6p21.31

FAAR,NR1C2,NUC1,NUCI,NUCII,PPARB

Colorectal cancer

PPARdelta is overexpressed in human colon cancers and genetic disruption of the gene in mice was shown to significantly reduce the incidence of colorectal cancer by reducing expression of vascular endothelial growth factor. Additionally, Wnt/beta-catenin has been shown to stimulate PPAR delta expression. Activation of the COX-2 pathway resulting in the production of prostaglandin E2 activated PPAR delta via the PI3K-Akt pathway. PPAR delta can also cross talk with other transcription factors such as nuclear factor kappa B. PPAR delta is highly expressed in the gastrointestinal tract in a constitutive manner where it regulates cell proliferation and differentiation. In mouse it has been shown that mouse PPAR delta has both ligand dependent and independent effects and ligand independent effects are involved in down regulation of inflammation whereas the ligand dependent effects include proliferation and differentiation. Contradicting results support that PPARdelta can induce or alleviate the disease progression.

Insulin resistance

Single nucleotide polymorphisms (SNPs) in the PPAR delta gene are associated with insulin resistance and increased fat storage due to an interference in mitochondrial functions. After having genotyped 156 patients for the reference SNPs (rs) who are in the risk group for type 2 diabetes, they were shown to carry the SNPs rs1053049, rs6902123, and rs2267668 (A:A, A:G, A:G respectively) in the PPAR delta gene.
Another study indicated that a (-87 T/C) polymorphism affects both plasma glucose levels in the fasting state, insulin sensitivity and cholesterol metabolism. Carriers with the C allele displayed increased plasma glucose levels and decreased insulin sensitivity with respect to the T allele carrying counterparts. Higher titer of low density lipoprotein was also observed in the C allele carriers. It was also concluded that higher levels of fasting plasma glucose levels were independent from the etiology of being diabetic or glucose tolerant. In both cases, insulin sensitivity was disrupted.

Obesity

Catabolism of fats has been shown to be regulated by PPAR delta which could thus be exploited as a potential target for the treatment of obesity and type-2 diabetes. Of the nine polymorphic markers sequenced in the PPAR delta gene four polymorphisms were found in the intronic regions, one in an untranslated region and four in the 3 untranslated region (UTR). The polymorphisms were -13454G>T, c.-87T>C, c.2022+12G>A, c.2629T>C, and c.2806C>G. The same polymorphisms, however, were not significantly associated with the risk for Type 2 diabetes. However in terms of fasting plasma glucose levels and body mass index, the findings were found to be associated with obesity.

Atherosclerosis

As lipid metabolism is involved in atherogenesis, the effects PPARdelta expression in atherosclerotic changes in macrophages were investigated. It has been shown that use of PPAR delta agonists reduces atherosclerosis in apoE double negative mice. The mechanism has been shown to be through elevation of high density lipoprotein level and suppression of inflammation possibly by the down regulation of chemokines which then results in a decrease in the chemoattractant signaling. PPARdelta activation is also associated with the increased expression of G-protein signaling genes which has been shown to block the chemokine receptors.