Abstract
As a marker for glomerular filtration, plasma cystatin C level is used to evaluate kidney function. To decipher genetic factors that control the plasma cystatin C level, we performed genome-wide association and pathway association studies using United Kingdom Biobank data. One hundred fifteen loci yielded p values less than 1 × 10−100, three genes (clusters) showed the most significant associations, including the CST8-CST9 cluster on chromosome 20, the SH2B3-ATXN2 gene region on chromosome 12, and the SHROOM3-CCDC158 gene region on chromosome 4. In pathway association studies, forty significant pathways had FDR (false discovery rate) and or FWER (family-wise error rate) ≤ 0.001: spermatogenesis, leukocyte trans-endothelial migration, cell adhesion, glycoprotein, membrane lipid, steroid metabolic process, and insulin signaling pathways were among the most significant pathways that associated with the plasma cystatin C levels. We also performed Genome-wide association studies for eGFR, top associated genes were largely overlapped with those for cystatin C.
Highlights
Chronic kidney disease (CKD) is a global public health problem with high morbidity (Coresh et al, 2003; Eckardt et al, 2013), which prevalence increases disproportionately with age (Coresh et al, 2007; Zhang et al, 2008; Stevens et al, 2010; Arora et al, 2013), and requires kidney dialysis or kidney transplantation to maintain life in the late stage (Levey et al, 2007; Jha et al, 2013)
Many SNPs which significantly related to cystatin C overlapped with other renal functional phenotypes, including eGFR and creatinine (Figure 2)
No association was found for other renal function related phenotypes for CST cluster SNPs
Summary
Chronic kidney disease (CKD) is a global public health problem with high morbidity (Coresh et al, 2003; Eckardt et al, 2013), which prevalence increases disproportionately with age (Coresh et al, 2007; Zhang et al, 2008; Stevens et al, 2010; Arora et al, 2013), and requires kidney dialysis or kidney transplantation to maintain life in the late stage (Levey et al, 2007; Jha et al, 2013). In addition to lifestyle and environmental factors, genetic factors play an important role in the progression of kidney disease (Kottgen et al, 2009). Mutation analysis has a high predictive value for monogenetic kidney diseases, finding genetic susceptibility variants for CKD by linkage mapping or candidate gene approaches has proven to be difficult (Hildebrandt, 2010). Cystatin C can inhibit the activity of extracellular cathepsins and participate in cardiovascular diseases (CVD), such as stroke, heart failure, coronary heart disease, and other
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