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.     

Codon 54 polymorphism of the fatty acid binding protein (FABP) 2 gene is associated with increased cardiovascular risk in the dyslipidemic diabetic participants of the Veterans Affairs HDL intervention trial (VA-HIT)

The threonine (Thr) for alanine (Ala) codon 54 polymorphism of the fatty acid binding protein (FABP) 2 gene, when compared to the wild type, is associated with dyslipidemia. Since dyslipidemia is common in diabetes and is associated with increased cardiovascular risk, we tested the hypothesis that Thr-54 is associated with increased cardiovascular risk in patients with diabetes. The secondary prevention veterans affairs HDL intervention trial (VA-HIT) was carried out in patients with dyslipidemia. The DNA of trial participants (n=776) was screened for the Thr-54 polymorphism and cardiovascular endpoints were monitored. The polymorphism was detected in 370 (47.7%). For first occurrence of the primary endpoint [myocardial infarction (MI) or coronary heart disease (CHD) death] the hazard ratio (HR) and confidence intervals (Cox proportional hazards model) was 2.5 (1.2, 5.3) p=.02 in diabetic carriers of Thr-54 versus carriers without diabetes or fasting glucose >7 mmol/L. For the expanded endpoint (stroke, MI or CHD death), the corresponding HR was 3.0 (1.4, 5.4) p=.0003 and for the stroke alone the corresponding HR was 3.5 (1.4-8.9) p=.01. The higher cumulative incidence of the expanded endpoint in diabetic participants carrying the FABP2 polymorphism versus non-diabetic carriers was consistently present throughout the 5 years of the study (p=.0002). We conclude that based on the VA-HIT data, the Thr-54 polymorphism of the FABP2 gene is associated with a 2-3.5-fold increase in cardiovascular risk in dyslipidemic men with diabetes compared to their non-diabetic counterparts.     

Unlike type 2 diabetes,type 1 does not interact with the codon 54 polymorphism of the fatty acid binding protein 2 gene

In type 2 diabetes, the threonine (Thr) for alanine (Ala) codon 54 polymorphism of the fatty acid binding protein 2 gene is associated with elevated fasting and postprandial triglycerides and dyslipidemia when compared with the wild type (Ala-54/Ala-54). To assess whether this is the case in patients with type 1 diabetes, who usually do not manifest the metabolic syndrome, we screened 181 patients with similar glycemic control as the type 2 patients. Thirty percent were heterozygous, and 9% were homozygous for the polymorphism. Mean (+/-SEM) fasting plasma triglyceride levels in patients with the wild type (n = 84), those heterozygous for Ala-54/Thr-54 (n = 44), and those homozygous for the Thr-54 (n = 13) were 1.0 +/- 0.07, 1.1 +/- 0.17, and 1.2 +/- 0.23 mmol/liter, respectively. In addition, there were no differences in total, low-density lipoprotein, high-density lipoprotein, and non-high density lipoprotein cholesterol among the three groups. After a fat load, the postprandial area under the curve of triglyceride in plasma, chylomicrons, and very low-density lipoprotein were similar between the wild type (n = 18) and the Thr-54 homozygotes (n = 12). In conclusion, in contrast to type 2, type 1 diabetes does not interact with the codon 54 polymorphism of the fatty acid binding protein 2 gene to cause hypertriglyceridemia/dyslipidemia. Insulin resistance could account possibly for this difference.     

Postchallenge hyperglycemia but not hyperinsulinemia is associated with angiographically documented coronary atherosclerosis in Korean subjects

Although hyperinsulinemia has attracted considerable attention as a possible risk factor for coronary artery disease (CAD), previous studies have not shown consistent results. Hyperglycemia could be an alternative explanation for the association between type 2 diabetes and atherosclerosis. Since previous studies have been mostly lacking coronary angiographic data, we analyzed the relationship between the presence and severity of coronary atherosclerosis based on angiography and hyperinsulinemia or hyperglycemia. Two hundred and thirty subjects underwent coronary angiography and a 75-g oral glucose tolerance test. Age, sex, waist-to-hip ratio, postchallenge 1-h and 2-h glucose levels, plasma triglyceride and HDL-cholesterol levels were different between those with or without CAD. However, there was no significant difference in the plasma insulin levels, area of insulin under the curve, and the ratio of the insulin- and glucose areas between the groups with and without CAD. Multiple logistic regression analysis including fasting-, 1-h, and 2-h glucose values and a variety of atherosclerosis risk factors showed that age, sex and postchallenge 2-h glucose levels were independent determinants of the presence of CAD. These results suggest that coronary atherosclerosis might be associated with postchallenge hyperglycemia, but not with hyperinsulinemia in Korean subjects.     

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.     

The effect of polymorphism in the intestinal fatty acid-binding protein 2 gene on fat metabolism is associated with gender and obesity amongst non-diabetic Japanese-Americans

Aim:  The role of the codon 54 polymorphism of the fatty acid-binding protein 2 (FABP2) gene on fat metabolism has been controversial. Assuming that the effects of the polymorphism were modulated by gender and obesity which were related to lipid and glucose metabolism, we investigated this polymorphism and its effect on fat metabolism according to such factors.
Methods:  Subjects were Japanese–Americans (123 men and 126 women) who were diagnosed as non-diabetic by a 75 g oral glucose tolerance test at the baseline.
Results:  During approximately 7.8 years, 49 (24 men and 25 women) were diagnosed with type 2 diabetes. In a Cox proportional hazards model, this polymorphism was not a significant variable in the incidence of diabetes in either gender. Amongst non-obese men with the Thr54 allele, there was a significant elevation of triglycerides (TGs) (p = 0.033) compared with alanine (Ala) homozygotes. Women with the Thr54 allele had significantly elevated total cholesterol (p = 0.033) and low-density lipoprotein-cholesterol (LDL-C) (p = 0.023) compared with Ala54 homozygotes.
Conclusions:  These results therefore suggested that the effects of the FABP2 polymorphism on TG, LDL-C and body mass index were associated with gender difference and obesity amongst non-diabetic Japanese–American subjects.     

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.     

Intronic polymorphism in the fatty acid transport protein 1 gene is associated with increased plasma triglyceride levels in a French population

Fatty acids play important biological roles in cells. The precise mechanism whereby fatty acids cross the plasma membrane is still poorly understood. They can cross membranes because of their hydrophobic properties and/or be transported by specific proteins. Recently, a gene coding for fatty acid transport protein 1 (FATP1), an integral plasma membrane protein implicated in this process, was cloned in humans. We screened the gene by single-strand conformation polymorphism analysis and detected an A/G polymorphism in intron 8. We analyzed the potential relations of this genetic polymorphism with various obesity markers and with plasma lipid profiles in a random sample of 1144 French subjects aged 35 to 64 years. We detected statistically significant associations between this FATP1 A/G polymorphism and an increase in plasma triglyceride levels, mainly in women. These results suggest that genetic variability in the FATP1 gene may affect lipid metabolism, especially in women, and reinforce the potential implication of FATP1 in lipid homeostasis.     

Variation in the fatty acid binding protein 2 gene is not associated with markers of metabolic syndrome in patients with coronary heart disease

BACKGROUND AND AIM: It has been suggested that the threonine (Thr) 54 allele of the intestinal fatty acid binding protein 2 (FABP2) gene is associated with insulin resistance and affects the fatty acid composition of serum lipids. Our aim was to investigate the frequency of the alanine (Ala) 54Thr polymorphism of the FABP2 gene in patients with coronary heart disease (CHD), and the association between the polymorphism and the markers of metabolic syndrome, serum lipid levels and the fatty acid profile of serum lipids. METHODS AND RESULTS: A total of 414 CHD patients (mean age 61 years, range 33-74) participated in the cross-sectional EUROASPIRE (European Action on Secondary Prevention through Intervention to Reduce Events) Study. Markers of metabolic syndrome included fasting plasma glucose concentration, serum high-density lipoprotein cholesterol and triglycerides (TG), waist circumference, the waist/hip ratio, body mass index (BMI) and blood pressure (BP). The frequency of the Thr54 allele was similar in the CHD patients (27.2%) and control subjects from two independent studies (27.8% and 28.7%). There were no significant differences in plasma glucose, serum lipids, BP, BMI, waist circumference or waist/hip ratio among the genotypes. Genotype frequency was not associated with the prevalence of diabetes or metabolic syndrome, but metabolic syndrome (as defined by National Cholesterol Education Program criteria) tended to be more frequent in subjects with the Thr/Thr genotype (p = 0.095). There were no differences in the fatty acid profiles of serum cholesteryl esters, TG or phospholipids among the genotypes. CONCLUSIONS: The Ala54Thr polymorphism of the FABP2 gene is not associated with CHD, markers of the metabolic syndrome, or the fatty acid profile of serum lipids in Finnish CHD patients.     

Serum C-reactive protein level but not its gene polymorphism is associated with Takayasu arteritis

Takayasu arteritis (TA) patients with active disease often have elevated serum C-reactive protein (CRP) levels, which usually decline with the disease remission. The serum CRP concentration has been showed to be related to CRP gene polymorphisms in previous studies. The present study aims to investigate the associations of serum level of CRP and CRP polymorphisms with TA. A total of 178 unrelated Chinese Han TA patients and 229 unrelated Chinese Han individuals without documented disease were enrolled in our studies. After a systemic search in the HapMap database, four single-nucleotide polymorphisms (SNPs) were selected, namely, rs1800947, rs3093077, rs1205, and rs2808630. The ligase detection reaction (LDR) was used in genotyping. CRP concentrations were determined using turbidimetric immunoassay. Genotype frequencies and allele frequencies of CRP variations were similar between TA patients and controls. CRP haplotype frequencies in patients were not significantly different from those of controls. No significant association between serum CRP concentrations and genotypes was found. Moreover, no association was found in CRP concentration between patients with types I, II, and III TA or between patients with or without pulmonary involvement. By contrast, serum CRP concentration was directly correlated with disease severity. In conclusion, CRP polymorphisms were not associated with TA susceptibility or serum CRP levels in the Chinese Han population. However, higher CRP level was correlated with a more serious disease status, which implies that CRP possibly contributes to the progression of TA.     

小肠脂肪酸结合蛋白基因的研究进展

小肠脂肪酸结合蛋白(FABP2)是由小肠单层柱状上皮细胞分泌的一种蛋白质,具有将长链脂肪酸从细胞膜转运至内质网的功能。编码该蛋白的基因存在多个位点多态性,外显子2中第54位上腺嘌呤和鸟嘌呤的置换会引起结合脂肪酸能力的变化,进而导致脂肪酸进入体内的量发生变化。由于在调节脂肪酸代谢方面的作用,该位点多态性与胰岛素抵抗、2型糖尿病及其并发症的发生密切相关。     

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.     

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.     

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     

Nicotinic acid-induced insulin resistance is related to increased circulating fatty acids and fat oxidation but not muscle lipid content

Insulin resistance is associated with increased circulating lipids and skeletal muscle lipid content. Chronic nicotinic acid (NA) treatment reduces insulin sensitivity and provides a model of insulin resistance. We hypothesized that the reduction in insulin sensitivity occurs via elevation of circulating nonesterified fatty acids (NEFAs) and an increase in intramyocellular lipid (IMCL). A total of 15 nondiabetic males (mean age 27.4 +/- 1.6 years) were treated with NA (500 mg daily for 1 week, 1 g daily for 1 week). Insulin sensitivity (glucose infusion rate [GIR]) was determined pre- and post-NA by euglycemic-hyperinsulinemic clamp. Substrate oxidation was determined by indirect calorimetry. Skeletal muscle lipid was assessed by estimation of long-chain acyl-CoA (LCACoA) and triglyceride (TG) content and by (1)H-magnetic resonance spectroscopy quantification of IMCL (n = 11). NA reduced GIR (P =.03) and nonoxidative glucose disposal (P <.01) and increased fasting NEFAs (P =.01). The decrease in GIR related significantly to the increase in fasting NEFAs (r(2) =.30, P =.03). The intrasubject increase in basal and clamp fat oxidation correlated with the decrease in GIR (r(2) =.45, P <.01 and r(2) =.63, P <.01). There were no significant changes in muscle LCACoA, TG, or IMCL content. Therefore, induction of insulin resistance by NA occurs with increased availability of circulating fatty acids to muscle rather than with increased muscle lipid content.     

A polymorphism within the vitamin D-binding protein gene is associated with Graves' disease but not with Hashimoto's thyroiditis

Graves' disease and Hashimoto's thyroiditis are common autoimmune thyroid disorders. Experimentally, 1,25(OH)(2) D(3) prevents Hashimoto's thyroiditis. Vitamin D serum levels in Graves' disease were found to be significantly lower than in nonautoimmune hyperthyroidism. The polymorphic vitamin D-binding protein (DBP) greatly facilitates vitamin D actions, and DBP alleles differ regarding their affinity for 1,25(OH)(2) D(3). Therefore, we investigated polymorphisms of the DBP gene for an association with thyroid autoimmunity. Families with an offspring affected by Graves' disease (95 pedigrees) or by Hashimoto's thyroiditis (92 pedigrees) encompassing 561 individuals of Caucasian origin were genotyped for three DBP polymorphisms [(TAAA)(N) in intron 8; StyI; and HaeIII in exon 11]. Indirect haplotyping and (extended) transmission disequilibrium testing were performed. There was a significant transmission disequilibrium of the intron 8 polymorphism in patients with Graves' disease (P < 0.03) but not of the exon 11 polymorphism. In contrast, neither the intron 8 nor the exon 11 polymorphism was associated with Hashimoto's thyroiditis. Maternal and paternal transmission as well as allele frequencies in DQ2(+) and DQ2(-) patients did not differ in either disease. Therefore, allelic variants of the DBP gene confer susceptibility to Graves' disease but not to Hashimoto's thyroiditis in our population. These findings support a role of the vitamin D endocrine system in thyroid autoimmunity.     

The T 54 allele of the intestinal fatty acid-binding protein 2 is associated with a parental history of stroke

To test the hypothesis that the A/T polymorphism of the fatty acid-binding protein 2 gene (FABP2) is associated with impaired lipid metabolism and cardiovascular disease, we compared clinical characteristics and a parental history of cardiovascular disease between 213 sibling pairs discordant for the polymorphism. Siblings with an excess of the T54 allele had higher triglyceride (P = 0.002) and cholesterol (P = 0.019) concentrations than siblings with the A54 allele. Parents of offspring with the T54T and T54A genotypes reported an increased prevalence of stroke compared to parents of offspring with the A54A genotype (P = 0.007). In summary, we have confirmed the association of the FABP2 T54 allele with increased concentrations of cholesterol and triglycerides in genotype-discordant sibling pairs. We also present novel evidence that genetic variation in the FABP2 gene may increase susceptibility to stroke.