Association study of fatty acid binding protein 2 gene polymorphism for diabetic nephropathy in Japanese patients with type 2 diabetes

To test the hypothesis whether the Ala54Thr polymorphism of the fatty acid binding protein 2 (FABP2) gene was associated with diabetic nephropathy, we studied a total of 397 Japanese type 2 diabetic patients. The diagnosis of diabetic nephropathy was based on measurements of urinary albumin:creatinine ratio (ACR). We subdivided subjects as those with normoalbuminuria (ACR < 30 mg/g Cr), those with micro- albuminuria (ACR:30–300 mg/g Cr), and those with macroalbuminuria (ACR ³300 mg/g Cr). FABP2 genotypes were determined with a fluorescent allele-specific DNA primer assay system. The results showed that the genotypes of Ala54Thr polymorphism of the FABP2 gene were not significantly different among normo-, micro- and macro-albuminuria groups, suggesting that polymorphism of this gene was not associated with diabetic nephropathy in Japanese type 2 diabetic subjects.     

Codon 54 polymorphism of the fatty acid binding protein 2 gene is associated with increased fat oxidation and hyperinsulinemia, but not with intestinal fatty acid absorption in Korean men

The alanine to threonine substitution at codon 54 (Ala54Thr) of the fatty acid binding protein 2 (FABP2) gene has been reported to be associated with increased fat oxidation and insulin resistance in several populations. It has been hypothesized that Ala54Thr substitution results in enhanced intestinal uptake of fatty acids and thereby an impairment of insulin action, but this hypothesis has not been proven in vivo. We studied the association between the Ala54Thr polymorphism of the FABP2 gene and intestinal (3)H-oleic acid absorption, as well as basal insulin level, basal metabolic rate, and fat oxidation rate in 96 healthy young Korean men. Among our subjects, the allele frequency of the Ala54Thr substitution was 0.34. Subjects with Thr54-encoding allele were found to have a higher mean fasting plasma insulin concentration and a higher basal fat oxidation rate compared with the subjects who were homozygous for the Ala54-encoding allele. However, there was no significant difference in basal metabolic rate or (3)H-oleic acid absorption according to the FABP2 gene polymorphism. These results suggest that the Ala54Thr substitution in the FABP2 gene is associated with increased fat oxidation and hyperinsulinemia in normal Korean men, but these effects are not mediated by an increase in the intestinal fatty acid absorption.     

小肠脂酸结合蛋白基因54号密码子变异与中国人糖尿病发病机制的关系

在２３１例中国人中观察小肠脂酸结合蛋白基因（ＦＡＢＰ２）５４号密码子变异与ＮＩＤＤＭ及其病理生理以及肥胖的关系。结果：ＦＡＢＰ２－Ｔｈｒ５４（＋）基因型个体呈糖耐量减退时的空腹Ｃ肽、糖负荷后２小时Ｃ肽、负荷后３小时内Ｃ肽总值及面积均显著低于Ｔｈｒ５４（－）基因型个体（Ｐ分别为０．０４、０．０３、０．０１及０．０１）。胰岛素有同样变化趋向。结果表明：中国人中的ＦＡＢＰ２－Ｔｈｒ５４（＋）个体胰岛β细胞的葡萄糖刺激胰岛素分泌功能储备不及Ｔｈｒ５４（－）者。ＦＡＢＰ２－５４号密码子变异可能参与糖尿病发病中胰岛素分泌不足的机制。     

Codon-54 polymorphism of the fatty acid-binding protein 2 gene is associated with elevation of fasting and postprandial triglyceride in type 2 diabetes

Patients with type 2 diabetes are frequently dyslipidemic or hypertriglyceridemic. To assess whether increased intestinal triglyceride input leads to elevated fasting and postprandial triglycerides in type 2 diabetes, we used the codon 54 polymorphism of the fatty acid-binding protein 2 gene, which results in the substitution of threonine (Thr) for alanine and is associated with increased intestinal input of triglyceride. Of the 287 diabetic patients screened, 108 (37.6%) were heterozygous and 31 (10.8%) were homozygous for the Thr-54 allele. Mean (+/-SEM) fasting plasma triglyceride levels in patients with the wild-type (n = 80), those heterozygous for the Thr-54 allele (n = 57), and those homozygous for it (n = 18) were 2.0 +/- 0.09, 2.7 +/- 0.20, and 3.8 +/- 0.43 mmol/L, respectively. A linear relationship of mean fasting plasma triglyceride levels (r2 = 0.97) between the 3 groups was found. After fat ingestion, the postprandial area under the curve of plasma triglyceride (P = 0.025) and chylomicrons (Sf > 400, P = 0.013) was higher in the Thr-54/Thr-54 (n = 6) than in the wild-type (n = 9). Our results are consistent with the hypothesis that, in type 2 diabetes, increased intestinal input of triglyceride can lead to elevated fasting and postprandial plasma triglycerides.     

Polymorphisms in fatty acid binding protein 5 show association with type 2 diabetes

Genes for the fatty acid binding proteins (FABP) family encode small 14-15 kDa cytosolic proteins and can be regulated during type 2 diabetes mellitus (T2DM) and obesity. This study compared association of single nucleotide polymorphisms (SNPs) in FABP1-5 with T2DM in different ethnic groups. Associations with T2DM of SNPs in these proteins were assessed in African American (AA), non-Hispanic White (NHW), and Hispanic American (HA) individuals. A total of 650 DNA samples were genotyped; control samples were obtained from Coriell's North American Human Variation Panel Repository (NAHVP) of apparently healthy individuals and T2DM cases were taken from the American Diabetes Association GENNID Study. The rs454550 SNP of FABP5 showed a significant association with T2DM in NHW (OR: 9.03, 95% CI: 1.13-71.73, p = 0.014). Our analysis also identified a new FABP5 SNP (nSNP) that showed a significant association with T2DM in NHW (OR: 0.44, 95% CI: 0.19-0.99, p = 0.045) and AA (OR: 0.17, 95% CI: 0.03-0.80, p = 0.016). The Ala54Thr FABP2 polymorphism was significantly associated with T2DM in HA individuals only (OR: 1.85, 95% CI: 1.05-3.27, p = 0.032). All other FABP SNPs did not show association with T2DM. These findings suggest a potential distinct role(s) of SNPs in FABP5 and FABP2 genes in T2DM in different populations.     

Codon 54 polymorphism of the fatty acid binding protein gene and insulin resistance in the Japanese population.

AIM: To determine the relationship of the polymorphism at codon 54 of the intestinal fatty acid binding protein gene (FABP2) with insulin resistance and susceptibility to Type 2 diabetes mellitus (DM) in the Japanese population. METHODS: We evaluated the polymorphism by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 150 Type 2 DM patients and 147 healthy control subjects. The frequency of alleles encoding threonine (Thr54) and alanine (Ala54) at codon 54 of FABP2 in Type 2 DM patients was compared with that of healthy controls. Insulin sensitivity was assessed by the hyperinsulinaemic euglycaemic clamp in Type 2 DM patients with Ala54 homozygotes, Ala54/Thr54 heterozygotes and Thr54 homozygotes and by homeostasis model assessment (HOMA) in the nondiabetic group. RESULTS: The frequency of alleles encoding Ala54 and Thr54 was 0.59 and 0.41 in Type 2 DM patients, respectively, similar to that observed in nondiabetic controls (0.64 for Ala54 and 0.36 for Thr54). Insulin sensitivity was not significantly different between subjects with and without Thr54 allele either within the DM group or healthy controls. CONCLUSIONS: The allele encoding threonine in the FABP2 does not predispose to Type 2 DM or insulin resistance in the Japanese population.     

小肠脂酸结合蛋白基因多态性与2型糖尿病合并冠心病的关系

为了解小肠脂酸结合蛋白基因（ＦＡＢＰ２）多态性与２型糖尿病合并冠心病（ＣＨＤ）的关系。方法２型糖尿病无冠心病组（ＤＭ－１）６４型糖尿病合并冠心病组（ＤＭ－２）８２例,非糖尿病冠心病组６２例,正常对照组６０例。应用聚合链酶反应（ＰＣＲ）技术检测２６８例对象ＦＡＢＰ２ＨｈａⅠ位点的限制性片段长度多态性（ＲＦＬＰｓ）。结果（１）武汉地区汉族人存在ＰＡＢＰ２ＨｈａＩ多态性位点,可产生Ｔｈｒ５４（－）和Ｔｈ     

The codon 17 polymorphism of the CTLA4 gene in type 2 diabetes mellitus

Several studies have demonstrated an association of CTLA4 (IDDM12) alanine-17 with type 1 diabetes, but CTLA4 variants have not yet been investigated in type 2 diabetes. The CTLA4 exon 1 polymorphism (49 A/G) was analyzed in 300 Caucasian patients with type 2 diabetes and 466 healthy controls. All patients were negative for glutamate decarboxylase and islet cell antibodies. CTLA4 alleles were defined by PCR, single-strand conformational polymorphism, and restriction length fragment polymorphism analysis using BBV:I. The distribution of alleles as well as the genotypic and phenotypic frequencies were similar among patients and controls [AA, 42 vs. 39%; AG, 47 vs. 46%; GG, 11 vs. 15%, P = not significant (n.s.); A/G, 65/35% vs. 62/38%, P = n.s.; alanine/threonine 92/58% vs. 85/61%, P = n.s.]. However, detailed analysis of clinical and biochemical parameters revealed a tendency of GG (alanine/alanine) toward younger age at disease manifestation (46.8 +/- 0.8 vs. 49.5 +/- 0.8 yr, mean +/- SEM), lower body mass index (21.4 +/- 0.5 vs. 24.4 +/- 0.5 kg/m(2), P = 0.042), and basal C-peptide level (0.33 +/- 0.07 vs. 0.53 +/- 0.07nmol/L), as well as earlier start of insulin treatment (5.8 +/- 1.2 vs. 8.7 +/- 0.6 yr) and higher portion of patients on insulin (71 vs. 61%). Patients with the AA genotype were significantly less likely to develop microangiopathic lesions (P < 0.0005). No differences were found for hypertension or family history of type 2 diabetes. In conclusion, CTLA4 alanine-17 does not represent a major risk factor for type 2 diabetes. Additional studies on larger groups and different ethnic groups are warranted to clarify the association of the GG genotype with faster ss-cell failure and the lower rate of microvascular complications in AA carriers.     

蒙、汉族人群小肠脂肪酸结合蛋白基因Ala54Thr多态性的频率

目的:调查蒙、汉族人群小肠脂肪酸结合蛋白(IFABP)基因exonⅡ54位点编码丙氨酸或苏氨酸(A/T)单核苷酸多态性(SNP),探讨不同种族、饮食习惯与IFABP基因多态性频率分布的关系.方法:采用聚合酶链反应(PCR),DNA限制性内切酶酶切及基因测序等技术,分别对208例牧区蒙古族人群、150例张家口市区蒙古族人群和190例汉族人群54A/TIFABP基因型分析.结果:牧区蒙古人群54T等位基因频率为0.51,54A等位基因频率为0.49;市区蒙古族人群54T等位基因频率为0.33,54A等位基因频率为0.67;汉族人群54T等位基因频率为0.30,54A等位基因频率为0.70.与市区蒙古族人群、汉族人群相比,牧区蒙古族人群突变型54T等位基因频率明显增高,且差别有统计学意义(分别为χ2=22.98,P<0.01;χ2=34.23,P<0.01).市区蒙古族和汉族相比较,突变型54T等位基因频率无明显差异(χ2=0.47P>0.05).结论:蒙、汉族人群IFABP基因54A/T多态性频率分布无种族差别;牧区蒙古族人群突变型54TIFABP基因高频率分布可能与高脂饮食习惯有关.     

PGC-1α基因多态性与2型糖尿病的相关性

目的 了解华南汉族人群PGC-1αt基因单核苷酸多态性与2型糖尿病的相关性.方法 采集350例2型糖尿病患者和其父母以及366名正常糖耐量志愿者的血样,提取基因组DNA.应用PCR.限制性片段长度多态性(RFLP)和DNA直接测序技术鉴定PGC-1α基因多态性位点的基因型.应用病例.对照方法和基于家庭的单倍型相对危险度分析(HRR)和传递不平衡检验(TDT)方法分析相关多态性及其单倍型与2型精尿病的相关性.结果 (1)病例-对照研究显示Gly482Ser(G/A)多态性G、A等位基因在2型糖尿病组和正常糖耐量组分布频率分别为0.589、0.411和0.687、0.313(x2=15.076,P<0.01).Thr394Thr(G/A)、Thr528Thr(A/G)和Thr612Met(C/T)等位基因在两组间分布频率差异无统计学意义(均P>0.05).394A-482A-528A单倍型在两组间分布差异有统计学意义(x2=40.2,P<0.05),且与2型糖尿病存在连锁不平衡(t=2.503,P<0.05).(2)基于家庭研究显示PGC-1α基因Gly482Ser变异的A等位基因由父母更多地向患者传递(x2=7.217,P=0.007,HRR=1.450),TDT-ETDT结果均显示482位点A等位基因由杂合子父母传递给患病子代的频率偏离0.5(均P<0.05),单倍型TDT分析显示394A-482A-528A.612C,394A-482A-528A-612T,394A-482A-528G-612C和394A-482A-528G-612T单倍型分布频率显著偏离0.5(P<0.05或P<0.01).结论 Gly482Ser(G/A)变异与华南汉族2型糖尿病的易感性密切相关,Thr394Thr(G/A)变异可能辅助了这种作用.     

小肠脂肪酸结合蛋白基因多态性与糖尿病肾病的相关性

目的 探讨小肠脂肪酸结合蛋白基因(FABP2)多态性与糖尿病肾病发生的关系.方法 以300例2型糖尿病(T2DM)患者[包括正常蛋白尿者(24hUAlb<30mg)80例,糖尿病肾病患者(24hUAlb≥30mg)220例]和80名无糖尿病对照者(NC)、85例非糖尿病性肾脏疾病(NDRD)患者为研究对象,应用PCR-RFLP检测FABP2密码子54基因型.比较各组间FABP2密码子54基因型分布特点.结果 (1)糖尿病肾病组 FABP2 Thr/Thr基因型频率显著高于NC组、NDRD组和正常白蛋白尿组(P均＜0.05).(2)T2DM患者中Thr54(+)基因型者的HOMA-IR、TG、FFA水平显著高于Thr54(-)基因型者(P均＜0.05).结论 (1)FABP2基因多态性可能与T2DM患者胰岛素抵抗、血脂紊乱密切相关.(2)FABP2基因多态性可能通过影响胰岛素敏感性与血脂水平而影响糖尿病肾病的发生.     

Fatty acid binding protein 1 (FABP1) and fatty acid binding protein 2 (FABP2) as a link between diabetic nephropathy and subclinical atherosclerosis in children and adolescents with type 1 diabetes

BackgroundDiabetic nephropathy is a major cause of morbidity and mortality in type 1 diabetes mellitus (T1DM). Fatty acid binding proteins (FABP1 and FABP2) play a role in the development and progression of chronic kidney disease including type 2 diabetes mellitus.AimWe assessed serum FABP1 and FABP2 levels in children and adolescents with T1DM as potential markers for diabetic nephropathy and their relation to carotid intima media thickness (CIMT).MethodsSixty patients with T1DM were divided into 2 groups according to the presence of nephropathy and compared with 30 healthy controls. CIMT, fasting blood glucose (FBG), hemoglobin A1c (HbA1c), urinary albumin creatinine ratio (UACR), fasting lipid profile and serum FABP1 and FABP2 levels were assessed.ResultsFABP1 and FABP2 levels were significantly higher among type 1 diabetic patient with and without nephropathy compared with healthy controls with the highest levels among patients with nephropathy (p < 0.001). There were significant positive correlations between FABP1 and FABP2 and each of systolic blood pressure, CIMT, FBG, HbA1c and total cholesterol among T1DM patients. FABP1 was negatively correlated to glomerular filtration rate. Multivariable linear regression analysis showed that systolic blood pressure, CIMT, FBG and HbA1c were the significant independent variables related to FABP1 levels in type 1 diabetic patients with nephropathy. ROC curve analysis was performed to determine the cutoff value of FABP1 and FABP2 that could detect nephropathy.ConclusionFABP1 and FABP2 levels are elevated in children and adolescents with T1DM and could represent a link between diabetic nephropathy and subclinical atherosclerosis.     

老年2型糖尿病患者PTP-1B基因多态性研究

目的 探讨蛋白酪氨酸磷酸酶-IB(protein tyrosine phosphastase-1B,PTP-1B)基因387位编码子Pro-Leu多态性与老年2型糖尿病(T2DM)的关系。方法 采用多聚酶链反应-限制性片段长度多态性(PCR-RFLP)的方法对湖北地区110例老年T2DM患者及125例正常老年对照者PTP-1B基因387位编码子酶切位点进行研究。结果 T2DM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97.3％和98.4％,无显著性差异(P>0.05)。结论 未发现PTP-1B基因387位Pro-Leu多态性与老年人2型糖尿病有关。     

Restriction fragment length polymorphism of the insulin receptor gene, type 2 diabetes and insulin binding.

In searching for a genetic marker of type 2 diabetes we estimated the frequency of alleles of the Bgl II restriction fragment length polymorphism (RFLP) of the insulin receptor gene in a group of type II diabetic patients (n = 50), characterized by OGTT (glucose, insulin, C-peptide) and insulin receptor binding parameters. Leucocyte DNA was incubated with restriction endonuclease Bgl II and specific fragments were determined by Southern blot technique, using radioactive plasmid pINSR 13.1 as insulin receptor gene probe for hybridization. Insulin receptor numbers and receptor affinity were estimated by 125I-(Tyr-A-14)- insulin binding to red blood cells. Among control subjects the 20 kb fragment (allele Bgl II+) had a frequency of 0.21. In our group of diabetic patients this allele had a frequency of 0.10 (n.s., p greater than 0.05). In our study the insulin receptor genotype had no influence on body mass index, insulin and C-peptide during OGTT as well as insulin receptor binding data. So far, etiopathogenetic linkage between diabetes and insulin receptor variants (mutants) could unambiguously be proved in patients with extreme insulin resistance only. In our opinion, the estimation of the role of the gene as the reason underlying the disease inevitably requires the investigation of large families with multiple occurrence of type 2 diabetes.     

蛋白酪氨酸磷酸酶1B基因多态性与2型糖尿病和肥胖的相关性研究

目的 研究中国人群中蛋白酪氨酸磷酸酶1B（PTP-1B）基因的单核苷酸多态性（SNP）与2型糖尿病及肥胖的相关性。方法 采用直接测序法对PTP—1B基因作SNP筛查，并在夫妻配对样本中对所检出的SNP作基因分型。结果 共检出6个SNPs位点，其中内含子区3个（15／37C→A，16／82A→G，17／301C→T），外显子区3个（E8／45C→T，E9／35G→A，E10／372G→A），其中E9／35G→A为新发现的突变类型；在病例-配偶对照研究中发现，15／37C→A，16／82A→G和17／301C→T等位基因频率在糖尿病患者和正常人配偶中差异有统计学意义（均P〈0．05），其余位点的等位基因频率在两组间的分布则无明显差异。与肥胖的相关性研究中发现15／37C→A和17／301C→T位点与男性的腰臀比（WHR）相关（P〈0．05）。结论 PTP-1B基因的SNP位点15／37C→A，16／82A→G和17／301C→T多态性可能和2型糖尿病的发病相关，其中15／37C→A和17／301C→T与男性的WHR相关。     

Variation of the fatty acid binding protein 2 gene is not associated with obesity and insulin resistance in Japanese subjects.

An alanine to threonine substitution at codon 54 of the fatty acid binding protein 2 (FABP2) gene has been associated with insulin resistance in Pima Indians and with obesity in aboriginal Canadians. We investigated whether this polymorphism contributes to obesity and insulin resistance in 258 Japanese subjects. Thirty-six subjects (13.9%) were homozygous for the Thr54 allele, 106 (41.1%) were heterozygous for the Ala54/Thr54 allele, and 116 (45.0%) were homozygous for the Ala54 allele. The frequency of the Thr54 allele was 0.34 and did not differ significantly between men and women. The incidence of non-insulin-dependent diabetes mellitus (NIDDM) was not different among the three genotypes. The variation at codon 54 of the FABP2 gene was not associated with obesity, hypertension, dyslipidemia, hyperuricemia, or hyperinsulinemia. These results suggest that the polymorphism at codon 54 of the FABP2 gene is not a major contributing factor to obesity and insulin resistance in Japanese subjects.