Lipolysis and gestational diabetes mellitus onset: a case-cohort genome-wide association study in Chinese

Abstract

Background 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. Methods 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. Results 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). Conclusions 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.

Identification of Tregs-Related Genes with Molecular Patterns in Patients with Systemic Sclerosis Related to ILD

“…In addition to its preference for short carbon chain substrates [ 30 ], Shirli et al reported that the LIPN gene encoding epidermal lipase N has been linked to congenital ichthyosis with a late-onset form associated with autosomal-recessive inheritance [ 31 ]. In another paper, gestational diabetes mellitus was associated with lipolysis-related genes such as LIPN [ 32 ]. However, there are few studies on LIPN in autoimmune diseases, especially SSc with ILD.…”

Genetics and epigenetics of gestational diabetes mellitus

“…При использовании полногеномного поиска ассоциаций (GWAS) варианты генов проверяются на наличие какой-либо связи с признаком или с заболеванием по всему геному непредвзятым образом, без гипотез. На сегодняшний день выполнено четыре GWAS для ГСД [29][30][31][32][33].…”

“…Исследования показывают, что мелатонин стимулирует секрецию глюкагона и инсулина в α-и β-клетках поджелудочной железы [34]. Метаболические и другие эффекты мелатонина опосредованы связыванием с трансмембранными рецепторами, связанными с G-белком, MT 1 и МТ 2 , последний из которых кодируется MTNR1B [33]. Варианты гена MTNR1B связаны не только с СД2, но и с изменениями важных маркеров метаболизма, включая глюкозу натощак, гликированный гемоглобин, раннюю секрецию инсулина в ответ на введение глюкозы, и скорость снижения секреции инсулина [34].…”

Genetics and Epigenetics: Implications for the Life Course of Gestational Diabetes

“…The first four loci are also associated with T2DM, while, as described in more detail below, HKDC1 was previously associated with maternal glycemia during pregnancy [ 49 ]. A final, recent GWAS performed in a Chinese population that included 193 women with GDM and 819 controls failed to identify any SNPs significantly associated with GDM [ 50 ]. Fourteen regions that contained copy number variants (CNVs) were significantly associated with GDM, but none of these were in genetic regions previously associated with GDM.…”