胰高血糖素样肽-1受体和δ-肌聚糖基因变异可影响接受血液透析的慢性肾病患者的心血管风险。

Glucagon-like peptide-1 receptor and sarcoglycan delta genetic variants can affect cardiovascular risk in chronic kidney disease patients under hemodialysis.

作者信息

Terranegra Annalisa, Arcidiacono Teresa, Macrina Lorenza, Brasacchio Caterina, Pivari Francesca, Mingione Alessandra, Tomei Sara, Mezzavilla Massimo, Silcock Lee, Cozzolino Mario, Palmieri Nicola, Conte Ferruccio, Sirtori Marcella, Rubinacci Alessandro, Soldati Laura, Vezzoli Giuseppe

机构信息

Research Branch, Sidra Medicine Hospital, Doha, Qatar.

Nephrology and Dialysis Unit, IRCCS San Raffaele Scientific Institute, Vita Salute University, Milan, Italy.

出版信息

Clin Kidney J. 2020 Feb 5;13(4):666-673. doi: 10.1093/ckj/sfz182. eCollection 2020 Aug.

DOI:10.1093/ckj/sfz182

PMID:32905248

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7467592/

Abstract

BACKGROUND

Chronic kidney disease (CKD) patients under hemodialysis show a higher risk of cardiovascular (CV) mortality and morbidity than the general population. This study aims to identify genetic markers that could explain the increased CV risk in hemodialysis.

METHODS

A total of 245 CKD patients under hemodialysis were recruited and followed up for 5 years to record CV events. Genetic analysis was performed using single-nucleotide polymorphisms (SNPs) genotyping by Infinium Expanded Multi-Ethnic Genotyping Array (Illumina, San Diego, CA, USA) comparing patients with and without a history of CV events [161 cardiovascular diseases (CVDs) and 84 no CVDs]. The fixation index (Fst) measure was used to identify the most differentiated SNPs, and gene ontology analysis [Protein Analysis THrough Evolutionary Relationships (PANTHER) and Ingenuity Pathway Analysis (IPA)] was applied to define the biological/pathological roles of the associated SNPs. Partitioning tree analysis interrogated the genotype-phenotype relationship between discovered genetic variants and CV phenotypes. Cox regression analysis measured the effect of these SNPs on new CV events during the follow-up (FU).

RESULTS

Fst analysis identified 3218 SNPs that were significantly different between CVD and no CVD. Gene ontology analysis identified two of these SNPs as involved in cardiovascular disease pathways (Ingenuity Pathway) and heart development (Panther) and belonging to 2 different genes: Glucagon-like peptide-1 receptor () and Sarcoglycan delta (). The phenotype-genotype analysis found a higher percentage of CVD patients carrying the rs10305445 allele A (P = 0.03) and lower percentages of CVD patients carrying the rs145292439 allele A (P = 0.038). Moreover, rs145292439 was associated with higher levels of high-density lipoprotein (P = 0.015). Cox analysis confirmed the increased frequency of CV events during the 5-year FU in patients carrying rs1035445 allele A but it did not show any significant association with rs145292439.

CONCLUSIONS

This study identified rs10305445 and rs145292439 as potential genetic markers that may explain the higher risk of CVD in hemodialysis patients.

摘要

背景

接受血液透析的慢性肾脏病（CKD）患者心血管（CV）死亡和发病风险高于普通人群。本研究旨在确定可解释血液透析中CV风险增加的遗传标记物。

方法

共招募245例接受血液透析的CKD患者，并随访5年以记录CV事件。使用Infinium扩展多民族基因分型阵列（Illumina，美国加利福尼亚州圣地亚哥）通过单核苷酸多态性（SNP）基因分型进行遗传分析，比较有和没有CV事件病史的患者[161例心血管疾病（CVD）患者和84例无CVD患者]。固定指数（Fst）测量用于识别差异最大的SNP，基因本体分析[通过进化关系进行蛋白质分析（PANTHER）和 Ingenuity 通路分析（IPA）]用于确定相关SNP的生物学/病理作用。分区树分析探讨了发现的遗传变异与CV表型之间的基因型-表型关系。Cox回归分析测量了这些SNP对随访（FU）期间新CV事件的影响。

结果

Fst分析确定了3218个在CVD患者和无CVD患者之间存在显著差异的SNP。基因本体分析确定其中两个SNP参与心血管疾病通路（Ingenuity通路）和心脏发育（Panther），且属于2个不同基因：胰高血糖素样肽-1受体（）和δ-肌聚糖（）。表型-基因型分析发现携带rs10305445等位基因A的CVD患者比例较高（P = 0.03），而携带rs145292439等位基因A的CVD患者比例较低（P = 0.038）。此外，rs145292439与高密度脂蛋白水平较高相关（P = 0.015）。Cox分析证实携带rs1035445等位基因A的患者在5年随访期间CV事件发生率增加，但未显示与rs145292439有任何显著关联。