Association of Vitamin D Receptor Gene Variants with Diabetic Nephropathy: Scope for Further Exploration Using Epigenetics

This manuscript is in response to the Letter entitled “Investigating the Association of TaqI (rs731236), ApaI (rs7975232) and BsmI (rs1544410) with Diabetic Nephropathy: A Case for Broader Genetic and Epigenetic Research” by Siham.[1] We thank the author for his letter regarding our article on the association of vitamin D receptor (VDR) gene polymorphisms with diabetic nephropathy.[2] We agree with the author’s points on how our work can progress further in terms of exploring the role of VDR in modulating the downstream immune and kidney-related pathways and performing comparative studies across diverse ethnic groups to get a better understanding of the role of VDR in nephropathy. The suggestion to investigate whether epigenetic mechanisms such as deoxyribonucleic acid (DNA) methylation in conjunction with the genetic variants in VDR influence diabetic kidney disease progression is well accepted. Epigenetic study to compare the DNA methylation patterns in individuals with and without diabetic nephropathy is currently ongoing in the lab. Once the work is completed, we will be able to analyze the single nucleotide polymorphism (SNP)–CpG interactions in the VDR gene. Further, we have genotyping data on SNPs located in nine genes (CNDP1, TCF7L2, SLC12A3, ELMO1, AUH, PVT1, LIMK2, RPS12, and SASH1),[3,4] leading to the possibility of analyzing additional genetic and epigenetic interactions. We also appreciate the author’s suggestion to explore haplotype and gene-gene interactions to unravel the genetic effects that single SNP analyses may overlook. With the available genotype data of the three VDR SNPs [TaqI (rs731236), ApaI (rs7975232), and BsmI (rs1544410)], we estimated the linkage disequilibrium between these SNPs and found that the pairwise linkage disequilibrium between any of these SNPs was not high [r2 values in Table 1]. To perform haplotype-based analyses, three locus haplotypes were constructed and analysis was restricted to those haplotypes that have a frequency of at least 0.01 in either cases or controls [Table 2]. None of the haplotypes showed any association with diabetic nephropathy.Table 1: Linkage disequilibrium between the VDR SNPsTable 2: Haplotype frequencies of the VDR SNPs in the study groupsThe suggestion to stratify the participants based on glycemic control, hypertension, and lipid profile to better understand the interaction between vitamin D status and VDR polymorphisms leading to nephropathy will be considered in the future. The current dataset with vitamin D measurements on just 47 type 2 diabetes mellitus (T2D) without nephropathy and 74 T2DM with nephropathy does not allow for a well-powered comparative study. As pointed out by the author, some studies have shown that therapeutic intervention by Vitamin D supplementation may reduce proteinuria and improve glomerular filtration rates in kidney disease patients. Previous studies from our center have also shown the protective role of vitamin D in T2DM and metabolic traits.[5-7] However, whether genetic predisposition will play a role in therapeutic intervention in nephropathy cannot be ascertained from our study[1] as it is under-powered to detect genetic association and lacks sufficient power to detect the differences in the minor allele frequency between T2DM without nephropathy and with nephropathy groups for all three VDR SNPs. Furthermore, studies in larger cohorts are required to detect if these VDR SNPs will impact therapeutic intervention and pave the way for precision medicine. Acknowledgements The work on VDR SNPs was financially supported by the Scientific and Engineering Research Board, Government of India, under the Early Career Research Scheme (ECR/2017/000640/LS) granted to author DB. The ongoing work on epigenetics is funded to author DB by the Indian Council of Medical Research, Government of India, under the investigator-initiated research proposals (IIRP) for small extramural grants (IIRP-2023-4956). Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.