Abstract
BackgroundThe energy homeostasis-associated gene (ENHO), retinoid X receptor alpha gene (RXRA), and liver X receptor alpha gene (LXRA) are involved in adipogenic/lipogenic regulation. We investigated whether single-nucleotide polymorphisms in these genes (ENHO rs2281997, rs72735260; RXRA rs749759, rs10776909, rs10881578; LXRA rs2279238, rs7120118, rs11039155) are associated with dyslipidaemia, related comorbidities and survival of haemodialysis (HD) patients also tested for T-helper (Th) cell interleukin genes (IL).MethodsThe study was carried out in 873 HD patients. Dyslipidaemia was diagnosed by the recommendations of the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines (2003); atherogenic dyslipidaemia was referred to if the TG/HDL cholesterol ratio was equal to or higher than 3.8. Genotyping of ENHO SNPs, LXRA SNPs, and IL12A rs568408 was carried out using HRM analysis. RXRA SNPs, IL12B rs3212227, and IL18 rs360719 were genotyped using PCR-RFLP analysis. The circulating adropin concentration was determined in 126 patients by enzyme-linked immunosorbent assay. Survival probability was analysed using the Kaplan-Meier method in 440 patients followed through 7.5 years.ResultsDyslipidaemia by K/DOQI was diagnosed in 459 patients (91% revealed hyper-LDL- cholesterolaemia), atherogenic dyslipidaemia was diagnosed in 454 patients, and 231 patients were free of dyslipidaemia by both criteria. The variant allele (T) of ENHO rs2281997 was associated with the hyper-LDL cholesterolaemic pattern of dyslipidaemia by K/DOQI. The frequency of atherogenic dyslipidaemia was lower in T-allele bearers than in CC-genotype patients. The rs2281997 T allele was associated with lower cardiovascular mortality in HD patients showing atherogenic dyslipidaemia. ENHO, RXRA, and LXRA showed epistatic interactions in dyslipidaemia. Circulating adropin was lower in atherogenic dyslipidaemia than in non-atherogenic conditions. RXRA rs10776909 was associated with myocardial infarction. Bearers of LXRA rs2279238, rs7120118 or rs11039155 minor alleles showed higher mortality. ENHO SNP positions fell within the same DNase 1 hypersensitivity site expressed in the Th1 cell line. Epistatic interactions occurred between rs2281997 and Th1 IL SNPs (rs360719, rs568408).ConclusionsAtherogenic dyslipidaemia occurs in HD patients in whom ENHO encodes less adropin. ENHO, RXRA, and LXRA SNPs, separately or jointly, are associated with dyslipidaemia, myocardial infarction, and survival in HD patients. Differences in the availability of transcription binding sites may contribute to these associations.
Highlights
The energy homeostasis-associated gene (ENHO), retinoid X receptor alpha gene (RXRA), and liver X receptor alpha gene (LXRA) are involved in adipogenic/lipogenic regulation
Due to complex human genetic associations, in which many genes may be associated with the phenotype to some extent, we evaluated the reproducibility of genetic associations for candidate loci using the Better Associations for Disease and GEnes (BADGE) system [47] and compared the results using the Bonferroni corrected P-value of 0.0004 obtained for 8 tested single-nucleotide polymorphisms (SNPs), 5 phenotypes (2 types of dyslipidaemia, Coronary artery disease (CAD), myocardial infarction, diabetic nephropathy), and 3 models of inheritance
The results are shown in the supplementary material (Additional file 1: Tables S4 and S5 for ENHO SNPs; Additional file 1: Table S6 – S8 for RXRA SNPs; Additional file 1: Table S9 – S11 for LXRA SNPs)
Summary
The energy homeostasis-associated gene (ENHO), retinoid X receptor alpha gene (RXRA), and liver X receptor alpha gene (LXRA) are involved in adipogenic/lipogenic regulation. In 1990, atherogenic dyslipidaemia was defined as a serum lipid profile comprising the higher proportion of small dense LDL particles (LDL phenotype B), reduced HDL cholesterol, and increased TG [1]. The TG/ HDL cholesterol ratio ≥ 3.8 ( referred to as the atherogenic index) was found to be reliable to identify LDL phenotype B in men and women [2] and became a marker of atherogenic dyslipidaemia closely associated with the measures of adiposity [3], cardio-metabolic risk [4], and even mortality risk [5]. Hypertriglyceridaemia and reduced HDL cholesterol plasma levels are the most commonly observed lipid abnormalities among end-stage renal disease (ESRD) patients, including haemodialysis (HD) subjects. The plasma levels of total and LDL cholesterol are generally normal among HD patients; the proportion of small dense LDL particles is increased [13]. The TG/HDL cholesterol ratio is used in HD patients as an indicator of atherogenic dyslipidaemia, and its values in the highest quintiles were prognostic for mortality in the incident and prevalent HD patients [15, 16]
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