Polymorphism Of Uncoupling Protein Research Articles

Relationship of ‐55C/T Polymorphism of Uncoupling Protein 3 (UCP3) Gene with Metabolic Syndrome by ATP III Classification

The relation of -55C/T polymorphism of uncoupling protein 3 (UCP3) with metabolic syndrome (MS) has been evaluated only in one previous study with contradictory results. The aim of our study was to investigate the association of -55C/T polymorphism of UCP3 gene with MS. A population of 817 obese Caucasian patients was analyzed in a cross-sectional survey. Genotype of UCP3 gene -55C/T was studied. To estimate the prevalence of MS , the definitions of the ATPIII were considered. Five hundred and ninety-four patients (72.7%) had the genotype -55CC (wild group), whereas 223 patients (27.3%) had the genotype -55C/T. Genotype -5TT was not detected. Prevalence of mutant UCP genotypes was similar in patients with MS (75.7% wild genotype and 24.3% mutant genotype) and without MS (69.7% wild genotype and 30.3% mutant genotype). Odds ratio of MS wild vs. mutant genotype was 1.17 CI 95%: 0.99-1.38). Total cholesterol and low density lipoprotein (LDL) cholesterol concentrations were lower in mutant-type group than wild-type group in patients with MS. No differences in other parameters were detected between genotypes in the same group of MS. -55C/T UCP polymorphism is not major risk factor for the MS. However, in mutant group of -55CC UCP3 gene in patients with MS, total cholesterol and LDL cholesterol were lower than wild-type patients.

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.

The Uncoupling Protein 2 ‐866G &gt; A Polymorphism is Associated with the Risk of Ischemic Stroke in Chinese Type 2 Diabetic Patients

To determine genetic predispsitions for diabetic cerebral ischemia, we investigated the relationship between the -866G>A polymorphism of uncoupling protein (UCP) 2 and the risk of ischemic stroke in two cohorts of type 2 diabetic patients. A total of 844 type 2 diabetic patients with 4-year prospective study were examined using a case-control methodology. And 404 cases with ischemical stroke, 440 cases without ischemical stroke. The -866G>A polymorphism in UCP2 was genotyped by TaqMan MGB probe method. The -866G>A SNP in UCP2 was significantly associated with diabetic ischemical stroke (odds ratio [OR]= 1.94; 95% confidence interval [CI]= 0.68 to1.31; P < 0.037). Similar results were observed for baseline cases of IS. Stratification by sex confirmed an allelic association with IS in women, whereas no association was observed in men. The A allele of the -866G>A variant of UCP2 was associated with increased risk of IS in Chinese diabetic women with type 2 diabetes in a 4-year prospective study. This association was independent of other common IS risk factors.

Differential Association of Uncoupling Protein 2 Polymorphisms with Pattern Identification among Korean Stroke Patients: A Diagnostic System in Traditional Korean Medicine.

Uncoupling protein 2 (UCP2), a mitochondrial protein present in many organs and cell types, is known to dissipate the proton gradient formed by the electron transport chain. Its function is correlated with predictive parameters, such as obesity, diabetes, and metabolic syndromes. We analyzed the distribution of UCP2 polymorphisms in stroke patients diagnosed with one of the following four stroke subtypes based on the TKM standard pattern identification (PI): Qi-deficiency (QD), Dampness and Phlegm (D&P), Yin-deficiency (YD), and Fire and Heat (F&D). We studied a total of 1,786 stroke patients (397/QD, 645/D&P, 223/YD, and 522/F&D, 586/normal). Genotyping for the G-1957A, G-866A and A55V UCP2 polymorphisms was performed using the TaqMan. G-866A and A55V were significantly associated with the D&P and H&F subtypes. The frequency of subjects with the A allele of G-866A was significantly lower than the frequency of subjects with the GG type. The A55V polymorphism was also shown similar effect with G-866A in the dominant model. In contrast, no SNPs were shown to be associated with the QD or YD subtypes in this study. These results showed that the G-866A and A55V UCP2 polymorphisms may be genetic factors for specific PI types among Korean stroke patients.

The absence of polymorphisms in ADRB3, UCP1, PPARγ, and ADIPOQ genes protects morbid obese patients toward insulin resistance

The insulin resistance (IR) is a major metabolic impairment in severe obesity, a multifactorial disease in which the importance of the effect of single nucleotide polymorphisms (SNP) associations in different rather than individual genes was established. The aim of this study was to test the predictive value of presence/absence of polymorphisms/ variants in β3-adrenergic receptor (ADRB3), uncoupling protein 1 (UCP1), peroxisome proliferator-activated receptor γ (PPARγ), and adiponectin (ADIPOQ) genes in diagnosing the IR in obesity. We studied 112 (40 males, 72 females) severely obese (body mass index: 48.5±7.5 kg/m2) subjects recruited from the outpatient obesity clinic of Federico II University Hospital in Naples. Genomic DNA was extracted from peripheral leukocytes with a commercial kit. The gene polymorphisms Trp64Arg in ADRB3, -3826 A>G in UCP1, Pro12Ala in PPARγ, and c.268G>A, c.331T>C, and c.334C>T in ADIPOQ were characterized by TaqMan assay or by direct sequencing (ADIPOQ). Our results demonstrate that -3826A>G UCP1 polymorphism is associated with IR in morbid obesity. Further, the lack of any polymorphisms, Trp64Arg in ADRB3 and/or -3826 A>G in UCP1 and/or Pro12Ala in PPARγ and/or c.268G>A, c.331T>C and c.334C>T in ADIPOQ, appears a useful prognostic factor (NPV=100%) toward the IR onset in these obese patients representing a further parameter for an earlier and appropriate therapy.

Supplementation of Korean fermented soy paste doenjang reduces visceral fat in overweight subjects with mutant uncoupling protein-1 allele

The purpose of this study was to examine the hypothesis that the antiobesity effect of doenjang, a Korean fermented soy paste is different between the mutant and the wild-type alleles of a polymorphism upstream of the uncoupling protein-1 (UCP-1) gene in overweight subjects. In our randomized, double-blind, placebo-controlled trial, a total of 51 subjects with a body mass index of 23 kg/m(2) or greater and a waist-to-hip ratio of 0.90 or greater for men or 0.85 or greater for women were randomly assigned to take 9.9 g/d of either a placebo or doenjang for 12 weeks. The relative frequency of the mutant G allele of the UCP-1 polymorphism was 0.60 in the placebo group and 0.62 in the doenjang group. Supplementation of doenjang had no significant effect on the visceral fat area compared with that of the placebo group, but there was a significantly reduced amount of visceral fat in subjects with the G allele of UCP-1 polymorphism. Doenjang supplementation was found to significantly increase the free fatty acid concentration in subjects with both the A allele and the G allele. There was a significant association between visceral fat and age in study subjects with both the wild-type and mutant alleles of the UCP-1 gene. Doenjang supplementation significantly reduced visceral fat and increased the free fatty acid concentrations in subjects with the G allele of the UCP-1 polymorphism, which suggests that doenjang may be related to increased free fatty acid levels caused by elevated lipolysis in these subjects.

UCP1 genetic polymorphism (–3826 A/G) diminishes resting energy expenditure and thermoregulatory sympathetic nervous system activity in young females

Recent findings regarding the existence of functional brown adipose tissue (BAT) in adult humans suggest a physiological role of BAT and uncoupling protein 1 (UCP1)-linked thermogenesis in energy balance. To investigate whether UCP1 polymorphism was associated with resting energy expenditure (REE) and thermoregulatory sympathetic nervous system (SNS) activity in humans. A total of 82 healthy females (20-22 years) were genotyped for the -3826 A/G polymorphism of the UCP1 gene using a fluorescent allele-specific DNA primer assay system. REE was measured by indirect calorimetry. The thermoregulatory SNS activity was assessed by heart rate variability power spectral analysis according to our previously reported method. Each subject was studied in the morning, after an overnight fast. Nutritional values were calculated on the basis of 2-day food records. The frequencies of A/A, A/G and G/G genotypes were 0.27, 0.45 and 0.28, respectively. No significant difference was found in anthropometric indexes among the three groups. However, in the G/G group, the percentage of energy consumed as fat was lower (A/A: 30.7 ± 1.1%, A/G: 31.3 ± 1.0%, G/G: 26.0 ± 1.2%, P<0.01), and energy intake tended to be lower (A/A: 7209 ± 310 kJ d(-1), A/G: 7075 ± 280 kJ d(-1), G/G: 6414 ± 264 kJ d(-1), P=0.16). With regard to metabolic parameters, group differences were observed in REE (A/A: 5599 ± 170 kJ d(-1), A/G: 5054 ± 115 kJ d(-1), G/G: 4919 ± 182 kJ d(-1), P<0.01) and in thermoregulatory SNS activity (A/A: 313 ± 47 ms(2), A/G: 333 ± 42 ms(2), G/G: 185 ± 23 ms(2), P<0.05). Diminished REE in G-allele carriers as well as reduced thermoregulatory SNS activity for the G/G genotype, suggest that attenuated UCP1-linked thermogenesis has an adverse effect on the regulation of energy balance.

Association study of the -866G/A UCP2 gene promoter polymorphism with type 2 diabetes and obesity in a Tehran population: a case control study.

A functional polymorphism in the uncoupling protein 2 (UCP2) gene promoter has been associated with obesity and type 2 diabetes (T2D) in some populations. The impact of UCP2 polymorphisms on diabetes and obesity is still under debate. Contradictory results have been reported in different populations world-wide. To clarify the contribution of the UCP2 gene -866 G/A polymorphism in the Iranian population, we studied its association with obesity and T2D. A total of 225 unrelated subjects were studied: 75 T2D patients without obesity, 75 obese patients without diabetes and 75 control subjects. The UCP2 -866 G/A polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). In the normal Iranian population, GG polymorphism was significantly associated with an increased HDL-C level (P=0.027). G/A polymorphism was not associated with obesity and T2D in our study population, but the odds ratio (OR) between GG and G/A polymorphism was 0.61 with a confidence interval (CI) range of 0.34 - 1.08 in obese patients. Subjects with AA genotypes in all of the studied groups showed a lower body mass index (BMI) than subjects with the GG genotype. Although the data in our study population is not statistically significant, the A allele in the UCP2 gene promoter seems to be protective against obesity. This may suggest the possibility of UCP2 as a target molecule for studies on the etiology and treatment of obesity.

Polymorphisms of the UCP2 gene are associated with proliferative diabetic retinopathy in patients with diabetes mellitus

Uncoupling protein 2 (UCP2) plays a role in controlling reactive oxygen species (ROS) production by mitochondria. As ROS overproduction is related to diabetic retinopathy (DR), UCP2 gene polymorphisms might be involved in the development of this complication. We investigated whether the -866G/A (rs659366), Ala55Val (rs660339) and 45 bp insertion/deletion (Ins/Del) polymorphisms in the UCP2 gene might be associated with proliferative DR (PDR). In this case-control study, we analysed 501 type 2 diabetic patients (242 patients with PDR and 259 subjects without any degree of DR) and 196 type 1 diabetic patients (85 cases with PDR and 111 without DR). Haplotypes constructed from the combination of the three UCP2 polymorphisms were inferred using a Bayesian statistical method. In the type 2 diabetic group, multivariate analyses confirmed that the haplotype [A Val Ins] was an independent risk factor for PDR when present in one [adjusted odds ratio (aOR) = 2.12; P = 0.006], at least one (aOR = 2.75; P = 0.00001), or two copies (aOR = 5.30; P = 0.00001), suggesting an additive model of inheritance. Nevertheless, in type 1 diabetic patients, the association of this haplotype with PDR was confirmed only when it was present in at least one (aOR = 2.68; P = 0.014) or two copies (aOR = 6.02; P = 0.005). The haplotype [A Val Ins] seems to be an important risk factor associated with PDR in both type 2 and 1 diabetic groups.

Sex-specific effects of CNTF, IL6 and UCP2 polymorphisms on weight gain

The human proteins ciliary neurotrophic factor (CNTF) and interleukin-6 (IL6) and their receptors share structural homology with leptin and its receptor. In addition, uncoupling protein-2 (UCP2) has been shown to participate the regulation of leptin on food intake. All three proteins are active in the hypothalamus. Experiments have shown that CNTF and IL6, like leptin, can influence body weight in humans and animals, while the effect of UCP2 is not consistent. In a Dutch general population ( n = 545) we investigated associations of CNTF (null G/A, rs1800169), IL6 (174 G/C, rs1800795) and UCP2 (A55V, rs660339 and del/ins) polymorphisms with weight gain using interaction graphs and logistic regression analysis. The average follow-up period was 6.9 years. Individuals who gained weight ( n = 264) were compared with individuals who remained stable in weight ( n = 281). In women the CNTF polymorphism (odds ratio (OR) = 2.15, 95%CI: 1.27–3.64, p = 0.004) and in men the IL6 polymorphism by itself (OR = 2.26, 95%CI: 1.08–4.75, p = 0.03) or in combination with the CNTF polymorphism, were associated with weight gain. Furthermore, CNTF and IL6 polymorphisms in interaction with UCP2 polymorphisms had similar strong effects on weight gain in women and men, respectively. All observed effects were statistically shown to be independent of serum leptin level. These results are incorporated in a biological model for weight regulation with upstream effects of CNTF and IL6, and downstream effects of UCP2. The results of this study suggest a novel mechanism for weight regulation that is active in both women and men, but strongly influenced by sex.

Uncoupling protein 2 Ala55Val polymorphism is associated with a higher acute insulin response to glucose

Recent evidence suggests that mitochondrial uncoupling protein 2 (UCP2) in pancreatic β-cells plays a crucial role in insulin production and secretion. We hypothesized that 2 UCP2 polymorphisms, a −55C/T (Ala55Val) substitution in exon 4 and an exon 8 insertion, would alter the acute insulin response to glucose (AIRg). Subjects were 155 African American (AA) and European American (EA) women. Body composition was determined by dual-energy x-ray absorptiometry. Insulin sensitivity and AIRg were measured with an intravenous glucose tolerance test and minimal modeling. To account for the confounding effects of population stratification, estimates of African admixture were obtained from approximately 35 ancestry-informative markers. Uncoupling protein 2 genotyping was conducted with gel electrophoresis. Information was analyzed using mixed linear models. A positive association between the −55C/T homozygous mutation and AIRg was identified in the total sample ( P < .01) and independently in EA women ( P = .02) but not AA women. The exon 8 insertion did not significantly affect AIRg. No interaction effects of the 2 polymorphisms on AIRg were noted. These results indicate that AIRg is associated with the −55C/T UCP2 homozygous mutation and that the presence of this mutation could alter postchallenge insulin concentration.

Uncoupling protein 2 polymorphisms as risk factors for NTDs

Both environmental and genetic factors are involved in the etiology of NTDs. Inadequate folate intake and obesity are important environmental risk factors. Several folate-related genetic variants have been identified as risk factors; however, little is known about how genetic variants relate to the increased risk seen in obese women. Uncoupling Protein 2 (UCP2) is an attractive candidate to screen for NTD risk because of its possible role in obesity as well as energy metabolism, type-2 diabetes, and the regulation of reactive oxygen species. Interestingly, a previous study found that a common UCP2 compound homozygous genotype was associated with a threefold increase in NTD risk. We evaluated three polymorphisms, -866G>A, A55V, and the 3'UTR 45 bp insertion/deletion, as risk factors for NTDs in Irish NTD cases (n = 169), their mothers (n = 163), their fathers (n = 167), and normal control subjects (n = 332). Allele and genotype frequencies were not significantly different when comparing NTD mothers, NTD fathers, or affected children to controls. Additionally, the previously reported risk genotype (combined homozygosity of 55VV and 3'UTR 45 bp deletion/deletion) was not present at a higher frequency in any NTD group when compared to controls. In our Irish study population, UCP2 polymorphisms did not influence NTD risk. Moreover, the prevalence of this allele in other populations was similar to the Irish prevalence but far lower than reported in the previous NTD study, suggesting that this previous finding of an association with NTDs might have been due to an unrepresentative study sample.

Is UCP2 Gene Polymorphism Associated With Decreased Resting Energy Expenditure in Nondialyzed Chronic Kidney Disease Patients?

The deletion/deletion (del/del) polymorphism of uncoupling protein 2 (UCP2) was associated with decreased energy expenditure in diabetic and obese patients. There is evidence of decreased resting energy expenditure (REE) in chronic kidney disease (CKD) patients not yet on dialysis. However, whether REE is associated with the UCP2 polymorphism was not previously investigated in this population. This study evaluated whether the del/del polymorphism of the UCP2 gene is associated with lower REE in nondialyzed CKD patients. This was a cross-sectional study. Forty-four nondialyzed CKD patients (29 male; aged 52 +/- 12 years; creatinine clearance, 37 +/- 13 mL/min/1.73 m(2) [values are mean +/- SD unless otherwise noted]) were included. Their REE was assessed by indirect calorimetry, and body composition by bioelectrical impedance. High-sensitivity C-reactive protein (hs-CRP) was also evaluated. The insertion/deletion (ins/del) polymorphism of the UCP2 gene was determined in all participants. To test whether the deletion/deletion (del/del) polymorphism of the UCP2 gene was associated with lower REE, the REE of carriers of the del/del genotype (n = 24; group Del) was compared with that of carriers of the insertion and ins/del genotype (n = 20; group Ins). The main outcome measure was REE. The REE of group Del was similar to that of the group Ins (1379 +/- 239 kcal/day vs. 1360 +/- 289 kcal/day, respectively, P = NS). This result was maintained even after the REE was adjusted for lean body mass by analysis of covariance. In addition, in a multiple-regression analysis using REE as the dependent variable, only lean body mass and hs-CRP were significant predictors of REE. The results suggest that the del/del polymorphism of the UCP2 gene is not associated with lower REE in nondialyzed CKD patients.

Lack of association between uncoupling protein-2 Ala55Val polymorphism and incident diabetes in the atherosclerosis risk in communities study

Type 2 diabetes mellitus (T2DM) is characterized by impaired insulin secretion, peripheral insulin resistance, and increased hepatic glucose production. Genes that contribute to genetic susceptibility to T2DM function in numerous biochemical pathways. Uncoupling protein-2 (UCP2) functions as a negative regulator of insulin secretion. Animal studies show induction of UCP2 plays a pathogenic role in the progression of obesity-induced T2DM and some human studies have shown an association between a common UCP2 polymorphism, Ala55Val (rs660339), and T2DM, obesity, and resting metabolic rate with the Val/Val genotype conferring increased risk. We investigated the relationship between the Ala55Val variant and incidence of T2DM among 12,056 participants in the Atherosclerosis Risk in Communities (ARIC) Study aged 45-64 years at baseline. Incident T2DM (n = 1,406) cases were identified over 9 years of follow-up. The Val55 allele frequency was 44% in blacks and 41% in whites. The rate of T2DM per 1,000 person was 15.0, 15.6, and 15.6 yearsfor Ala/Ala, Ala/Val, and Val/Val genotypes, respectively. We found no significant association between UCP2 genotypes and incident T2DM in the whole cohort, in race-gender subgroups, or in categories of body mass index (normal, overweight and obese). The Ala55Val polymorphism of UCP2 was not associated with incident T2DM in the ARIC cohort.

Association of the ins/del polymorphisms of uncoupling protein 2 ( UCP2) with BMI in a Korean population

To elucidate the potential impact of the variants of the UCP2 gene on obesity phenotypes, we have genotyped four polymorphisms in UCP2 among 988 Korean subjects using TaqMan ® methods, and three common haplotypes with frequency greater than 0.1 were constructed in the Korean population. No significant associations were detected with the risk of metabolic syndrome by logistic regression analyses. However, the 45 base-pair ins/del polymorphism (+3474 ins/del) in the 3′ untranslated region (3′ UTR) showed significant association with body mass index ( P = 0.007, P corr = 0.02) and waist circumference ( P = 0.005). Further subgroup analysis revealed that the genetic effects were more apparent among female subjects. In addition, a summary of the controversial genetic effects on obesity mediated by UCP2 polymorphisms from previous studies is also given. Our results suggest that subjects with a 45 bp insertion allele of UCP2+3474 ins/del might have a higher risk of developing obesity, although the biological effects of this variant are not completely known.

Effects of genetic polymorphism of uncoupling protein 2 on body fat and calorie restriction-induced changes1

The purpose of this study is to estimate the effects of Ala55Val genetic polymorphism of uncoupling protein 2 on computed tomography-measured body fat area and calorie restriction-induced changes. Among 386 Korean female subjects, the AlaAla type was seen in 30.3%, the AlaVal type was seen in 47.2%, and the ValVal type was seen in 22.5%. This finding was in agreement with Hardy-Weinberg equilibrium. The frequency of the major Ala allele was 0.54, and that of the minor Val allele was 0.46, which were similar to those seen in Caucasian populations. When cross-sectional areas of fat tissues in the subjects were measured by computed tomography, it was shown that the total abdominal fat area and abdominal subcutaneous fat area were significantly smaller in the ValVal type compared with the AlaVal or AlaAla type (p=0.043 and p=0.044, respectively). The Ala55Val polymorphism had no effects on visceral fat area and thigh subcutaneous fat area. Among the 386 subjects, 236 subjects finished the 1-month calorie restriction program. The results showed that the body fat was reduced significantly less in the ValVal type compared with the other types (p=0.016), whereas the changes in lean body mass, protein, mineral, and water contents were not significantly different according to the Ala55Val polymorphism.

Association of n‐6 long‐chain polyunsaturated fatty acids to −866 G/A genotypes of the human uncoupling protein 2 gene in obese children

To investigate the association of plasma fatty acids with the -866 G/A polymorphism of uncoupling protein 2 (UCP2) in obese children. Fatty acid composition of plasma phospholipids and sterol esters were investigated in 80 obese children. Values of dihomo-gamma-linolenic acid (C20:3n-6) were significantly lower in children with the -866 A/A (n = 12) than in those with the -866 G/A (n = 34) or -866 G/G (n = 34) genotype in plasma phospholipids (3.01 [0.42] vs. 3.56 [1.02] vs. 3.53 [0.84], % weight/weight, median [interquartile range], p < 0.05), and were significantly lower in children with the -866 A/A genotype than in the other two groups in plasma sterol esters (0.73 [0.22] vs. 0.92 [0.23] vs. 0.94 [0.25], p < 0.05). Phospholipid C20:3n-6 and arachidonic acid (C20:4n-6) values showed only in children with the -866 G/G and -866 G/A genotypes significant positive correlations with plasma insulin concentrations. Significantly lower values of C20:3n-6 can be detected in obese children with the homozygous (-866 A/A) mutation of UCP2 than in equally obese children with heterozygous mutation or the normal genotype. High glucose-stimulated insulin response is associated with high plasma C20:3n-6 and C20:4n-6 values only in obese children with the G allele of the -866 G/A polymorphism.

Interaction between the UCP2–866G/A, mtDNA 10398G/A and PGC1α p.Thr394Thr and p.Gly482Ser polymorphisms in type 2 diabetes susceptibility in North Indian population

In the recent past, we have observed a possible role of 10398A and 16189C mtDNA and PGC1alpha p.Thr394Thr (rs2970847) and p.Gly482Ser (rs8192673) variant genotypes providing susceptibility/protection against type 2 diabetes mellitus (T2DM) in two North Indian population groups. These initial observations encouraged us to look at the candidate genes in combination with -866G/A (rs659366) polymorphism in uncoupling protein 2 (UCP2) in a single study of a relatively large sample size, constituted of both the cohorts, to unravel an interesting outcome of an additive interaction in-between the studied genes. In a total of 1,686 individuals (762 cases and 924 controls) belonging to Indo-European linguistic group from North India, a comparison of risk genotype combinations of: UCP2-866GG, mtDNA 10398A and PGC1alpha p.Thr394Thr or p.Gly482Ser against the protective genotypes: UCP2-866XA, mtDNA 10398G and PGC1alpha p.Thr394Thr (nominal P value = 1.75 x 10(-14), Odds ratio, OR = 5.29, 3.40-8.22 at 95% CI) or PGC1alpha p.Gly482Ser (nominal p value = 4.42 x 10(-24), OR = 8.59, 5.53-13.35 at 95% CI), showed a highly significant difference and increased ORs. In a complex disease, it is always encouraging to find an additive interaction of multiple small effects of the studied candidate gene variations.

The −3826 A → G variant of the uncoupling protein-1 gene diminishes thermogenesis during acute cold exposure in healthy children

Uncoupling protein-1 (UCP1) activity in brown adipose tissue increases energy expenditure, and contributes to diet-induced or cold-induced thermogenesis. We previously reported that children with -3826 A → G nucleotide variant of the UCP1 gene had lowered postprandial thermogenesis in response to a high-fat meal. In this study, we investigated whether the UCP1 polymorphism was associated with cold-induced thermogenesis in healthy children. Resting energy expenditure was measured in 19 children (6-10 years) by indirect calorimetry for 30 min under thermoneutral (25 °C) or cold conditions (10 °C) in an environmental chamber. The activity of autonomic nervous system (ANS) was assessed by power spectral analysis of heart rate variability (HRV). Samples of saliva were collected for cortisol determination at the end of the experimental session. Each experiment was performed on 2 consecutive days. Children were genotyped for the UCP1 polymorphism with a PCR-restriction fragment length analysis using buccal samples. During cold exposure, total power of the HRV, an index of the overall ANS activity, as well as the salivary cortisol concentration significantly increased in the children with homozygous (GG) for the UCP1 polymorphism while only cortisol response was found in the carriers of the wild-type (AA) and heterozygous (AG) alleles; however, the GG allele group showed a lower cold-induced thermogenesis compared to the AA + AG group. In conclusion, despite cold-induced autonomic stimulation, the GG allele carriers have a reduced capacity for thermogenesis in response to acute cold exposure, suggesting that such reduced UCP1-linked thermogenesis may have adverse effects on the regulation of body weight.:

Uncoupling Protein 2 Promoter Polymorphism −866G/A Affects Peripheral Nerve Dysfunction in Japanese Type 2 Diabetic Patients

To determine genetic predispositions for diabetic polyneuropathy, we investigated the relationship between the -866G/A polymorphism of uncoupling protein (UCP) 2 and neurological manifestations in 197 type 2 diabetic patients. We first examined whether UCP2 mRNA had been expressed in the dorsal root ganglion (DRG) in four Long-Evans Tokushima Otsuka rats using RT-PCR and electrophoresis. Genotyping of UCP2 promoter polymorphism -866G/A was then performed in 197 unrelated Japanese type 2 diabetic patients, who were subjected to nerve conduction, quantitative vibratory perception, head-up tilt, and heart rate variability tests, by PCR restriction fragment-length polymorphism. The relationships between UCP2 genotype and various nerve functions were analyzed by uni- and multivariable analysis. Expression of UCP2 mRNA was confirmed in rat DRG. Multiple regression analysis clarified the hypothesis that the G/A + A/A genotype was significantly related to decreased motor nerve conduction velocity and impaired blood pressure maintenance on the head-up tilt test. Multiple logistic regression analysis revealed that the G/A + A/A genotypes are a significant risk factor for sensory nerve conduction slowing and orthostatic hypotension. UCP2 promoter gene polymorphism -866 G/A was significantly associated with nerve conduction slowing and vasomotor sympathetic functions. These findings suggest that the higher UCP2 activity related to the A allele has an energy-depleting effect on peripheral nerve function in type 2 diabetic patients.