The kidneys are vital organs that function as filtration systems in humans and other vertebrates. They regulate water, electrolyte, and pH balance by filtering blood, maintaining homeostasis. A significant and permanent decline in kidney function leads to chronic kidney disease (CKD) and kidney failure, which affect 9% of the global population. Kidney function is clinically assessed using serum biomarkers, substances that accumulate in the blood when kidney function decreases and are subsequently cleared by the kidneys. Using multiple biomarkers provides a more accurate representation of loci affecting kidney function. Genome-wide association studies (GWAS) have identified several loci linked to kidney function biomarkers. The human kidney cCREs are genome-wide, with 191,501 open chromatin regions. Heritability plays a major role in kidney function and diseases, with 56% of kidney function heritability localized to kidney tubule epithelial cCREs (candidate cis- regulatory elements) and 7% to kidney podocyte cCREs. The majority of heritable differences in adult kidney function stem from gene expression changes in these two cell types.
Gabriel B. Loeb and his research colleagues conducted an in-depth examination of the elements, variants, cellular structures, and molecular mechanisms that influence kidney function. Their main purpose was to obtain a new insight into these mechanisms and determine which genetic variants impact kidney function, particularly in the aging population. To achieve this, they performed various techniques and studies, demonstrating that numerous kidney function variants have impacts on the epithelial cCRE chromatin accessibility and kidney function.
This study primarily focuses on loci that affect multiple orthogonal biomarkers, thereby influencing kidney function. Creatinine and cystatin C are utilized as biomarkers to identify loci, variants, regulatory elements, cell types, and genes associated with changes in kidney function in aging humans. To detect probable causal variants and their effects on chromatin accessibility, regulatory element function, and gene expression, a GWAS was conducted on 406,504 individuals, identifying 430 loci that influence kidney function in middle-aged adults. Additionally, to define the kidney function loci, eGFR is measured based on both serum creatinine (eGFRcr) or cystatin C (eGFRcys) levels, particularly eGFRcr-cys. A key component of this study is cCREs, open chromatin regions, determined for podocytes, parietal epithelial cells, proximal tubule, loop of Henle, distal tubule, collecting duct intercalated cells, endothelial cells, stromal cells, Tβcells and other immune cells by performing scATACβseq on kidney cortex and medulla. Researchers utilized stratified linkage disequilibrium score regression to determine if the kidney function variants were enriched in cCREs of specific cells. There was no enrichment for kidney function heritability in cCREs associated with endothelial cells, stromal cells, or immune cells. However, cCREs in specific kidney tubule epithelial cells and podocytes were enriched for kidney function heritability. Another benefit of stratified linkage disequilibrium score regression was to clarify which part of the kidney function heritability was localized to kidney tubule epithelial regulatory. It was demonstrated that the variants impact kidney function heritability within kidney tubule epithelial cell cCREs (%56), coding region variants (%10) and podocyte-specific cCREs totaling %73. Additionally, functionally informed fine-mapping was performed on both kidney tubule epithelial cells and podocyte cCREs to define the causal variants. This process, carried out using scATAC-seq data with and without annotations, identified many more variants. Furthermore, CRISPR was used to find the genes that control cCREs and associate the cCREs with kidney function variants and kidney genes.
After performing many methods like GWAS, eGFRcr-cys, scATACβseq, stratified linkage disequilibrium score regression, and cCRE-informed fine-mapping, researchers identified that variants in tubule epithelial cell cCREs impact kidney function heritability. It is now known that especially variants in kidney proximal tubule, distal tubule, and podocyte-specific cCREs are enriched for kidney function heritability. Also, NDRG1, STC1 and CCNB1 genes were described as putative kidney function genes affecting human kidney function, by CRISPR. Furthermore, deductions from the fine-mapping indicate that the enrichment of kidney function variants within tubule epithelial cCREs supports the idea that many kidney function variants affect tubule epithelial regulatory elements. Moreover, kidney function fine-mapped cCRE variants had greater estimated effects on chromatin accessibility than other cCRE variants and affected more developed functions. By examining cCREs, kidney tubule epithelial and podocyte cells were confirmed as impact the main heritable differences in human kidney function.In conclusion, this study shifts the paradigm from merely focusing on kidney diseases to a proactive approach that utilizes genetic variants linked to kidney function biomarkers for accurate diagnosis. Through comprehensive methodologies and analyses, the research elucidates kidney function heritability and the impact of variants in tubule epithelial regulatory elements with remarkable precision. Furthermore, the insights gained extend beyond kidney function, shedding light on other polygenic traits by identifying crucial cell types, variants, and genes. The findings from this investigation hold the potential to pave the way for innovative clinical treatments for various kidney diseases.
Author: Fatma Beyza Εahin
Editor: Elif Duymaz
Reference: Loeb, G. B., Kathail, P., Shuai, R. W., Chung, R., Grona, R. J., Peddada, S., Sevim, V., Federman, S., Mader, K., Chu, A. Y., Davitte, J., Du, J., Gupta, A. R., Ye, C. J., Shafer, S., Przybyla, L., Rapiteanu, R., Ioannidis, N. M., & Reiter, J. F. (n.d.). Variants in tubule epithelial regulatory elements mediate most heritable differences in human kidney function. https://doi.org/10.1038/s41588-024-01904-6
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