背景:中国女性对妊娠期糖尿病(GDM)的遗传知识相当有限。本研究旨在从基因水平探讨中国人群GDM的危险因素和发病机制。
方法:我们基于单核苷酸多态性(SNP)阵列基因分型(ASA-CHIABeadchip,Illumina)和病例队列研究设计。包括SNP在内的变体,拷贝数变体(CNVs),从基因分型数据中调用插入-缺失(InDels)。2018年2月至2020年12月,安徽省安庆市立医院共纳入2232名孕妇的孕早期/中期,中国。GWAS包括193名GDM患者和819名没有糖尿病诊断的受试者。和风险比(RR)及其95%置信区间(CI)通过基于回归的方法以人口结构为条件进行估计。基因分型数据的调用和质量控制是按照公布的指南进行的。将CNV合并到CNV区(CNVR)中以简化分析。为了解释GWAS结果,进一步进行基因定位和过表达分析(ORAs),以确定候选基因和相关生物学机制的优先级.
结果:我们确定了14个与GDM相关的CNVR(错误发现率校正P值<0.05)和两个暗示性显著的SNP(P值<0.00001),共定位了19个候选基因。10个基因显著富集了与脂肪酶(甘油三酯脂肪酶和脂蛋白脂肪酶)活性相关的基因集(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),通过两种ORA方法(调整后的P值<0.05)在基因本体资源(BRCA1和SYCP2基因)中的横向元素。
结论:与脂解相关的基因,氧化还原反应,中国女性胰岛β细胞增殖与GDM相关。能量代谢,尤其是脂解,可能在GDM的病因和病理中起重要作用,这需要进一步的分子研究来验证。
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.