Background. The peroxisome proliferatoractivated receptor-γ co-activator 1-α (PPARGC1A), a key transcription factor involved in the control of metabolism and energy homeostasis, is an important biological and positional candidate of the metabolic syndrome. Association studies of its polymorphisms, however, yielded inconsistent sometimes conflicting results, pointing to important ethnic differences, which call for replication in various populations. Objective. In order to study its most common-potentially functional-polymorphism Gly482Ser (rs8192678), we carried out a case-control study in a central Romanian population. Material and methods. Two hundred and ninety six patients affected by the metabolic syndrome diagnosed according to the International Diabetes Federation proposed criteria and 166 middle-aged control subjects have been investigated. Genotyping was done by PCR-RFLP, using the restriction enzyme MspI. Results. While the G(Gly)/A(Ser) allele frequencies (66.89/33.11 vs. 71.68/28.31 %) and GG/GA/AA genotype distribution (45.27-43.24-11.48 vs. 54.21-34.93-10.84 %) differed in the metabolic syndrome and control group, the risk of developing the metabolic syndrome did not reach the limit of statistical significance (OR=1.43; p=0.06, CI 95%: 0.97-2.09). Metabolic parameters in the two study groups did not show significant differences according to the genotype (p>0.05). Conclusion. rs8192678 could be a functional polymorphism contributing to the development of the metabolic syndrome, but probably its effect is minor, and might depend on gene-gene and gene-environment interactions. Clarification of very small effects would require larger sample sizes.
Objective: Methylene-tetrahydrofolate reductase (MTHFR) is involved in adapting metabolism to environmental challenges by various mechanisms, including the control of gene expression by epigenetic and post-translational changes of transcription factors. Though a metabolic syndrome candidate gene, association studies of its common polymorphism rs1801133 (MTHFR-Ala222Val) remain inconclusive with important ethnic differences, and the effect on disease progression was not addressed. Methods: 307 middle-aged metabolic syndrome patients in a central Romanian hospital setting were investigated metabolically, and genotyped by PCR-RFLP. Disease progression was assessed by the age of onset of metabolic components, as well as development of non-alcoholic fatty liver disease and atherosclerotic complications. Results: The minor allele frequency of rs1801133 was 30.13%. Metabolic parameters showed no statistically significant differences according to genotype, but variant carriers developed dysglycemia and dyslipidemia earlier (53.28±10.8 vs 59.44±9.31 years, p<0.05 and 58.57±11.31 vs 64.72±10.6 years, p<0.1).While the polymorphism did not influence hepatic complications, an inverse association was found for manifest atherosclerosis (OR=0.49, p=0.006, 95%CI:0.29-0.81), which may be folate-status dependent, and needs further investigations. Simultaneous analysis with transcription factor polymorphisms (rs1801282, rs8192678) showed that the more protective genotypes were present the later metabolic disturbances developed, and in the presence of the other two variants the apparent protective cardiovascular effect disappeared. Conclusions: The common functional polymorphism rs1801133 may influence metabolic syndrome progression, the age of onset of components and development of atherosclerotic complications. Besides simple additive effects, complex mitigating and aggravating variant interactions may exist, and the protective or predisposing outcome may depend on modifiable environmental factors.
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