Genetic Variants Associated with Chronic Kidney Disease in a Spanish Population

Abstract

Chronic kidney disease (CKD) patients have many affected physiological pathways. Variations in the genes regulating these pathways might affect the incidence and predisposition to this disease. A total of 722 Spanish adults, including 548 patients and 174 controls, were genotyped to better understand the effects of genetic risk loci on the susceptibility to CKD. We analyzed 38 single nucleotide polymorphisms (SNPs) in candidate genes associated with the inflammatory response (interleukins IL-1A, IL-4, IL-6, IL-10, TNF-α, ICAM-1), fibrogenesis (TGFB1), homocysteine synthesis (MTHFR), DNA repair (OGG1, MUTYH, XRCC1, ERCC2, ERCC4), renin-angiotensin-aldosterone system (CYP11B2, AGT), phase-II metabolism (GSTP1, GSTO1, GSTO2), antioxidant capacity (SOD1, SOD2, CAT, GPX1, GPX3, GPX4), and some other genes previously reported to be associated with CKD (GLO1, SLC7A9, SHROOM3, UMOD, VEGFA, MGP, KL). The results showed associations of GPX1, GSTO1, GSTO2, UMOD, and MGP with CKD. Additionally, associations with CKD related pathologies, such as hypertension (GPX4, CYP11B2, ERCC4), cardiovascular disease, diabetes and cancer predisposition (ERCC2) were also observed. Different genes showed association with biochemical parameters characteristic for CKD, such as creatinine (GPX1, GSTO1, GSTO2, KL, MGP), glomerular filtration rate (GPX1, GSTO1, KL, ICAM-1, MGP), hemoglobin (ERCC2, SHROOM3), resistance index erythropoietin (SOD2, VEGFA, MTHFR, KL), albumin (SOD1, GSTO2, ERCC2, SOD2), phosphorus (IL-4, ERCC4 SOD1, GPX4, GPX1), parathyroid hormone (IL-1A, IL-6, SHROOM3, UMOD, ICAM-1), C-reactive protein (SOD2, TGFB1,GSTP1, XRCC1), and ferritin (SOD2, GSTP1, SLC7A9, GPX4). To our knowledge, this is the second comprehensive study carried out in Spanish patients linking genetic polymorphisms and CKD.Chronic kidney disease (CKD) is becoming a major public health problem worldwide. CKD is defined as a progressive loss of renal function, measured by a decline in glomerular filtration rate (GFR < 60 mL/min/1.73 m 2 ) 1 , which is typically associated with irreversible pathological changes within the kidney. This pathology has a complicated interrelationship with other diseases 2,3 . Diabetes (DM) and hypertension (HT) are the primary risk factors for CKD 4 , and CKD is also associated with cardiovascular morbidity and mortality 5,6 , even in early stages and in young patients 7 .CKD patients are also characterized by a high genomic instability [8][9][10][11] . This instability could be translated to high levels of genetic damage measured by the incidence of chromosomal damage (micronuclei) when their cells are challenged with ionizing radiation 12 and could be either the cause or the consequence of renal pathologies. In addition, it has been observed that CKD patients repair less efficiently DNA damage 13 .CKD patients present increased levels of C-reactive protein (CRP), which is indicative of an inflammatory status 12,14,15 . Oxidative stress is also a characteristic usually shown by CKD patients [16][17][18][19] . Variants in genes reg...

Advances in understanding the innate immune‐associated diabetic kidney disease

“…In a recent genome-wide association study (GWAS), the genotyping of 722 Spanish adults identified the single nucleotide variants of IL-1A (rs17561), IL-4 (rs2070874), IL-6 (rs1800797), and ICAM-1 (rs5498) genes that showed association with biochemical parameters of DKD, that is, glomerular filtration rate, phosphorus, and parathyroid hormone. 80 The same variant of IL-4 and IL-6 genes were also associated with kidney function in the Japanese population. 81 In addition, GWAS variants in some other inflammation regulatory genes such as engulfment and cell motility protein 1 (ELMO1), TGF-β, TNF-α, CCR5, IL-1β, IL-8, IL-10, IL-18, MMP9, and TNF receptor-associated factor 6 are linked with the pathogenesis of DKD, 82,83 and some of these variants differ across populations.…”

Common genetic variants and pathways in diabetes and associated complications and vulnerability of populations with different ethnic origins

“…For example, diabetes associated risk alleles have been reported in genes that regulate pancreatic beta cell development and function, insulin gene expression, secretion and action 15 – 18 . Many SNPs have also been associated with hypertension 19 , inflammation 20 , chronic kidney disease 21 , cardiovascular disease 22 , diabetic retino- 23 and nephropathies 24 . Prevalence of diabetes associated complications varies among different ethnic groups 25 – 27 .…”

MUTYH: Not just polyposis

“…Chronic kidney disease: A recent study of a Spanish population, including 548 patients and 174 controls, aimed to identify 38 SNPs from 31 candidate genes associated with chronic kidney disease (CKD) and other related diseases, such as hypertension, diabetes and inflammation[ 152 ]. CKD shows a progressive and irreversible loss of renal function and is associated with high genomic instability and the presence of positive markers of inflammation.…”

“…CKD shows a progressive and irreversible loss of renal function and is associated with high genomic instability and the presence of positive markers of inflammation. Of the examined variants in BER genes, the genetic change MUTYH c.1014G > C, p.Gln338His (also known as c.972G > C, p.Gln324His), rs3219489, was not associated with CKD[ 152 ]. In contrast, an association between MUTYH rs3219489 and genomic instability was revealed by a recent study on polymorphisms in genes of BER, nucleotide excision repair, phase II metabolism, and antioxidant enzymes in 415 CKD patients and 174 controls[ 153 ].…”