Peroxisome Proliferator-Activated Receptor Delta Polymorphisms - Essay Example

Peroxisome proliferator-activated receptorδ polymorphism are associated with physical performance and plasma lipids: the HERITAGE Family study. Summary: 1) Introduction and background of study Peroxisome Proliferator-Activated Receptors (PPARs) are nuclear receptor presents on nuclear membrane and based on signaling from cytoplasm it modulates expression of various gene. There are three different types of PPPARs, characterized till date. which includes PPARα, PPARγ, and PPARδ. These three different forms are present in different tissues and have different cellular role. PPARα have well established role in lipid metabolism and fatty acid oxidation while PPARγ have role in lipid storage, adipocyte differentiation or growth and insulin sensitivity. PPARδ is predominantly found in skeletal muscle and its activation was clearly correlated with fatty acid oxidation. In conclusion all these three different type of PPARs plays crucial role in lipid metabolism. Mice studies pertaining to investigation of role of PPARδ have been shown to accumulate this protein in skeletal muscles in case of exhaustive physical exercise. Similarly mice injected with activated PPARδ increases the formation of type 1 muscle fibers and thus improve running capacity of mice to almost double. Further more it was also observed that injection with this protein makes mice more resistance to high fat diet induced obesity and glucose intolerance. These observations have indicated role of PPARδ in physical fitness and its indirect role in obesity. In another sets of observation PPARδ shown to play role in cholesterol metabolism and use of anti PPARδ substance leads to increase in blood cholesterol in form of high density lipoprotein (HDL-C). To understand its role in human, Scientist have identified four different variant of PPARδ in human population (four polymorphic gene). These variation is arises due to alteration or variation in DNA sequence of this gene. One of these variations was found on exon 4 where 15th nucleotide of sequence gets change from T (thymine) to C (cytosine). The transition or alteration in sequence from T to C leads development of rare allele C which is responsible for higher LDL (low density lipoprotein) in blood and thus increases the risk of coronary diseases in that particular human. The effect of C allele will be more profound in case of person having both copy of gene as C (Homozygous for C or C/C) compared to C/T (Heterozygous having one copy of gene as T and One copy of gene as C) while the person having both copy of T allele are least prone to coronary diseases (T/T homozygous). Risk associated with cardio vascular diseases and diabetes are closely associated with life style and routine exercise but it also depend on genetic make up of an individual and thus two person doing similar exercise and performing similar life style demonstrate different response against cardiac health. Based on this observations and established role of PPARδ in lipid and cholesterol metabolism author have tried to investigate role of polymorphic PPARδ on exercise capacity and blood lipid level in two different group of individual under going 20 weeks training. They choose two polymorphic group 1) PPARδ exon 4 having transition of C/T at nucleotide 15 (exon 4 +15 C/T). and exon 7 having transition A/G at nucleotide 67th (exon 7 +65 A/G) in HERITAGE family . 2) Subjects : In the given study they have selected 478 white subjects (231 male and 247 female) all from nuclear families and 272 black subjects (89male and 183 female). Subject having age from 17 years to 65 years and those who have cardiovascular disease, diabetic, undergoing treatment for lowering the lipid etc were excluded from the study. Thus sample subject have inclusion of almost all factors like family background, ethnic group, gender age etc. and all are medically healthy. 3) Methodology: 1) Exercise and training program: The intensity of exercise regime was standardized using two parameters Heart rate (HR) and oxygen consumption. Ratio of HR/VO2(oxygen consumption) was taken as baseline parameter. After optimizing various parameters, subjects were given training equivalent to 75% of baseline VO2max for six week 2) VO2max test: two test were performed on before training and after 20wks training and V02 max and Wmax was determined as mention by Shiner et al 3) Body composition: body composition was determined by calculating BMI and fat weight was determined using underwater weighing technique. 4) Plasma lipid determination: Blood samples were drown by vain puncture and cholesterol and triglyceride concentration was determined in baseline and after training period. 5) Genotyping: genotyping for polymorphic PPARδ ( i.e exon 4 C/T and exon 7 A/G). was determined by primer extention methodology using template directed incorporation of florescence polarization detection. 6) Data analysis and statistics: various statistical methods were used for evaluating the data which includes ×2 test for equilibrium testing, QTDT software based correlation between SNP and physical fitness was determined using two variables. 4) Results: Followings are the important outcome of this study. The frequency of exon 4 +15 C and exon 7 +65 G alleles were found to be 0.209 and 0.267 in white subject while in black subject it was found to be 0.280 and 0.515. and there was no significant difference in allele frequency between male and female. Table 1 represents different parameters of baseline.VO2 max and Wmax (maximal oxygen Consumption and maximal Work out put) was found to be unaffected by genotype or polymorphism in PPARδ gene. As shown if figure 1,In both cases of Black and white subjects, exon 4+15 C/C have smaller increase in Vo2 max and Wmax compared to other genotype (fig 1A &B, C &D). While it did not found to be significantly influences the body composition in baseline and training induced. In white subject baseline Apo-A-1 level was found to be higer in case of exon 4 +15 C/C genotype compared to other. while in black, similar genotype have higher HDL-C plasma level but in both the cases other baseline lipid component of blood remains unaffected by genotype. In white subject Homozygous (exon 4 +15C/C and exon7 +65 G/G) shows training induced increase in HDL-C by 3 times and 2.3 times respectively, compared to its corresponding T/T and A/A homozygous (Table 2,4) In case of Black subject similar training induced increase was observed in terms of Apo A-1 level where subject was found to be C/C homozygous.(table 3,5) Merlin software based PPARδ haplotype construction have reveled that. Highest level of training induced increase in HDL-C was observed in case of homozygous C/C for exon 4 irrespective of allele composition of exon 7 (TA/TA or TA/TG). Similarly exon 4 +15 T/T have least increase in plasma HDL-C irrespective of composition of exon 7 +65. (Table 6) In case of heterozygous on exon 4 , HDL-C is highly influence by genotype of exon 7 +65 and its concentration varies with different genotype on exon 7.(Figure 2) In case of black subject, increase in Wmax was clearly correlated with genotype of exon 4 +15 where homozygous C/C have minimum training induced increase in Wmax while T/G haplotype have highest increase in Wmax. (Figure 2) Discussion: The present study have demonstrated correlation between genetic make up in terms of haplotype of gene PPARδ and variation (polymorphism) have distinct impact on training mediated increase in cardiovascular fitness. Similarly it was also shown that, training induced increase in cardiovascular fitness might be smaller ( in terms of work out put Wmax and Vo2 max) but it has profound effect on increase in plasma HDL-C level in white and Apo A-1 in black Thus before predicting the cardiovascular fitness improvement in particular patient and deigning the treatment procedure one should take note of its genetic make up. Conclusion: Present study has significance in terms of uncoupling lipid composition of blood and cardiovascular fitness. It was clearly demonstrated and statistically validated that, genotype of an individual, particularly PPARδ gene have profound effect on training and exercise mediated improvement of cardiovascular fitness irrespective of plasma lipid profile. Read More