Whole-exome and whole-genome sequencing of 1064 individuals with type 1 diabetes reveals novel genes for diabetic kidney disease.

IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Diabetologia Pub Date : 2024-11-01 Epub Date: 2024-08-06 DOI:10.1007/s00125-024-06241-1
Jani K Haukka, Anni A Antikainen, Erkka Valo, Anna Syreeni, Emma H Dahlström, Bridget M Lin, Nora Franceschini, Andrzej S Krolewski, Valma Harjutsalo, Per-Henrik Groop, Niina Sandholm
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引用次数: 0

Abstract

Aims/hypothesis: Diabetic kidney disease (DKD) is a severe diabetic complication that affects one third of individuals with type 1 diabetes. Although several genes and common variants have been shown to be associated with DKD, much of the predicted inheritance remains unexplained. Here, we performed next-generation sequencing to assess whether low-frequency variants, extending to a minor allele frequency (MAF) ≤10% (single or aggregated) contribute to the missing heritability in DKD.

Methods: We performed whole-exome sequencing (WES) of 498 individuals and whole-genome sequencing (WGS) of 599 individuals with type 1 diabetes. After quality control, next-generation sequencing data were available for a total of 1064 individuals, of whom 541 had developed either severe albuminuria or end-stage kidney disease, and 523 had retained normal albumin excretion despite a long duration of type 1 diabetes. Single-variant and gene-aggregate tests for protein-altering variants (PAV) and protein-truncating variants (PTV) were performed separately for WES and WGS data and combined in a meta-analysis. We also performed genome-wide aggregate analyses on genomic windows (sliding window), promoters and enhancers using the WGS dataset.

Results: In the single-variant meta-analysis, no variant reached genome-wide significance, but a suggestively associated common THAP7 rs369250 variant (p=1.50 × 10-5, MAF=49%) was replicated in the FinnGen general population genome-wide association study (GWAS) data for chronic kidney disease and DKD phenotypes. The gene-aggregate meta-analysis provided suggestive evidence (p<4.0 × 10-4) at four genes for DKD, of which NAT16 (MAFPAV≤10%) and LTA (also known as TNFβ, MAFPAV≤5%) are replicated in the FinnGen general population GWAS data. The LTA rs2229092 C allele was associated with significantly lower TNFR1, TNFR2 and TNFR3 serum levels in a subset of FinnDiane participants. Of the intergenic regions suggestively associated with DKD, the enhancer on chromosome 18q12.3 (p=3.94 × 10-5, MAFvariants≤5%) showed interaction with the METTL4 gene; the lead variant was replicated, and predicted to alter binding of the MafB transcription factor.

Conclusions/interpretation: Our sequencing-based meta-analysis revealed multiple genes, variants and regulatory regions that were suggestively associated with DKD. However, as no variant or gene reached genome-wide significance, further studies are needed to validate the findings.

Abstract Image

对 1064 名 1 型糖尿病患者进行全外显子组和全基因组测序,发现了糖尿病肾病的新基因。
目的/假设:糖尿病肾病(DKD)是一种严重的糖尿病并发症,影响着三分之一的 1 型糖尿病患者。尽管有多个基因和常见变异被证明与 DKD 相关,但大部分预测的遗传仍未得到解释。在此,我们进行了下一代测序,以评估小等位基因频率(MAF)≤10%(单个或聚集)的低频变异是否导致了 DKD 遗传性的缺失:我们对498名1型糖尿病患者进行了全外显子组测序(WES),对599名1型糖尿病患者进行了全基因组测序(WGS)。经过质量控制后,共有 1064 人获得了新一代测序数据,其中 541 人出现了严重的白蛋白尿或终末期肾病,523 人尽管 1 型糖尿病持续时间较长,但白蛋白排泄仍保持正常。我们对 WES 和 WGS 数据分别进行了蛋白质改变变体(PAV)和蛋白质截断变体(PTV)的单变体和基因组检测,并在荟萃分析中进行了合并。我们还使用 WGS 数据集对基因组窗口(滑动窗口)、启动子和增强子进行了全基因组汇总分析:在单变异荟萃分析中,没有变异达到全基因组显著性,但在FinnGen普通人群慢性肾病和DKD表型全基因组关联研究(GWAS)数据中复制了一个提示性相关的常见THAP7 rs369250变异(p=1.50 × 10-5,MAF=49%)。基因聚集荟萃分析为 DKD 的四个基因提供了提示性证据(p-4),其中 NAT16(MAFPAV≤10%)和 LTA(又称 TNFβ,MAFPAV≤5%)在芬兰基因组普通人群全基因组关联研究数据中得到了复制。在 FinnDiane 参与者的一个子集中,LTA rs2229092 C 等位基因与 TNFR1、TNFR2 和 TNFR3 血清水平的显著降低有关。在提示与DKD相关的基因间区域中,染色体18q12.3上的增强子(p=3.94 × 10-5,MAFvariants≤5%)显示与METTL4基因相互作用;主导变异被复制,并被预测会改变MafB转录因子的结合:我们基于测序的荟萃分析揭示了与DKD有提示性关联的多个基因、变体和调控区域。然而,由于没有变异或基因达到全基因组的显著性,因此需要进一步的研究来验证这些发现。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Diabetologia
Diabetologia 医学-内分泌学与代谢
CiteScore
18.10
自引率
2.40%
发文量
193
审稿时长
1 months
期刊介绍: Diabetologia, the authoritative journal dedicated to diabetes research, holds high visibility through society membership, libraries, and social media. As the official journal of the European Association for the Study of Diabetes, it is ranked in the top quartile of the 2019 JCR Impact Factors in the Endocrinology & Metabolism category. The journal boasts dedicated and expert editorial teams committed to supporting authors throughout the peer review process.
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