Identification of common heme-coordinating polymorphisms in human intracellular and secreted proteomes

Heme (Iron II-Protoporphyrin IX) is the pigment of life among all organisms and as a prosthetic group in hemoproteins contributes to vital multifunctional processes. In plasma, free heme is scavenged by hemopexin, albumin and several other heme-binding proteins (HeBPs). Based on our earlier identification of human intracellular HeBPs with putative heme-binding motifs (HBMs) that exhibit pathology-associated encoded genetic variations, we expanded our efforts to cover hundreds of additional catalogued intracellular and secreted-extracellular species aiming to identify HeBPs carrying common polymorphisms (≥5% MAF-Minor Allele Frequency) in central heme-coordinating residue positions of HBMs. Using the UniProt protein database, the HeMoQuest-WESA engine, as well as the NCBI dbSNP and ClinVar databases, we manually screened 2,915 unique UniProt reviewed entries and identified 808 with polymorphisms in central heme-coordinating positions. Among those, 44 proteins of diverse protein class ontologies exhibited common polymorphisms, while in terms of global distribution profiling among the four major world groups, 7 variants that are common among EUR (European) and SAS (South Asian) populations, show sharp declines (C8G: rs17613, CFH: rs1061170, NODAL: rs1904589, RAET1E: rs2151910 and WFDC5: rs17422688) or diminishment (CYP4F11: rs8104361, TMPRSS11E: rs2603188) in AFR (African) and/or EAS (East Asian) populations. Such downregulation could reflect possible immune and metabolic adaptations, and highlight the contributions of heme as an epigenetic regulator in protein-protein interactions of diverse molecular processes.