不耐热性基因突变频率为13.1%,突变等位基因频率为38.7%.病例组与对照组基因型分布和突变等位基因频率无显著性差异.然而,病例组叶酸和B12浓度高于对照组.结论:本研究未发现升高的同型半胱氨酸水平、MTHFR基因突变是原发性高血压的独立危险因素.高血压病人较高的叶酸和B12水平可能降低了同型半胱氨酸的危险性.     

同型半胱氨酸水平,MTHFR基因突变与原发性高血压的病例对照研究

从上海一个社区中随机选取１２７例３５～７５岁的原发性高血压病人和１７０例正常血压者。采用聚合酶链反应－限制性片段长度多态性分析ＭＴＨＦＲ基因多态性。使用高效液相色谱结合电化学方法检测血清中同型半胱氨酸总浓度,使用放射免疫法同时测定血甭中叶酸和Ｂ１２浓度。结果：调整年龄和性别后,病例和对照组同型半胱氨酸水平分别为１０．５６μｍｏｌ／Ｌ和１０．３４μｍｏｌ／Ｌ,差异无显著性（Ｐ＝０．６３）。在未服降压     

The mitochondrial rhomboid protease PSARL is a new candidate gene for type 2 diabetes

Aims/hypothesis This study aimed to identify genes that are expressed in skeletal muscle, encode proteins with functional significance in mitochondria, and are associated with type 2 diabetes.Methods We screened for differentially expressed genes in skeletal muscle of Psammomys obesus (Israeli sand rats), and prioritised these on the basis of genomic localisation and bioinformatics analysis for proteins with likely mitochondrial functions.Results We identified a mitochondrial intramembrane protease, known as presenilins-associated rhomboid-like protein (PSARL) that is associated with insulin resistance and type 2 diabetes. Expression of PSARL was reduced in skeletal muscle of diabetic Psammomys obesus, and restored after exercise training to successfully treat the diabetes. PSARL gene expression in human skeletal muscle was correlated with insulin sensitivity as assessed by glucose disposal during a hyperinsulinaemic–euglycaemic clamp. In 1,031 human subjects, an amino acid substitution (Leu262Val) in PSARL was associated with increased plasma insulin concentration, a key risk factor for diabetes. Furthermore, this variant interacted strongly with age to affect insulin levels, accounting for 5% of the variation in plasma insulin in elderly subjects.Conclusions/interpretation Variation in PSARL sequence and/or expression may be an important new risk factor for type 2 diabetes and other components of the metabolic syndrome.     

高血压和糖尿病患者餐后状态血压及脉压变化特征的研究

目的：研究高血压病、2型糖尿病和高血压合并糖尿病患餐后状态血压和脉压变化的特点，探讨其可能机制。方法：328例住院患，分为高血压病组（EH组，116例）、2型糖尿病组（DM组，100例）和高血压伴糖尿病组（EH＋DM组，112例），行24小时态血压（ABPM）检测，其中30例患再行有创桡动脉压测量，观察餐前和餐后收缩压（SBP）、舒张压（DBP）和脉压（PP）变化特点。结果：EH组餐后SBP和DBP升高（P＜0．01），而以SBP升高更明显，列后PP升高（P＜0．01）。DM组SBP和DBP均下降（P＜0．05），但餐后PP无明显变化（P＞0．05）。结论：EH＋DM组和DM组患各餐后SBP和DBP降低，其中EH＋DM组餐后DBP下降较显，餐后PP也增大。而H组患餐后SBP和DBP升高，而以SBP升高较显，餐后PP也增大。DM组患各餐后SBP和DBP降低幅度相似，其餐后PP无明显变化。三组患餐后血压和脉压变化各有其特征，其机制可能与大动脉硬化程度、外周血管舒缩功能及糖尿病自主神经病变等因素有关。     

SHIP 2基因与2型糖尿病

2型糖尿病主要特征是胰岛素分泌异常和胰岛素抵抗,环境因素和遗传因素交互作用共同促成了糖尿病的发生。研究发现多种基因参与糖尿病的发生,最近发现SHIP2基因与胰岛素抵抗及2型糖尿病相关,该基因可抑制胰岛素分泌、降低机体对胰岛素的敏感性,研究也表明当该基因不起作用时,胰岛素分泌就会失控,可导致严重的低血糖发生,因此,SHIP2基因可成为2型糖尿病的一个重要的治疗靶点。