Department of Epidemiology, School of Public Health, Fudan University, Shanghai, 200032, China.
Key Laboratory for Health Technology Assessment, National Commission of Health and Family Planning, Fudan University, Shanghai, 200032, China.
J Transl Med. 2023 Jan 25;21(1):47. doi: 10.1186/s12967-023-03902-4.
Genetic knowledge of gestational diabetes mellitus (GDM) in Chinese women is quite limited. This study aimed to identify the risk factors and mechanism of GDM at the genetic level in a Chinese population.
We conducted a genome-wide association study (GWAS) based on single nucleotide polymorphism (SNP) array genotyping (ASA-CHIA Bead chip, Illumina) and a case-cohort study design. Variants including SNPs, copy number variants (CNVs), and insertions-deletions (InDels) were called from genotyping data. A total of 2232 pregnant women were enrolled in their first/second trimester between February 2018 and December 2020 from Anqing Municipal Hospital in Anhui Province, China. The GWAS included 193 GDM patients and 819 subjects without a diabetes diagnosis, and risk ratios (RRs) and their 95% confidence intervals (CIs) were estimated by a regression-based method conditional on the population structure. The calling and quality control of genotyping data were performed following published guidelines. CNVs were merged into CNV regions (CNVR) to simplify analyses. To interpret the GWAS results, gene mapping and overexpression analyses (ORAs) were further performed to prioritize the candidate genes and related biological mechanisms.
We identified 14 CNVRs (false discovery rate corrected P values < 0.05) and two suggestively significant SNPs (P value < 0.00001) associated with GDM, and a total of 19 candidate genes were mapped. Ten genes were significantly enriched in gene sets related to lipase (triglyceride lipase and lipoprotein lipase) activity (LIPF, LIPK, LIPN, and LIPJ genes), oxidoreductase activity (TPH1 and TPH2 genes), and cellular components beta-catenin destruction complex (APC and GSK3B genes), Wnt signalosome (APC and GSK3B genes), and lateral element in the Gene Ontology resource (BRCA1 and SYCP2 genes) by two ORA methods (adjusted P values < 0.05).
Genes related to lipolysis, redox reaction, and proliferation of islet β-cells are associated with GDM in Chinese women. Energy metabolism, particularly lipolysis, may play an important role in GDM aetiology and pathology, which needs further molecular studies to verify.
中国女性对妊娠糖尿病（GDM）的遗传知识相当有限。本研究旨在从遗传水平上确定中国人群中 GDM 的风险因素和机制。
我们进行了一项基于单核苷酸多态性（SNP）阵列基因分型（ASA-CHIA Bead 芯片，Illumina）的全基因组关联研究（GWAS）和病例-对照研究设计。从基因分型数据中调用变体，包括 SNPs、拷贝数变异（CNVs）和插入缺失（InDels）。2018 年 2 月至 2020 年 12 月，共有 2232 名孕妇在中国安徽省安庆市医院进行了第一/二孕期检查。GWAS 纳入了 193 例 GDM 患者和 819 例无糖尿病诊断的患者，采用基于回归的方法，在人群结构条件下估计风险比（RR）及其 95%置信区间（CI）。按照已发表的指南对基因分型数据进行了调用和质量控制。将 CNVs 合并为 CNV 区域（CNVR）以简化分析。为了解释 GWAS 结果，进一步进行了基因映射和过表达分析（ORAs），以确定候选基因及其相关的生物学机制。
我们确定了 14 个 CNVR（错误发现率校正后 P 值 < 0.05）和两个提示性显著 SNP（P 值 < 0.00001）与 GDM 相关，共映射到 19 个候选基因。10 个基因在与脂肪酶（甘油三酯脂肪酶和脂蛋白脂肪酶）活性（LIPF、LIPK、LIPN 和 LIPJ 基因）、氧化还原酶活性（TPH1 和 TPH2 基因）和细胞成分 β-连环蛋白破坏复合物（APC 和 GSK3B 基因）、Wnt 信号体（APC 和 GSK3B 基因）和基因本体资源中的侧元件（BRCA1 和 SYCP2 基因）相关的基因集显著富集，这两个 ORAs 方法（调整后 P 值 < 0.05）。
与脂肪分解、氧化还原反应和胰岛β细胞增殖相关的基因与中国女性的 GDM 有关。能量代谢，特别是脂肪分解，可能在 GDM 的发病机制和病理生理学中发挥重要作用，这需要进一步的分子研究来验证。
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