影响线粒体功能的遗传变异为肾脏疾病提供了更多的见解。

Genetic variants affecting mitochondrial function provide further insights for kidney disease.

机构信息

Molecular Epidemiology and Public Health Research Group, Centre for Public Health,, Queen's University Belfast, Institute for Clinical Sciences A, Royal Victoria Hospital, Belfast, BT12 6BA, UK.

Genomic Oncology Area, Centre for Genomics and Oncological Research: Pfizer, GENYO, University of Granada-Andalusian Regional Government, PTS Granada. Avenida de La Ilustración 114, 18016, Granada, Spain.

出版信息

BMC Genomics. 2024 Jun 10;25(1):576. doi: 10.1186/s12864-024-10449-1.

DOI:10.1186/s12864-024-10449-1

PMID:38858654

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11163707/

Abstract

BACKGROUND

Chronic kidney disease (CKD) is a complex disorder that has become a high prevalence global health problem, with diabetes being its predominant pathophysiologic driver. Autosomal genetic variation only explains some of the predisposition to kidney disease. Variations in the mitochondrial genome (mtDNA) and nuclear-encoded mitochondrial genes (NEMG) are implicated in susceptibility to kidney disease and CKD progression, but they have not been thoroughly explored. Our aim was to investigate the association of variation in both mtDNA and NEMG with CKD (and related traits), with a particular focus on diabetes.

METHODS

We used the UK Biobank (UKB) and UK-ROI, an independent collection of individuals with type 1 diabetes mellitus (T1DM) patients.

RESULTS

Fourteen mitochondrial variants were associated with estimated glomerular filtration rate (eGFR) in UKB. Mitochondrial variants and haplogroups U, H and J were associated with eGFR and serum variables. Mitochondrial haplogroup H was associated with all the serum variables regardless of the presence of diabetes. Mitochondrial haplogroup X was associated with end-stage kidney disease (ESKD) in UKB. We confirmed the influence of several known NEMG on kidney disease and function and found novel associations for SLC39A13, CFL1, ACP2 or ATP5G1 with serum variables and kidney damage, and for SLC4A1, NUP210 and MYH14 with ESKD. The G allele of TBC1D32-rs113987180 was associated with higher risk of ESKD in patients with diabetes (OR:9.879; CI:4.440-21.980; P = 2.0E-08). In UK-ROI, AGXT2-rs71615838 and SURF1-rs183853102 were associated with diabetic nephropathies, and TFB1M-rs869120 with eGFR.

CONCLUSIONS

We identified novel variants both in mtDNA and NEMG which may explain some of the missing heritability for CKD and kidney phenotypes. We confirmed the role of MT-ND5 and mitochondrial haplogroup H on renal disease (serum variables), and identified the MT-ND5-rs41535848G variant, along with mitochondrial haplogroup X, associated with higher risk of ESKD. Despite most of the associations were independent of diabetes, we also showed potential roles for NEMG in T1DM.

摘要

背景

慢性肾脏病（CKD）是一种复杂的疾病，已成为全球高发的健康问题，其主要的病理生理驱动因素是糖尿病。常染色体遗传变异只能解释部分肾脏疾病的易感性。线粒体基因组（mtDNA）和核编码线粒体基因（NEMG）的变异与肾脏疾病和 CKD 进展的易感性有关，但尚未得到充分研究。我们的目的是研究 mtDNA 和 NEMG 变异与 CKD（及其相关特征）的关联，特别关注糖尿病。

方法

我们使用了英国生物银行（UKB）和英国-爱尔兰（UKB-ROI），这是一组独立的 1 型糖尿病（T1DM）患者。

结果

在 UKB 中，有 14 个线粒体变体与估计肾小球滤过率（eGFR）相关。线粒体变体和单倍群 U、H 和 J 与 eGFR 和血清变量相关。线粒体单倍群 H 与所有的血清变量相关，无论是否存在糖尿病。线粒体单倍群 X 与 UKB 的终末期肾病（ESKD）相关。我们证实了几个已知的 NEMG 对肾脏疾病和功能的影响，并发现了 SLC39A13、CFL1、ACP2 或 ATP5G1 与血清变量和肾脏损伤的新关联，以及 SLC4A1、NUP210 和 MYH14 与 ESKD 的新关联。TBC1D32-rs113987180 的 G 等位基因与糖尿病患者的 ESKD 风险增加相关（OR：9.879；95%CI：4.440-21.980；P=2.0E-08）。在 UK-ROI 中，AGXT2-rs71615838 和 SURF1-rs183853102 与糖尿病肾病相关，TFB1M-rs869120 与 eGFR 相关。

结论

我们发现了 mtDNA 和 NEMG 中的新变体，这些变体可能解释了 CKD 和肾脏表型的一些遗传缺失。我们证实了 MT-ND5 和线粒体单倍群 H 对肾脏疾病（血清变量）的作用，并确定了 MT-ND5-rs41535848G 变体以及线粒体单倍群 X 与 ESKD 风险增加相关。尽管大多数关联独立于糖尿病，但我们还发现了 NEMG 在 T1DM 中的潜在作用。