The acidic glycoprotein chromogranin A (CHGA) is co-stored/co-secreted with catecholamines and crucial for secretory vesicle biogenesis in neuronal/neuroendocrine cells. CHGA is dysregulated in several cardiovascular diseases, but the underlying mechanisms are not well established. Here, we sought to identify common polymorphisms in the CHGA promoter and to explore the mechanistic basis of their plausible contribution to regulating CHGA protein levels in circulation. Resequencing of the CHGA promoter in an Indian population (n=769) yielded nine single-nucleotide polymorphisms (SNPs): G-1106A, A-1018T, T-1014C, T-988G,G-513A,G-462A, T-415C, C-89A, and C-57T. Linkage disequilibrium (LD) analysis indicated strong LD among SNPs at the -1014, -988, -462, and -89 bp positions and between the -1018 and -57 bp positions. Haplotype analysis predicted five major promoter haplotypes that displayed differential promoter activities in neuronal cells; specifically, haplotype 2 (containing variant T alleles at -1018 and -57 bp) exhibited the highest promoter activity. Systematic computational and experimental analyses revealed that transcription factor c-Rel has a role in activating the CHGA promoter haplotype 2 under basal and pathophysiological conditions(viz. inflammation and hypoxia). Consistent with the higher in vitro CHGA promoter activity of haplotype 2, individuals carrying this haplotype had higher plasma CHGA levels,plasma glucose levels, diastolic blood pressure, and body mass index. In conclusion, these results suggest a functional role of the CHGA promoter haplotype 2 (occurring in a large proportionof the world population) in enhancing CHGA expression in haplotype 2 carriers who may be at higher risk for cardiovascular/metabolic disorders.
Bibliographical noteFunding Information:
This work was supported in part by Grant BT/PR9546/MED/12/349/2007 from the Department of Biotechnology and Grant SR/SO/HS-084/2013A from the Science and Engineering Research Board, Government of India. The authors declare that they have no conflicts of interest with the contents of this article.
This article contains supplemental Figs. S1–S5, Tables S1–S8, and “Experi-mental procedures.” 1Supported by fellowships from the Ministry of Human Resource Develop-ment, Department of Biotechnology and Department of Science & Tech-nology, Government of India.
2Supported by a fellowship from the Ministry of Human Resource Develop-ment, Government of India.
3 Supported by a fellowship from the University Grants Commission, Govern-ment of India. Present address: Dept. of Medicine, University of California, San Francisco, CA.
4 Supported by a fellowship from Council of Scientific and Industrial Research, Government of India.
5Supported by fellowships from the Council of Scientific and Industrial Research, and Defence Research and Development Organization, Govern-ment of India. Present address: Dept. of Integrative Biology and Physiol-ogy, University of Minnesota, MN.