Methylation Patterns of Diabetes and Obesity Susceptibility Genes in Gestational Diabetes Mellitus: A Cross-Sectional Analysis from Karachi, Pakistan

<b><i>Background:</i></b> Women with gestational diabetes mellitus (GDM) and their offspring have an increased risk of adverse perinatal and long-term health outcomes, which may be attributable to epigenetic modification of diabetes and obesity susceptibility genes. We aimed to investigate the methylation patterns of eight genes in GDM and normoglycemic (NG) mothers, and their respective offspring. <b><i>Methods:</i></b> This cross-sectional study, conducted at Aga Khan University from August 2019 to December 2022, recruited pregnant women in the first trimester of gestation from the outpatient obstetrics clinic. Participants were classified as NG or GDM based on the Society of Obstetricians and Gynecologists Pakistan. Venous blood samples were collected from mothers and cord blood from neonates. Peripheral blood mononuclear cells were used for DNA extraction and methylation analysis using methylation-specific PCR. Maternal and neonatal clinical data were recorded. Statistical analysis was performed using R, including binary logistic regression to assess the association between various gene methylation levels and GDM. <b><i>Results:</i></b> The study found that GDM mothers had significantly higher fasting blood glucose, 2-hr OGTT, and serum carboxymethyl lysine (CML) levels compared to NG mothers, but no significant differences in neonatal birth weight or serum CML levels. Chemerin methylation was significantly lower in GDM mothers and their babies, while <i>NAMPT, MTNR1B, FNDC5, FAT4</i>, and <i>FTO</i> methylation levels were higher in GDM offspring compared to NG offspring. GDM mothers also had higher methylation levels of brain-derived neurotrophic factor gene (<i>BDNF</i>). Multivariable binary logistic regression identified methylation levels of maternal BDNF and neonatal MTNR1B to be independently associated with GDM. <b><i>Conclusions:</i></b> Our study shows a trend of epigenetic modifications in both GDM mothers and their offspring in various genes related to metabolism and inflammation, suggesting an intergenerational transmission of increased risk of developing metabolic disorders. These findings emphasize the need for high throughput studies, early screening, tight glucose control during pregnancy, and postnatal follow-up to mitigate long-term health risks.