Association of PON1 and PON2 Polymorphisms with PON1 Activity and Significant Coronary Stenosis in a Tunisian Population

PON1 and PON2 have attracted considerable attention as candidate genes for coronary heart disease because their enzymes function as key factors in lipoprotein catabolism pathways. We studied the distribution of PON1 and PON2 polymorphisms, including genotyping, lipid profile, and PON1 activity, and their association with PON1 activity and significant coronary stenosis (SCS) in a Tunisian population. PON1 activity was lower in patients with SCS than in controls. It increased with the R allele (QQ < QR < RR) in PON1-192 genotypes and with the L allele (MM < ML < LL) in PON1-55 genotypes. In the presence of metabolic syndrome and diabetes, PON1-192RR and PON2-311CC were associated with an increased risk of SCS and PON1-55MM seems to have lower risk. This association was evident among nonsmokers for PON1-55MM and among smokers for PON1-192RR and PON2-311CC. The GTGC haplotype seemed to increase the risk of SCS compared with the wild haplotype in a Tunisian population.     

Association of DPP4 Gene Polymorphisms with Type 2 Diabetes Mellitus in Malaysian Subjects

BackgroundGenetic polymorphisms of the Dipeptidyl Peptidase 4 (DPP4) gene may play a role in the etiology of type 2 diabetes mellitus (T2DM). This study aimed to investigate the possible association of single nucleotide polymorphisms (SNPs) of the DPP4 gene in Malaysian subjects with T2DM and evaluated whether they had an effect on the serum levels of soluble dipeptidyl peptidase 4 (sDPP-IV).MethodTen DPP4 SNPs were genotyped by TaqMan genotyping assays in 314 subjects with T2DM and 235 controls. Of these, 71 metabolic syndrome (MetS) subjects were excluded from subsequent analysis. The odds ratios (ORs) and their 95% confidence interval (CIs) were calculated using multiple logistic regression for the association between the SNPs of DPP4 and T2DM. In addition, the serum levels of sDPP-IV were investigated to evaluate the association of the SNPs of DPP4 with the sDPP-IV levels.ResultsDominant, recessive, and additive genetic models were employed to test the association of DPP4 polymorphisms with T2DM, after adjusting for age, race, gender and BMI. The rs12617656 was associated with T2DM in Malaysian subjects in the recessive genetic model (OR = 1.98, p = 0.006), dominant model (OR = 1.95, p = 0.008), and additive model (OR = 1.63, p = 0.001). This association was more pronounced among Malaysian Indians, recessive (OR = 3.21, p = 0.019), dominant OR = 3.72, p = 0.003) and additive model (OR = 2.29, p = 0.0009). The additive genetic model showed that DPP4 rs4664443 and rs7633162 polymorphisms were associated with T2DM (OR = 1.53, p = 0.039), and (OR = 1.42, p = 0.020), respectively. In addition, the rs4664443 G>A polymorphism was associated with increased sDPP-IV levels (p = 0.042) in T2DM subjects.ConclusionsDPP4 polymorphisms were associated with T2DM in Malaysian subjects, and linked to variations in sDPP-IV levels. In addition, these associations were more pronounced among Malaysian Indian subjects.     

GTP Cyclohydrolase I Gene Polymorphisms Are Associated with Endothelial Dysfunction and Oxidative Stress in Patients with Type 2 Diabetes Mellitus

Background

The genetic background of atherosclerosis in type 2 diabetes mellitus (T2DM) is complex and poorly understood. Studying genetic components of intermediate phenotypes, such as endothelial dysfunction and oxidative stress, may aid in identifying novel genetic components for atherosclerosis in diabetic patients.

Methods

Five polymorphisms forming two haplotype blocks within the GTP cyclohydrolase 1 gene, encoding a rate limiting enzyme in tetrahydrobiopterin synthesis, were studied in the context of flow and nitroglycerin mediated dilation (FMD and NMD), intima-media thickness (IMT), and plasma concentrations of von Willebrand factor (vWF) and malondialdehyde (MDA).

Results

Rs841 was associated with FMD (p = 0.01), while polymorphisms Rs10483639, Rs841, Rs3783641 (which form a single haplotype) were associated with both MDA (p = 0.012, p = 0.0015 and p = 0.003, respectively) and vWF concentrations (p = 0.016, p = 0.03 and p = 0.045, respectively). In addition, polymorphism Rs8007267 was also associated with MDA (p = 0.006). Haplotype analysis confirmed the association of both haplotypes with studied variables.

Conclusions

Genetic variation of the GCH1 gene is associated with endothelial dysfunction and oxidative stress in T2DM patients.     

Onychomycosis Incidence in Type 2 Diabetes Mellitus Patients

The onychomycosis incidence was determined in 250 type 2 diabetes mellitus (T2DM) patients who were registered at the Internal Medicine Service from a Mexico city General Hospital throughout a year (January-December 2006). Out of the total of studied T2DM patients, 93 (37.2%) showed ungual dystrophy and from these, in 75.3% a fungal etiology was corroborated. Out of 70 patients, 34 were men and 36 women, with an average of 63.5 years. Correlation between T2DM evolution time and onychomycosis was significant (P < 0.01). Distal-lateral subungual and total dystrophic onychomycosis were the most frequent clinical types (55.1% and 33.7%, respectively). Fifty-eight fungal isolates were obtained; 48.6% corresponded to dermatophytes, Trichophyton rubrum being the first species (37.1%). All these strains corresponded to two morphological varieties: "yellow" and typical downy. From the yeast-like isolates, 12 corresponded to Candida spp., firstly C. albicans and C. parapsilosis; three to Cryptococcus spp. (C. albidus, C. uniguttulatus and C. laurentii); two Trichosporon asahii; and only one to Pichia ohmeri. Six non-dermatophytic molds were isolated: two Chrysosporium keratinophylus, two Scopulariopsis brevicaulis, one Aspergillus fumigatus, and one Acremonium sp. The fungal mixture corresponded to T. mentagrophytes with C. guilliermondii; T. mentagrophytes with C. glabrata; T. rubrum with C. glabrata; T. rubrum with P. ohmeri.     

Q192R polymorphism in the PON1 gene and nasal polyp in a Turkish population

The pathogenesis of nasal polyps is not completely understood. Oxidative damage contributes to polyp formation in the nasal mucosa. The paraoxonase 1 (PON1) enzyme is an important liver enzyme with high antioxidant activity. In this study, we investigated the correlation between Q192R genotypic polymorphism of the PON1 enzyme and nasal‐polyp disease. The study examined 62 nasal‐polyp patients and 88 controls. PON1 Q192R polymorphism was determined using polymerase chain reaction‐restriction fragment length polymorphism. The genotype distribution of the PON1 gene was significantly different between nasal‐polyp patients (QQ = 69.35%, QR = 25.81%, RR = 4.83%) and healthy controls (QQ = 52.27%, QR = 44.31%, RR = 3.40%). Our results suggest that the PON1 QQ genotype (odds ratio [OR] = 2.066, P = .036) is associated with a higher risk of developing the nasal‐polyp disease while QR genotype (OR = 0.437, P = .021) showed a lower risk.     

De-Intensification of Diabetes Treatment in Elderly Patients with Type 2 Diabetes Mellitus

Objective: De-intensification of diabetes treatment is recommended in elderly patients with tight glycemic control at high risk of hypoglycemia. However, rates of de-intensification in endocrine practice are unknown. We conducted a retrospective study to evaluate the rate of de-intensification of antidiabetic treatment in elderly patients with type 2 diabetes mellitus (T2DM) and tight glycemic control.Methods: All patients with ≥2 clinic visits over a 1-year period at a major academic diabetes center were included. De-intensification of diabetes treatment was defined as a decrease or discontinuation of any antidiabetic drug without adding another drug, or a reduction in the total daily dose of insulin or a sulfonylurea drug with or without adding a drug without risk of hypoglycemia.Results: Out of 3,186 unique patients, 492 were ≥65 years old with T2DM and hemoglobin A1c (HbA1c) <7.5% (<58 mmol/mol). We found 308 patients treated with a sulfonylurea drug or insulin, 102 of whom had hypoglycemia as per physician note. Among these 102 patients, 38 (37%) were advised to de-intensify therapy. In a subgroup analysis of patients ≥75 years old with HbA1c <7% (<53 mmol/mol), we found that out of 23 patients treated with a sulfonylurea drug or insulin and reporting hypoglycemia, 11 (43%) were advised de-intensification of therapy. There were no significant predictors of de-intensification of treatment.Conclusion: Our study suggests that de-intensification of antidiabetic medications is uncommon in elderly patients with T2DM. Strategies may need to be developed to prevent the potential harm of overtreatment in this population.Abbreviations: ADA = American Diabetes Association; CGM = continuous glucose monitoring; HbA1c = hemoglobin A1c; T2DM = type 2 diabetes mellitus; UKPDS = United Kingdom Prospective Diabetes Study     

Diabetic Ketoacidosis in Peruvian Patients with Type 2 Diabetes Mellitus

ObjectiveTo describe the clinical and laboratory characteristics of diabetic ketoacidosis (DKA) in adult Peruvian patients with type 2 diabetes mellitus.MethodsIn this cross-sectional analysis, we reviewed clinical charts of type 2 diabetic patients with DKA admitted to Cayetano Heredia Hospital between 2001 and 2005 for data on demographics, previous treatment, previous hospital admissions for DKA, family history of diabetes, precipitating factors, hospital course, mortality, and insulin use 3 and 6 months after the index DKA episode. Patients older than 18 years who had confirmed DKA were included. Patients with type 1 diabetes mellitus were excluded.ResultsWe report on 53 patients with DKA for whom complete clinical and laboratory data were available. Of the 53 patients, 39 (74%) were men; mean age (± SD) was 45 ± 12 years; and 22 (42%) had no previous diagnosis of type 2 diabetes. The following mean (± SD) laboratory values were obtained at DKA diagnosis: glucose, 457 ± 170 mg/dL; pH, 7.15 ± 0.14; bicarbonate, 7.73 ± 6 mEq/L; and anion gap, 24.45 ± 7.44 mEq/L. Of the 53 DKA episodes, 35 (66%) were severe (arterial pH < 7.0 and/or serum bicarbonate < 10 mEq/L). The following precipitating factors were discerned: discontinuation of treatment in 21 (40%), infections in 16 (30%), intercurrent illness in 3 (6%), and no identifiable cause in 13 (25%). Mortality rate was 0%. Three and 6 months after the index DKA episode, insulin was used by 65% and 56% of patients, respectively.ConclusionIn countries with a low incidence of type 1 diabetes, DKA is frequently reported in patients with type 2 diabetes. In this study, 42% of patients had new-onset disease. Most DKA episodes were severe and were related to infection or noncompliance with treatment. (Endocr Pract. 2008;14:442-446)     

Prevalence of Sleep Apnea in a Population of Adults with Type 2 Diabetes Mellitus

ObjectiveTo assess the prevalence of sleep apnea (SA) in adults with type 2 diabetes mellitus (T2DM) and examine whether demographics and comorbid factors were associated with SA in this population.MethodsThis study enrolled 330 consecutive adults with T2DM referred to a diabetes clinic, 279 of whom completed the study. Evaluation of the presence of SA was performed with use of a single-channel recording device that measures disordered breathing events from a nasal cannula airflow signal. The device was worn by the study participants in their home, after instruction in appropriate use by clinical staff at the diabetes center. The presence and severity of SA were determined by use of an apnea-hypopnea index (AHI), reflecting periods of diminished and absent breathing. Demographic and medical information data were collected to detect factors associated with SA in this study population. In addition, a time and cost analysis was conducted regarding the screening process for SA by clinical staff at the diabetes center.ResultsThe results show a high prevalence of SA in adults with T2DM, ranging from 48% (AHI level of ≥ 10 events/h) to 29% (AHI level of ≥ 20 events/h). At an AHI cutoff value of ≥ 15 events/h, the overall prevalence rate was 36% (49% in male and 21% in female participants). The following variables were associated with SA: age ≥ 62 years, male sex, body mass index ≥ 30 kg/m², snoring, and reports of stopping breathing during sleep. The time and cost analysis showed that the screening device involved minimal setup time, was simple to use, and was a cost-effective method to screen for SA.ConclusionSA is a common disorder associated with major morbid conditions, including hypertension, obesity, cardiovascular disease, and insulin resistance. Predisposing factors for SA and T2DM are similar. This study showed that SA has a high prevalence in adults with T2DM and identified factors that may be associated with its presence in this population. Assessment for SA can be easily performed in an outpatient setting with a portable recording device such as the one used in this study. Screening for SA should be considered in the T2DM population. (Endocr Pract. 2007;13:355-362)     

A preliminary study of human paraoxonase and PON 1 L/M55–PON 1 Q/R 192 polymorphisms in Turkish patients with coronary artery disease

Paraoxonase 1 (PON 1) is a high‐density lipoprotein (HDL)‐associated enzyme with antioxidant function protecting low‐density lipoprotein (LDL) from oxidation. PON 1 has two amino acid polymorphisms in coding region; L/M 55 and Q/R 192. These polymorphisms modulate paraoxonase activity of the enzyme. PON 1 activity decreases in coronary artery disease (CAD). In the present study, distribution of PON 1 L/M 55 and Q/R 192 polymorphisms and the effect of these polymorphisms on the activities of PON 1, and on the severity of CAD in 277 CAD (+) patient and 92 CAD (?) subjects were examined. PON 1 L/M 55 and Q/R 192 genotypes were determined by PCR, RFLP and agarose gel electrophoresis techniques. Genotype distributions and allele frequencies for PON 1 Q/R 192 polymorphism were not significantly different between controls and CAD (+) patient group (p > 0.05), but in genotype and allele distribution of PON 1 L/M55 polymorphism, there was significantly difference among groups (p < 0.05). Genotype distributions for both polymorphisms were not significantly different between subgroups of single‐vessel disease (SVD), double‐vessel disease (DVD) and triple‐vessel disease (TVD). Serum PON 1 activity was lower in CAD (+) group than in controls and this was also statistically significant (p < 0.001). In both groups, the highest PON activities were detected in LL and RR genotypes. In summary, our results suggest that there is an association between the PON 1 L/M 55 polymorphism of paraoxonase and CAD in Turkish patients but not with PON 1 Q/R 192 polymorphism. However, it is hard to correlate these polymorphisms and severity of CAD. Copyright © 2009 John Wiley & Sons, Ltd.     

Association of Complement C5 Gene Polymorphisms with Proliferative Diabetic Retinopathy of Type 2 Diabetes in a Chinese Han Population

Purpose

To investigate the association of C5 SNPs with proliferative diabetic retinopathy (PDR) of type 2 diabetes (T2D).

Methods

A total of four C5 SNPs including rs2269067, rs7040033, rs1017119 and rs7027797 were genotyped in 400 PDR patients with T2D (cases) and 600 non- proliferative diabetic retinopathy PDR (NPDR) with T2D patients (controls) by using PCR-RFLP method. mRNA expression was examined by real-time PCR. Cytokine production was detected by ELISA.

Results

The frequency of GG genotype of C5 rs2269067 was significantly increased in cases compared with controls (Pc = 3.4×10⁻⁵, OR = 1.87). And C5 mRNA expression was significantly increased in rs2269067 GG cases as compared with CG or CC cases (P = 0.003, P = 0.001, respectively). Moreover, the production of IL-6 was significantly increased in rs2269067 GG cases compared to CG cases or CC cases (P = 0.002, P = 0.001, respectively).

Conclusions

C5 rs2269067 GG genotype confers risk for PDR of T2D in Chinese han population and is associated with an elevated C5 mRNA expression and an increased IL-6 production.     

新生儿PON2基因多态性与早产的关系

探讨新生儿对氧磷酶2基因多态性（PON2148,PON2311）对早产的影响。采用横断面调查方法,使用统一的调查表,由安庆市各县医院对入院分娩孕妇及其单胎、活产、早产和对照新生儿进行调查,共得到有效样本194个母亲-新生儿对。单因素分析结果显示：PON2 Ala148Ala纯合子基因型与Gly148Gly纯合子基因型 / Ala148Gly杂合子基因型比较致早产的危险性升高且有显著意义;同样,PON2 Ser311Ser纯合子基因型致早产的危险性升高且有显著意义。进一步分析PON2148位点多态性和PON2311位点多态性是否存在交互作用,结果显示：这两个位点多态性之间无明显交互作用。对氧磷酶2基因PON2148位点多态性和PON2311位点多态性与新生儿早产相关,但PON2148位点多态性和PON2311位点多态性之间对早产的影响无明显交互作用。 Association of PON2 Gene Polymorphisms in Neonates with Preterm LIANG Hong-ye1,WU Bai-yang1,CHEN Da-fang1,YANG Fan2,HU Hai-yan2,CHEN Li1,XU Xi-ping1. 1.Department of Biology & Genetics,Peking University Health Science Center,Beijing 100083,China; 2.Anqing Branch of Institute for Biomedicine,Anhui Medical University,Anqing 246000,China Abstract:The objective is to investigate whether gene polymorphisms in the PON2 gene (PON2148 and PON2311) of neonates are associated with preterm. Using standard questionnaires,194 singleton live born mother-neonate pairs (include preterm cases and term controls) were investigated by the trained field workers with cross-sectional survey at the hospitals in Anqing,Anhui Province,China. Epidemiological and clinical data and blood samples were obtained from 194 mother-neonate pairs. Among neonates,PON2 Ala148Ala homozygote is significantly associated with preterm,compared with Gly148Gly homozygote / Ala148Gly heterozygote before and after adjustment confounders and the same was true for PON2 Ser311Ser homozygote. However,when PON2148 polymorphism and PON2311 polymorphism were considered jointly,no significant gene interaction between PON2148 polymorphism and PON2311 polymorphism in relation to preterm was observed. We draw a conclusion from this research that both PON2148 polymorphism and PON2311 polymorphism in neonates are significantly associated with preterm respectively. But the gene interactions between PON2148 polymorphism and PON2311 polymorphism in neonates are not significantly associated with preterm. Key words：paraoxonase 2 gene (PON2 gene);gene polymorphism;preterm;genotype     

磺酰脲类受体基因多态性与2型糖尿病的相关性研究

研 究磺酰脲类受体1（SUR1）基因外显子16-3c/t多态性在中国某南方汉族人群中是否为2型糖尿病的致病基因座。采用聚合酶链反应-限制酶酶切片段长度多态性（PCR-RFLP）方法对南方汉族46个2型糖尿病高发家系成员的SUR1基因外显子16的多态性进行分析。利用Mantel-Haenszel分层分析研究该基因座多态性与2型糖尿病的关系。在高发家系人群中,SUR1基因外显子16-3c/t多态性的基因型频率为：cc型29.3%、ct型507%、tt型20%,c等位基因频率为54.7%;患者组基因型频率为：cc型30.2% 、ct型53.8%、tt型16.0% ,c等位基因频率为57.1% ;未患病亲属组基因型频率为：cc型28.3% 、ct型47.2%、tt型24.5%,c等位基因频率为519%,两组间基因型和等位基因的差异经检验无统计学意义（分别为χ2=3.224,P=0.199;χ2=1.250,P=0264）。在性别、吸烟、饮酒、肥胖、高血压等混杂因素中的频率差异亦无显著性。c等位基因频率低于北方汉族人。在中国某南方汉族2型糖尿病高发家族人群中,未发现SUR1基因外显子16-3c/t多态性与2型糖尿病存在关联,该基因座可能不是该人群的致病基因。 Abstract:To study whether the 3c/t polymorphism of the sulfonylurea receptor 1 (SUR1) gene exon16 increased the risk of type 2 diabetes mellitus in type 2 diabetes mellitus pedigrees in Han population in south area of China.Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used in 46 type 2 diabetes mellitus pedigrees.The polymorphism in SUR1 was tested and analyzed by Mantel-Haenszel χ2 test.Frequencies of SUR1-3c/t polymorphism had no significant difference between type 2 diabetes mellitus and normal relatives（genotypes χ2=3.224,P=0.199;frequency of allele χ2=1.250,P=0.264）.In all subjects,type 2 diabetes mellitus and normal relatives,SUR1-3c/t genotypes were listed (cc:29.3%,30.2%,28.3%;ct:50.7%,53.8%,47.2%;tt:20%,16.0%,24.5% respectively).The frequencies of c were 54.7%,57.1% and 51.9% respectively.The frequency of c is lower than Han population in northern China.The results show that SUR1 exon16-3c/t polymorphism is not associated with type 2 diabetes mellitus in the population.     

Identification of KCNJ15 as a Susceptibility Gene in Asian Patients with Type 2 Diabetes Mellitus

Recent advances in genome research have enabled the identification of new genomic variations that are associated with type 2 diabetes mellitus (T2DM). Via fine mapping of SNPs in a candidate region of chromosome 21q, the current study identifies potassium inwardly-rectifying channel, subfamily J, member 15 (KCNJ15) as a new T2DM susceptibility gene. KCNJ15 is expressed in the β cell of the pancreas, and a synonymous SNP, rs3746876, in exon 4 (C566T) of this gene, with T allele frequency among control subjects of 3.1%, showed a significant association with T2DM affecting lean individuals in three independent Japanese sample sets (p = 2.5 × 10⁻⁷, odds ratio [OR] = 2.54, 95% confidence interval [CI] = 1.76–3.67) and with unstratified T2DM (p = 6.7 × 10⁻⁶, OR = 1.76, 95% CI = 1.37–2.25). The diabetes risk allele frequency was, however, very low among Europeans in whom no association between this variant and T2DM could be shown. Functional analysis in human embryonic kidney 293 cells demonstrated that the risk allele of the synonymous SNP in exon 4 increased KCNJ15 expression via increased mRNA stability, which resulted in the higher expression of protein as compared to that of the nonrisk allele. We also showed that KCNJ15 is expressed in human pancreatic β cells. In conclusion, we demonstrated a significant association between a synonymous variant in KCNJ15 and T2DM in lean Japanese patients with T2DM, suggesting that KCNJ15 is a previously unreported susceptibility gene for T2DM among Asians.     

Micro-RNA Binding Site Polymorphisms in the WFS1 Gene Are Risk Factors of Diabetes Mellitus

The absolute or relative lack of insulin is the key factor in the pathogenesis of diabetes mellitus. Although the connection between loss of function mutations of the WFS1 gene and DIDMOAD-syndrome including diabetes mellitus underpins the significance of wolframin in the pathogenesis, exact role of WFS1 polymorphic variants in the development of type 1 and type 2 diabetes has not been discovered yet. In this analysis, 787 patients with diabetes and 900 healthy people participated. Genotyping of the 7 WFS1 SNPs was carried out by TaqMan assays. Association study was performed by χ²-test in combination with correction for multiple testing. For functional analysis, the entire 3’ UTR of the WFS1 gene was subcloned in a pMIR-Report plasmid and relative luciferase activities were determined. Linkage disequilibrium analysis showed a generally high LD within the investigated region, however the rs1046322 locus was not in LD with the other SNPs. The two miR-SNPs, rs1046322 and rs9457 showed significant association with T1DM and T2DM, respectively. Haplotype analysis also confirmed the association between the 3’ UTR loci and both disease types. In vitro experiments showed that miR-185 reduces the amount of the resulting protein, and rs9457 miRSNP significantly influences the rate of reduction in a luciferase reporter assay. Genetic variants of the WFS1 gene might contribute to the genetic risk of T1DM and T2DM. Furthermore demonstrating the effect of rs9457 in binding of miR-185, we suggest that the optimal level of wolframin protein, potentially influenced by miR-regulation, is crucial in normal beta cell function.     

基因技术在治疗2型糖尿病中的应用*

2型糖尿病(type 2 diabetes mellitus, T2DM)是一类由于胰岛β细胞损伤和机体对胰岛素耐受引发的慢性代谢性疾病,其快速增长的患病率和并发症所带来的高病死率已成为人类面临的医学难题。目前,T2DM主要是以降糖药物及胰岛素增敏剂等药物进行治疗,但是这类药物会产生严重的副作用,而且不能长期良好控制血糖和防止各种慢性并发症。因此,基因治疗是未来医疗发展的主要方向。基因治疗不仅可以靶向调控血糖水平进而提高降糖的效果,而且能够减少糖代谢异常引起的并发症,保护组织器官免受损伤。在认识传统药物治疗糖尿病的基础上,综述了基因技术在治疗T2DM中的应用,讨论了基因技术治疗T2DM的意义及存在的问题。基因技术的应用不仅有利于T2DM的预防和个体化治疗,同时也为糖尿病并发症提供了新的治疗途径。     

基因技术在治疗2型糖尿病中的应用*

2型糖尿病(type 2 diabetes mellitus, T2DM)是一类由于胰岛β细胞损伤和机体对胰岛素耐受引发的慢性代谢性疾病,其快速增长的患病率和并发症所带来的高病死率已成为人类面临的医学难题。目前,T2DM主要是以降糖药物及胰岛素增敏剂等药物进行治疗,但是这类药物会产生严重的副作用,而且不能长期良好控制血糖和防止各种慢性并发症。因此,基因治疗是未来医疗发展的主要方向。基因治疗不仅可以靶向调控血糖水平进而提高降糖的效果,而且能够减少糖代谢异常引起的并发症,保护组织器官免受损伤。在认识传统药物治疗糖尿病的基础上,综述了基因技术在治疗T2DM中的应用,讨论了基因技术治疗T2DM的意义及存在的问题。基因技术的应用不仅有利于T2DM的预防和个体化治疗,同时也为糖尿病并发症提供了新的治疗途径。     

Genetic Polymorphisms of Sulfotransferases (SULT1A1 and SULT1A2) in a Turkish Population

Sulfotransferases (SULTs) play a significant role in the biotransformation of a variety of xenobiotics and endogenous compounds. SULTs are genetically polymorphic enzymes; to date, 12 human cytosolic SULT isoforms have been identified. This study investigated SULT1A1 and SULT1A2 gene polymorphism using a PCR-RFLP method (n = 303). The frequency of the SULT1A1*1 allele was 76.2% and SULT1A1*2 was 23.8%. The SULT1A1*3 allele could not be identified. The SULT1A2 frequencies were 69.2% (SULT1A2*1), 18.3% (SULT1A2*2), and 12.5% (SULT1A2*3). The SULT1A1 and SULT1A2 loci were in Hardy-Weinberg equilibrium (SULT1A1 χ2 = 0.58, P = 0.44; SULT1A2 χ2 = 7.28, P = 0.06). Linkage analysis indicated a close linkage between these two genes (χ2 = 5.31, P < 0.01); therefore, the statistical hypothesis that SULT1A1 and SULT1A2 alleles are independently distributed was rejected. Additionally, a strongly positive linkage was detected between SULT1A1*2 and SULT1A2*2 alleles in this population (D' = 0.79, χ2 = 33.33).     

中国汉族人群2型糖尿病易感性相关基因多态性

2型糖尿病（type2 diabetes mellitus,T2DM）的发病与多个基因累加效应及多种环境因素相关。已在中国汉族人群中研究过的与T2DM易感性相关的基因多态性包括：全基因组相关研究中的CDKAL1、CDKN2A／B、SLC30A8、IGF2BP2、HHEX、FTO以及KCNQI基因;脂联素基因;核呼吸因子基因;葡萄糖激酶基因;肿瘤坏死因子α基因等。探索这些易感基因可以为人类治疗T2DM起到极大的推动作用。但至今已明确的基因依然很少,国内外的研究结果不尽相同,尚需进一步地深入研究。     

Polymorphic Gene Markers of Lipid Metabolism Are Associated with Diabetic Nephropathy in Patients with Type 1 Diabetes Mellitus

In groups of type 1 diabetes mellitus patients with and without clinical signs of diabetic nephropathy (n = 62 and 68, respectively), a search was made for associations between diabetic nephropathy and the polymorphic marker ε2/ε3/ε4 of apolipoprotein E gene (APOE), I/D marker of apolipoprotein B gene (APOB), and Ser447Ter marker of lipoprotein lipase-encoding gene (LPL). The risk of diabetic nephropathy was higher in the carriers of allele ε3 and genotype ε3/ε3 of the polymorphic marker ε2/ε 3/ε4 of APOE gene as well as in the carriers of allele I and APOB genotype I/I gene (OR = 2.08 and 2.16; 1.91 and 2.11, respectively). Conversely, the carriers of allele D showed a reduced risk of this complication (OR = 0.52). No significant differences in distribution of alleles and genotypes of the polymorphic marker Ser447Ter of LPL gene were found between the groups. Our results indicate that the genes encoding two major components of lipid metabolism are involved in the development of diabetic nephropathy in patients with type 1 diabetes mellitus.__________Translated from Genetika, Vol. 41, No. 7, 2005, pp. 931–937.Original Russian Text Copyright © 2005 by Yakunina, Shestakova, Voron’ko, Vikulova, Savost’yanov, Chugunova, Shamkhalova, Dedov, Nosikov.