Figure 11.

A schematic presentation of the plausible role and mechanistic basis behind the crucial role of CHGA promoter haplotype variants in contributing to cardiometabolic risk. The CHGA promoter Hap2 (comprised of variant alleles at −1018, −415, and −57 bp positions), the second most frequent haplotype in Indian population, has the highest promoter activity among all the haplotypes due to transcriptional activation by c-Rel across −1018T and −57T alleles. The higher promoter activity corroborates with the elevated levels of plasma CHGA observed in Hap2 individuals. Higher plasma levels of CHGA may lead to enhanced processing of CHGA resulting in elevated levels of PST peptide. PST peptide has previously been shown to promote insulin resistance and inflammation leading to elevated blood glucose and BMI. Pro-inflammatory molecules like TNF-α may increase the promoter activity of CHGA Hap2 by activating c-Rel, and thereby confer a higher risk of cardiometabolic disease to Hap2 subjects.