Identification of High-Risk SNPs in SLC22A transporter Genes: Their Potential Role in PCOS and Metformin uptake

Harini Ravindran, Balasundaram Usha, Satish Ramalingam, Pai Akshatha, T. M. Vijaya kumar
2024 · doi:10.21203/rs.3.rs-5201762/v1
preprint OA: closed CC-BY-4.0
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Abstract

Abstract Polycystic ovary syndrome (PCOS) presents as a multifaceted endocrine disorder impacting women of reproductive age. Metformin, a first-line medication for type 2 diabetes, has emerged as a promising therapeutic option for PCOS due to its beneficial effects on insulin resistance, hyperinsulinemia, and ovulation induction. Integral to the pharmacokinetic profile of metformin, the Organic Cation Transporter (OCT) family, encompassing OCT1 ( SLC22A1 ), OCT2 ( SLC22A2 ), and OCT3 ( SLC22A3 ), assumes a pivotal role in mediating the cellular uptake and distribution of this medication. In PCOS, alterations in OCT expression and function contribute to the diversity of metformin response among affected individuals. Numerous single nucleotide polymorphisms (SNPs) within OCT genes have been discovered, potentially affecting the uptake, distribution, and effectiveness of metformin. The human OCT family comprises three members: OCT1 ( SLC22A1 ), OCT2 ( SLC22A2 ), and OCT3 ( SLC22A3 ). In this study, we utilized sequence-based prediction methodologies to identify single nucleotide polymorphisms (SNPs) within SLC22A1, SLC22A2 , and SLC22A3 . Among the SNPs cataloged by the NCBI database, four nonsynonymous SNPs (nsSNPs) in SLC22A1 , three in SLC22A2 , and seven in SLC22A3 were consistently predicted to be highly damaging and deleterious by five in-silico tools (Align GVGD, PolyPhen-2, PANTHER, PROVEAN, and PhD-SNP). These nsSNPs were associated with reduced stability of the SLC22A1-SLC22A3 proteins. Specific mutations, such as L42R and F422S in SLC22A1 , R404C, G373D, and E227A in SLC22A2 , and G259R, R348W, and R407C in SLC22A3 , were identified as highly conserved and exposed, making them significant nsSNPs in our study. The insights gained from these mutations hold the potential to inform large-scale investigations aimed at developing precision medicine approaches for the management of PCOS.

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License: CC-BY-4.0