This study shows the association of two polymorphisms in the PAI-1 gene with the development of MetS and its components such as obesity and atherogenic dyslipidemia in a Mexican children population.
Regarding the distribution of genotype and allele frequencies of both polymorphisms, for the HindIII
C/G polymorphism we found a high frequency of C allele, similar to previous reports in Mexican mestizo population and Caucasian population, however the G allele frequency was lower in Mexican population [18
]. On the other hand, the -844 G/A polymorphism we observed that is distributed inversely to those reported in Caucasian populations, in which the A allele is more frequent than the G allele [12
]. In our study this polymorphism had a high frequency of G allele and a lower frequency of A allele, consistent with already reported frequencies in previous studies in Mexican mestizo population [20
], suggesting that in the Mexican population there is a high frequency of allele G.
According to our results, the differences observed in the distribution of -844 G/A polymorphism may be attributed to the racial influence, which is central to the heterogeneous distribution of genetic polymorphisms. It is known that the Mexican population originated from a mixture of European (4.2 to 70.8%) and African (0.9 to 40.5%) populations with Amerindian groups (27.6 to 94.5%), giving origin to the Mexican mestizo population, which has a higher genetic diversity in the distribution of this and other polymorphisms [31
]. This can explain the differences in the distribution of genotypic and allelic frequencies of our population with other populations in the world.
As an important finding, in our study we found significant differences in the distribution of genotype and allele frequencies of -844 G/A polymorphism in both groups, determining an OR of 2.2 for A allele, and an OR of 2.79 for G/A genotype, which indicates that children who carry the A allele are 2.2 fold more susceptible to develop MetS and children who are carriers of the G/A genotype have a 2.79 fold increased risk of developing the syndrome, compared to those who are carriers of G allele and G/G genotype. These results obtained in our study are similar to those reported in a previous study done in Caucasian population in which A/A genotype was associated with the susceptibility of developing MetS (OR, 4.87; p
< 0.001) [12
]. These consistent results reported in different populations may be due to the effect of the polymorphism on the levels of the protein, since it has been reported that the base change of G to A at position -844 of the promoter PAI-1
gene generates a binding site consensus sequence for Ets nuclear protein, which could be involved in regulating gene expression and influencing the increase in PAI-1 plasma protein levels [32
]. While for the HindIII
C/G polymorphism not significant differences were found in genotype and allele distribution, but it has been reported that the base change of C to G at the 3' UTR of PAI-1
gene might plays an important role in the disruption of the translational regulation process and cause changes in the translational levels of messenger ribonucleic acid (mRNA) in both physiological and pathological conditions, resulting in an increase in PAI-1 plasma protein levels [34
We described for first time in Mexican children that -844 G/A polymorphism contribute to a significant increase in subcutaneous fat, increasing the risk of developing obesity (OR, 2.6; p
= 0.01) in children who are carriers of the G/A and A/A genotypes. A possible explanation for this finding could be that the -844 G/A polymorphism contribute to the large amount of PAI-1 produced by adipose tissue expansion, as well as the increase of obesity. Studies of PAI-1
knockout mice have shown an effect of PAI-1 on weight gain and increased adipose cellularity associated with high-fat dieting [35
]. Besides, studies in which the PAI-1
gene was disrupted in ob/ob mice show a reduction of adiposity in these mice. This suggests that PAI-1
gene can control fat mass, although the mechanism of action is not yet known, may be PAI-1
gene can control fat mass at least in part, by inducing the proliferation of adipocytes through the effect on the expression of genes such as tumour necrosis factor alpha (TNF-α) and transforming growth factor beta (TGF-β), leptin and insulin [36
In addition the effect on the increase in adipose tissue, there was an association of G/A and A/A genotypes of -844 G/A polymorphism with increased triglyceride levels and decreased HDL-C levels, which indicates that those children who are carriers of these genotypes, have an increase in the risk to develop atherogenic dyslipidemia compared with genotype G/G. In the case of HindIII
C/G polymorphism, C/G and G/G genotypes were associated with a raise of total cholesterol explaining 8% of the variability of their plasma concentration, influencing along with -844 G/A polymorphism to the development of atherogenic profile that characterizes the MetS. It has been reported that a very-low-density lipoprotein (VLDL)-responsive element in the PAI-1
promoter could be responsible for the effect of plasma lipids on PAI-1 expression [14
]. Therefore, the increase in PAI-1 levels may contribute to the development of obesity and atherogenic dyslipidemia, and PAI-1 may be a causal link between obesity and cardiovascular disease.
The -844 G/A and HindIII
single nucleotide polymorphisms have not been associated with PAI-1 levels. Several adult studies showed that an increase in the level of PAI-1 was related to the genotype PAI-1
4 G/5 G polymorphism [37
]. However, in children some information is available on the influence of the 4 G/5 G polymorphism on PAI-1 levels or with others obesity-related phenotypes. In Children with obesity, Estelles et al. [39
] observed no influence of the 4 G/5 G polymorphism on PAI-1 levels. Moreover, no influence of the PAI-1
4 G/5 G polymorphism on lipid and glucose metabolism parameters was observed in Turkish obese children [40
A limitation of this study is the small number of sample, even though is a sample with children that were recruited with precise selection criteria and the control group did not have any of the components included in the definition of MetS. In addition, few studies of genetic association of PAI-1 gene with MetS have been conducted in children. Other limitation of this study is that lack of replication, the replication of genetic associations in independent populations is essential to reduce the number of false-positive results and to further define the role of these variants in the susceptibility to complex disease as MetS.
Although our study found an association of -844 G/A polymorphism with the MetS and its components such as obesity and a atherogenic dyslipidemia characterized by hypertriglyceridemia and low HDL-cholesterol, and the HindIII C/G polymorphism with increased plasma levels of total cholesterol, other of the limitations is that PAI-1 plasma levels were not measured; therefore the association of -844 G/A and HindIII C/G polymorphisms with PAI-1 levels remains uncertain in our population. Therefore it is necessary to determine PAI-1 plasma levels in future studies in Mexican children.