Mitochondrial Haplogroup T Is Associated with Obesity in Austrian Juveniles and Adults

Background

Recent publications have reported contradictory data regarding mitochondrial DNA (mtDNA) variation and its association with body mass index. The aim of the present study was to compare the frequencies of mtDNA haplogroups as well as control region (CR) polymorphisms of obese juveniles (n = 248) and obese adults (n = 1003) versus normal weight controls (n_juvenile = 266, n_adults = 595) in a well-defined, ethnically homogenous, age-matched comparative cohort of Austrian Caucasians.

Methodology and Principal Findings

Using SNP analysis and DNA sequencing, we identified the nine major European mitochondrial haplogroups and CR polymorphisms. Of these, only the T haplogroup frequency was increased in the juvenile obese cohort versus the control subjects [11.7% in obese vs. 6.4% in controls], although statistical significance was lost after adjustment for sex and age. Similar data were observed in a local adult cohort, in which haplogroup T was found at a significantly higher frequency in the overweight and obese subjects than in the normal weight group [9.7% vs. 6.2%, p = 0.012, adjusted for sex and age]. When all obese subjects were considered together, the difference in the frequency of haplogroup T was even more clearly seen [10.1% vs. 6.3%, p = 0.002, OR (95% CI) 1.71 (1.2–2.4), adjusted for sex and age]. The frequencies of the T haplogroup-linked CR polymorphisms C16294T and the C16296T were found to be elevated in both the juvenile and the adult obese cohort compared to the controls. Nevertheless, no mtDNA haplogroup or CR polymorphism was robustly associated with any of several investigated metabolic and cardiovascular parameters (e.g., blood pressure, blood glucose concentration, triglycerides, cholesterol) in all obese subjects.

Conclusions and Significance

By investigation of this large ethnically and geographically homogenous cohort of Middle European Caucasians, only mtDNA haplogroup T was identified as an obesity risk factor.     

Left ventricular noncompaction is associated with mutations in the mitochondrial genome

Left ventricular noncompaction (LVNC) is a genetically heterogeneous condition and several nuclear loci have been associated with the defect. However, they only account for a small percentage of patients. Existing evidences suggest that pathogenic mitochondrial DNA (mtDNA) mutations and consequent mitochondrial malfunction can be an important component in the etiology of LVNC. To investigate if mtDNA mutation can serve as a primary cause for LVNC, complete nucleotide sequences of mitochondrial genomes from 20 LVNC patients were determined by Illumina parallel sequencing technology and analyzed by MitoMaster. Substitutions of a highly conserved Met31 in ND1 caused by rare mitochondrial single nucleotide polymorphisms (mtSNP) A3397G and T3398C were identified from two LVNC patients. Previously, T3398C has been reported from another LVNC patient, indicating mutations in Met31 in ND1 and resultant defects in complex I can be associated with LVNC. Additionally, three mtSNPs in protein-coding genes, seven variants in rRNA genes, and two transitions in tRNA genes were unrelated to the haplogroup and infrequent in the general population, suggesting that these mtSNPs could also be pathogenic. Our study revealed some mtSNPs could represent pathogenic mutations, lead to compromised mitochondrial function, and be associated with LVNC.     

Association of resistin gene polymorphisms with insulin resistance in Egyptian obese patients

Background

Obesity associated insulin resistance is a major risk factor for type 2 diabetes mellitus. Resistin is recently reported to provide a link between obesity, insulin resistance and type 2 diabetes mellitus. We aimed to investigate the possible associations of resistin gene (RETN) polymorphisms with obesity, and to detect whether these polymorphisms are associated with glucose intolerance and type 2 diabetes mellitus in obese patients.

Methods

One hundred and forty-five Egyptian obese patients with or without glucose intolerance and 155 unrelated healthy controls were enrolled in this study. Polymorphisms of RETN + 299G>A and RETN –420 C>G gene were detected by polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP). Serum resistin was measured by ELISA.

Results

RETN + 299 AA and RETN − 420 GG genotypes were significantly associated with obesity in Egyptian population. Moreover, the mutant alleles or genotypes of both examined polymorphisms were associated with impaired glucose tolerance and diabetes mellitus compared to normal glucose tolerant obese patients. Furthermore, our results revealed elevated waist/hip ratio, BMI, blood pressure, fasting blood glucose level, HOMA-IR, triglycerides, total cholesterol, resistin level, and decreased HDL cholesterol level in homozygote mutant genotypes carriers of both RETN polymorphisms among obese patients.

Conclusion

Resistin gene polymorphisms may play an important role in pathogenesis and susceptibility to obesity, impaired glucose tolerance, and type 2 diabetes mellitus in Egyptian population.     

Genetic association study of common mitochondrial variants on body fat mass

Mitochondria play a central role in ATP production and energy metabolism. Previous studies suggest that common variants in mtDNA are associated with several common complex diseases, including obesity. To test the hypothesis that common mtDNA variants influence obesity-related phenotypes, including BMI and body fat mass, we genotyped a total of 445 mtSNPs across the whole mitochondrial genome in a large sample of 2,286 unrelated Caucasian subjects. 72 of these 445 mtSNPs passed quality control criteria, and were used for subsequent analyses. We also classified all subjects into nine common European haplogroups. Association analyses were conducted for both BMI and body fat mass with single mtSNPs and mtDNA haplogroups. Two mtSNPs, mt4823 and mt8873 were detected to be significantly associated with body fat mass, with adjusted P values of 4.94×10^-3 and 4.58×10^-2, respectively. The minor alleles mt4823 C and mt8873 A were associated with reduced fat mass values and the effect size (β) was estimated to be 3.52 and 3.18, respectively. These two mtSNPs also achieved nominally significant levels for association with BMI. For haplogroup analyses, we found that haplogroup X was strongly associated with both BMI (adjusted P = 8.31×10^-3) and body fat mass (adjusted P = 5.67×10^-4) Subjects classified as haplogroup X had lower BMI and fat mass values, with the β estimated to be 2.86 and 6.03, respectively. Our findings suggest that common variants in mitochondria might play a role in variations of body fat mass. Further molecular and functional studies will be needed to clarify the potential mechanism.     

Association of Genes,Pathways, and Haplogroups of the Mitochondrial Genome with the Risk of Colorectal Cancer: The Multiethnic Cohort

The mitochondrial genome encodes for the synthesis of 13 proteins that are essential for the oxidative phosphorylation (OXPHOS) system. Inherited variation in mitochondrial genes may influence cancer development through changes in mitochondrial proteins, altering the OXPHOS process, and promoting the production of reactive oxidative species. To investigate the role of the OXPHOS pathway and mitochondrial genes in colorectal cancer (CRC) risk, we tested 185 mitochondrial SNPs (mtSNPs), located in 13 genes that comprise four complexes of the OXPHOS pathway and mtSNP groupings for rRNA and tRNA, in 2,453 colorectal cancer cases and 11,930 controls from the Multiethnic Cohort Study. Using the sequence kernel association test, we examined the collective set of 185 mtSNPs, as well as subsets of mtSNPs grouped by mitochondrial pathways, complexes, and genes, adjusting for age, sex, principal components of global ancestry, and self-reported maternal race/ethnicity. We also tested for haplogroup associations using unconditional logistic regression, adjusting for the same covariates. Stratified analyses were conducted by self-reported maternal race/ethnicity. In European Americans, a global test of all genetic variants of the mitochondrial genome identified an association with CRC risk (P = 0.04). In mtSNP-subset analysis, the NADH dehydrogenase 2 (MT-ND2) gene in Complex I was associated with CRC risk at a P-value of 0.001 (q = 0.015). In addition, haplogroup T was associated with CRC risk (OR = 1.66, 95% CI: 1.19–2.33, P = 0.003). No significant mitochondrial pathway and gene associations were observed in the remaining four racial/ethnic groups—African Americans, Asian Americans, Latinos, and Native Hawaiians. In summary, our findings suggest that variations in the mitochondrial genome and particularly in the MT-ND2 gene may play a role in CRC risk among European Americans, but not in other maternal racial/ethnic groups. Further replication is warranted and future studies should evaluate the contribution of mitochondrial proteins encoded by both the nuclear and mitochondrial genomes to CRC risk.     

Mitochondrial Genetic Variants Identified to Be Associated with BMI in Adults

It has been suggested that mitochondrial dysfunction plays a role in metabolic disorders including obesity, diabetes, and hypertension. The fact that mitochondrial defects can be accumulated over time as a normal part of aging may explain why some individuals can eat all sorts of foods and remain at normal weight while they are young. However, around the fourth decade of life there is a trend towards “middle-age spread” with weight gain and the body''s decreasing ability to metabolize calories efficiently. To test the hypothesis that mitochondrial variants are associated with BMI in adults, we analyzed a total number of 984 mitochondrial single nucleotide polymorphisms (mtSNPs) in a sample of 6,528 individuals participating in the KORA studies. To assess mtSNP association while taking heteroplasmy into account we used the raw signal intensity values measured on the microarray and applied linear regression. Significant results were obtained for 2 mtSNPs located in the Cytochrome c oxidase subunit genes (MT-CO1: P_adjusted = 0.0140 and MT-CO3: P_adjusted = 0.0286) and 3 mtSNPs located in the NADH dehydrogenase subunit genes (MT-ND1, MT-ND2 and MT-ND4L: P_adjusted = 0.0286). Polymorphisms located in the MT-CO3 and MT-ND4L genes have not been associated with BMI or related phenotypes in the past. Our results highlight the importance of the mitochondrial genome among the factors that contribute to the risk of high BMI. Focusing on mitochondrial variants may lead to further insights regarding effects of existing medications, or even to the development of innovative treatments.     

Mitochondrial haplogroups and control region polymorphisms in age-related macular degeneration: a case-control study

Background

Onset and development of the multifactorial disease age-related macular degeneration (AMD) are highly interrelated with mitochondrial functions such as energy production and free radical turnover. Mitochondrial dysfunction and overproduction of reactive oxygen species may contribute to destruction of the retinal pigment epithelium, retinal atrophy and choroidal neovascularization, leading to AMD. Consequently, polymorphisms of the mitochondrial genome (mtDNA) are postulated to be susceptibility factors for this disease. Previous studies from Australia and the United States detected associations of mitochondrial haplogroups with AMD. The aim of the present study was to test these associations in Middle European Caucasians.

Methodology/Principal Findings

Mitochondrial haplogroups (combinations of mtDNA polymorphisms) and mitochondrial CR polymorphisms were analyzed in 200 patients with wet AMD (choroidal neovascularization, CNV), in 66 patients with dry AMD, and in 385 controls from Austria by means of multiplex primer extension analysis and sequencing, respectively. In patients with CNV, haplogroup H was found to be significantly less frequent compared to controls, and haplogroup J showed a trend toward a higher frequency compared to controls. Five CR polymorphisms were found to differ significantly in the two study populations compared to controls, and all, except one (T152C), are linked to those haplogroups.

Conclusions/Significance

It can be concluded that haplogroup J is a risk factor for AMD, whereas haplogroup H seems to be protective for AMD.     

A Rare Variant in the Visfatin Gene (NAMPT/PBEF1) Is Associated With Protection From Obesity

Visfatin was recently reported as a novel adipokine encoded by the NAMPT (PBEF1) gene. This study was aimed at investigation of the possibility that single‐nucleotide polymorphisms (SNPs) in the visfatin gene are associated with either obesity or type 2 diabetes (T2D). A set of eight “tag‐SNPs” were selected and ABI SNPlex assays designed for genotyping purposes. A total of 1,709 severely obese subjects were typed (896 class III obese adults and 813 children) together with 2,367 T2D individuals and 2,850 controls. For quantitative trait analysis, an additional 2,362 subjects were typed for rs10487818 from a general population sample. One rare SNP, rs10487818, located in intron 4 of NAMPT was associated with severe obesity, with a minor allele frequency of 1.6% in controls, 0.4% in the class III obese adults and, remarkably, 0% in the severely obese children. A highly significant association was observed for the presence or absence of the rare allele, i.e., (A,A) vs. (A,T + T,T) genotypes, in children (P = 6 × 10^?9) and in adults (P = 8 × 10^?5). No other significant (P < 0.05) association was observed with obesity or T2D for this or any other SNP. No association with BMI or waist‐to‐hip ratio was observed in a general population sample (n = 5,212). This is one of the first rare SNPs shown to be protective against a common polygenic disease and provides further evidence that rare alleles of strong effect can contribute to complex diseases such as severe obesity.     

Lack of association of glutamate decarboxylase 2 gene polymorphisms with severe obesity in utah

Three polymorphisms of the glutamate decarboxylase 2 gene, which encodes the glutamic acid decarboxylase enzyme, have been associated with severe obesity in a large French cohort. One of these polymorphisms was shown to have functional consequences on promoter expression. Another polymorphism was associated with insulin levels and secretion. These associations were examined in 855 severely obese Utah subjects (mean BMI = 48 kg/m(2)) and a normal-weight and normoglycemic subset (N = 130, mean BMI = 22 kg/m(2)) of a random sample of the Utah population (N = 462). Comparisons of the normal-weight random group with the severely obese group did not result in significant genotype or allele frequency differences for any of the three polymorphisms, C61450A, T83897A, or A-243G (all p > or = 0.18). Haplotypes were also not related to severe obesity (p = 0.10). None of the polymorphisms was significantly related to fasting glucose, insulin levels, or homeostasis model assessment insulin resistance or secretion indices. This study of normal-weight and severely obese subjects from Utah does not provide evidence for involvement of the three genotyped polymorphisms in the glutamate decarboxylase 2 gene with obesity or with insulin- and glucose-related measures associated with obesity.     

Missense mutations and polymorphisms of the <Emphasis Type="Italic">MC4R</Emphasis> gene in Polish obese children and adolescents in relation to the relative body mass index

Extensive studies of the MC4R gene polymorphism showed that, among numerous variants, there are mutations responsible for monogenic obesity, as well as polymorphisms negatively correlated with the risk of obesity. In this report, we present the first studies of the whole coding sequence of the MC4R gene in 243 Polish obese children and adolescents (the mean relative body mass index [RBMI] was 163.6). In addition, 101 non-obese adults were also analyzed. Direct sequencing facilitated the identification of six missense (K73R, V103I, T112M, S127L, M215L, and I251L) and one silent (c.756 C > T) single-nucleotide polymorphisms (SNPs). Two non-synonymous polymorphisms (K73R and M215L) appeared to be novel and one was found in obese patients (M215L, one patient) and one in non-obese adults (K73R, one person). The overall frequency of non-synonymous variant carriers reached 4.1% and 6.9% in obese patients and non-obese adults, respectively. Only one obesity-associated variant (127L) was found in two obese patients (0.82%) and in two non-obese adults (1.98%). The obesity-protecting variants (103I and 251L) appeared to be the most common in both groups: 3.3% and 4.0%, respectively. It was also observed that the RBMI in obese children and adolescents carrying the minor variants did not differ significantly from the non-carriers; however, the expected trends for the associated and protecting variants were observed. We conclude that the contribution of the MC4R gene variants to the pathogenesis of obesity in Polish children and adolescents is low.     

Mitochondrial haplogroups associated with Japanese centenarians,Alzheimer＇s patients,Parkinson＇s patients,type 2 diabetic patients and healthy non-obese young males

The relationships between five classes of Japanese people （i.e., 96 centenarians, 96 Alzheimer＇s disease （AD） patients, 96 Parkinson＇s disease （PD） patients, 96 type 2 diabetic （T2D） patients, and 96 healthy non-obese young males） and their mitochondrial single nucleotide polymorphism （mtSNP） frequencies at individual mtDNA positions of the entire mitochondrial genome were examined using the radial basis function （RBF） network and the modified method. New findings of mitochondrial haplogroups were obtained for individual classes. The five classes of people were associated with the following haplogroups： Japanese centenarians-M7b2, D4b2a, and B5b; Japanese AD patients-G2a, B4cl, and N9b1; Japanese PD patients-M7b2, B4e, and B5b; Japanese T2D patients-B5b, M8al, G, D4, and F1; and Japanese healthy non-obese young males-D4g and D4b1b. From the points of common haplogroups among the five classes, the cente- narians have the common haplogroups M7b2 and B5b with the PD patients and common haplogroup B5b with the T2D patients. In addition, the 112 Japanese semi-supercentenarians （over 105 years old） recently reported were also examined by the method proposed. The results obtained were the haplogroups D4a, B4c1a, M7b2, F1, M1, and B5b. These results are different from the previously reported haplogroup classifications. As the proposed analysis method can predict a person＇s mtSNP constitution and the probabilities of becoming a centenarian, AD patient, PD patient, or T2D patient, it may be useful in initial diagnosis of various diseases.     

Further evidence for the role of ENPP1 in obesity: association with morbid obesity in Finns

The aim of this study was to investigate a series of single-nucleotide polymorphisms (SNPs) in the genes MC2R, MC3R, MC4R, MC5R, POMC, and ENPP1 for association with obesity. Twenty-five SNPs (2-7 SNPs/gene) were genotyped in 246 Finns with extreme obesity (BMI > or = 40 kg/m2) and in 481 lean subjects (BMI 20-25 kg/m2). Of the obese subjects, 23% had concomitant type 2 diabetes. SNPs and SNP haplotypes were tested for association with obesity and type 2 diabetes. Allele frequencies differed between obese and lean subjects for two SNPs in the ENPP1 gene, rs1800949 (P = 0.006) and rs943003 (P = 0.0009). These SNPs are part of a haplotype (rs1800949 C-rs943003 A), which was observed more frequently in lean subjects compared to obese subjects (P = 0.0007). Weaker associations were detected between the SNPs rs1541276 in the MC5R, rs1926065 in the MC3R genes and obesity (P = 0.04 and P = 0.03, respectively), and between SNPs rs2236700 in the MC5R, rs2118404 in the POMC, rs943003 in the ENPP1 genes and type 2 diabetes (P = 0.03, P = 0.02 and P = 0.02, respectively); these associations did not, however, remain significant after correction for multiple testing. In conclusion, a previously unexplored ENPP1 haplotype composed of SNPs rs1800949 and rs943003 showed suggestive evidence for association with adult-onset morbid obesity in Finns. In this study, we did not find association between the frequently studied ENPP1 K121Q variant, nor SNPs in the MCR or POMC genes and obesity or type 2 diabetes.     

Mitochondrial DNA backgrounds might modulate diabetes complications rather than T2DM as a whole

Mitochondrial dysfunction has been implicated in rare and common forms of type 2 diabetes (T2DM). Additionally, rare mitochondrial DNA (mtDNA) mutations have been shown to be causal for T2DM pathogenesis. So far, many studies have investigated the possibility that mtDNA variation might affect the risk of T2DM, however, when found, haplogroup association has been rarely replicated, even in related populations, possibly due to an inadequate level of haplogroup resolution. Effects of mtDNA variation on diabetes complications have also been proposed. However, additional studies evaluating the mitochondrial role on both T2DM and related complications are badly needed. To test the hypothesis of a mitochondrial genome effect on diabetes and its complications, we genotyped the mtDNAs of 466 T2DM patients and 438 controls from a regional population of central Italy (Marche). Based on the most updated mtDNA phylogeny, all 904 samples were classified into 57 different mitochondrial sub-haplogroups, thus reaching an unprecedented level of resolution. We then evaluated whether the susceptibility of developing T2DM or its complications differed among the identified haplogroups, considering also the potential effects of phenotypical and clinical variables. MtDNA backgrounds, even when based on a refined haplogroup classification, do not appear to play a role in developing T2DM despite a possible protective effect for the common European haplogroup H1, which harbors the G3010A transition in the MTRNR2 gene. In contrast, our data indicate that different mitochondrial haplogroups are significantly associated with an increased risk of specific diabetes complications: H (the most frequent European haplogroup) with retinopathy, H3 with neuropathy, U3 with nephropathy, and V with renal failure.     

Methylenetetrahydrofolate reductase gene polymorphism in diabetes and obesity

Methylenetetrahydrofolate reductase (MTHFR) polymorphism may play an important role in the pathophysiology of obesity and diabetes accompanied by obesity due to its influence on plasma homocysteine levels. There are significant and sometimes very strong relationship between levels of homocysteine and several multi-system diseases including CHD and CVA. To examine the association between MTHFR gene C677T polymorphism in diabetes and obesity with serum homocysteine levels. A total of 682 subjects were recruited in four groups (Normal, obese, diabetic and obese and diabetics). MTHFR gene C677T polymorphism was detected using PCR-RFLP technique. Serum homocysteine levels were measured using HPLC. There was a significant increase in the mean serum homocysteine levels in subjects carrying TT genotype (34.6 ± 26.5) compared to subjects carrying CC (15.1 ± 8) or CT genotype (16.4 ± 7.8) (P < 0.000). We found no significant differences for MTHFR allele and genotype frequencies between different groups. Our data have confirmed the association between serum homocysteine levels and MTHFR C677T genotype reported in other populations.     

Origin of Amerindian Y-chromosomes as inferred by the analysis of six polymorphic markers

We analysed the frequency of six Y-specific polymorphisms in 105 Amerindian males from seven different populations, 42 Caucasian males, and a small number of males of African, Chinese, and Melanesian origin. The combination of three of the six polymorphisms studied produced four different Y-haplogroups. The haplogroup A (non-variant) was the most frequent one. Eighty-five percent of Amerindians showing haplogroup A have the alphoid II (αhII) and the DYS19A Y-specific markers, an association that is found only in 10% of Caucasians and that has not been detected in Asiatics and Africans. Haplogroups C (YAP+) and D (YAP+ plus an A → G transition in the locus DYS271) are of African origin. Four percent of Amerindians and ∼12% of Caucasians showed haplogroup C; ∼1% of Amerindians and ∼2% of Caucasians had haplogroup D. Haplogroup B is characterized by a C → T transition in nucleotide position 373 of the SRY gene domain; this haplogroup is found in Caucasians (∼12%) and Amerindians (∼4%). None of the Amerindians exhibiting the haplogroups B, C, or D show the haplotype αhII/DYS19A. By haplotyping the Alu insert and the DNA region surrounding the insert in YAP+ individuals, we could demonstrate that Amerindian Y chromosomes bearing African markers (haplogroups C and D) are due to recent genetic admixture. Most non-αhII/DYSl9A Amerindian Y-chromosomes in haplogroup A and most cases in haplogroup B are also due to gene flow. We show that haplotype αhII/DYS19A is in linkage disequilibrium with a C → T transition in the locus DYS199. Our results suggest that most Amerindian Y-chromosomes derive from a single paternal lineage characterized by the αhII/DYS19A/DYS199T Amerindian-specific haplotype. The analysis of a larger sample of native American Y-chromosomes will be required in order to confirm or correct this hypothesis. Am J Phys Anthropol 102:79–89, 1997. © 1997 Wiley-Liss, Inc.     

Analysis of 825C/T polymorphism of G proteinbeta3 subunit in obese/diabetic Japanese

The GNB3 825C/T polymorphism, which is common worldwide, is associated with enhanced G-protein activation. The frequency of 825-T allele was increased with body mass index (BMI) and finally had a high frequency in relatively mild obese (BMI >27 kg/m(2)) subjects in some populations. In the present study, we investigated 208 severely obese [BMI >or=30 kg/m(2) (97th percentile)] Japanese subjects including 146 probands with diabetes. No increase in the 825-T allele frequency was observed in the 208 severely obese and even in a subgroup of the 55 most obese [BMI >or=35 kg/m(2) (99.7th percentile)] subjects compared with that in 150 controls (BMI <25 kg/m(2)) (0.48 and 0.48 vs 0.51, respectively). Also, the frequency was not increased in the 146 obese subjects with diabetes (0.48). We concluded that the 825-T allele is not associated with obesity or diabetes associated with obesity at least in the Japanese population.     

Association of the UCP polymorphisms with susceptibility to obesity: case–control study and meta-analysis

This paper describes a case–control study and a meta-analysis performed to evaluate if the following polymorphisms are associated with presence of obesity: ?3826A/G (UCP1); ?866G/A, Ala55Val and Ins/Del (UCP2) and ?55C/T (UCP3). The case–control study enrolled 282 obese and 483 non-obese patients with type 2 diabetes. A literature search was made to identify all studies that evaluated associations between UCP1–3 polymorphisms and obesity. In the case–control study the distributions of the UCP variants did not differ between obese and non-obese groups (P > 0.05). Forty-seven studies were eligible for the meta-analysis and the results showed that the UCP2 ?866G/A and UCP3 ?55C/T polymorphisms were associated with protection to obesity in Europeans (OR = 0.89, 95 % CI 0.82–0.97 and OR = 0.88, 95 % CI 0.80–0.97, respectively). The UCP2 Ala55 val polymorphism was associated with obesity in Asians (OR = 1.61, 95 % CI 1.13–2.30). The UCP2 Ins/Del polymorphism was associated with obesity mainly in Europeans (OR = 1.19, 95 % CI 1.00–1.42). There was no significant association of the UCP1 ?3826A/G polymorphism with obesity. In our case–control study we were not able to demonstrate any association between UCP polymorphisms and obesity in T2DM patients; however, in the meta-analysis we detected a significant association of UCP2 ?866G/A, Ins/Del, Ala55Val and UCP3 ?55C/T polymorphisms with obesity.     

Impact of the <Emphasis Type="Italic">PPAR gamma-2</Emphasis> gene polymorphisms on the metabolic state of postmenopausal women

The relationship Pro12Ala (rs1801282) and C1431T (rs3856806) polymorphisms of PPAR gamma-2 with glucose and lipid metabolism is not clear after menopause. We investigated the impact of the Pro12Ala and C1431T silent substitution in the 6th exon in PPAR gamma-2 gene on nutritional and metabolic status in 271 postmenopausal women (122 lean and 149 obese). The general linear model (GLM) approach to the two-way analysis of variance (ANOVA) was used to infer the interactions between the analysed genotypes. The frequency of the Pro-T haplotype was higher in obese than in lean women (p<0.0349). In the analysed GLM models according to obesity status, the C1431C genotype was related to a lower glucose concentration (β=?0.2103) in lean women, and to higher folliculotropic hormone FSH levels (β=0.1985) and lower waist circumferences (β=?0.1511) in obese women. The influence of C1431C was present regardless of the occurrence of the Pro12Ala polymorphism. The co-existence of the C1431C and Pro12Pro genotypes was related to lower values for triceps skinfold thickness compared those for the T1241/X and Ala12/X polymorphisms (β=?0.1425). The presence of C1431C decreased the differences between triceps values that were determined by Pro or Ala allele. In conclusion, C1431T polymorphism seems to have a more essential influence on anthropometric and biochemical parameters than is the case with Pro12Ala polymorphism.