34 PROMISING RISK FACTORS

evidence entity Function Complexity of Clinical Examination eGDM Tags Reference (PMID) KEGG Pathway ID Risk factor name
ADPN Important adipokine involved in the control of fat metabolism and insulin sensitivity, with direct anti-diabetic, anti-atherogenic and anti-inflammatory activities. Stimulates AMPK phosphorylation… Convenient The most promising risk factor 30470912, 15126557, 32747382, 11479627 Adipocytokine signaling pathway, Insulin signaling pathway, AMPK signaling pathway, PPAR signaling pathway, NF-kappa B signaling pathway Adiponectin
ALT Key enzyme reflecting hepatocellular injury;
Indicator of liver function and metabolic health;
Correlated with non-alcoholic fatty liver disease and obesity;
Predictor of drug-… 		Convenient Potential risk factor 38836232, 39462412, 27264612 Alanine, aspartate and glutamate metabolism, Carbon metabolism, 2-Oxocarboxylic acid metabolism, Glycolysis / Gluconeogenesis Alanine Aminotransferase
ANT Primary index for neutrophil-mediated immune defense;
Indicator of bacterial infection risk;
Predictor of neutropenia severity and related complications;
Reflective of bone… 		Convenient Potential risk factor 32332157, 35000498 Neutrophil extracellular trap formation, Th17 cell differentiation, IL-17 signaling pathway, Non-alcoholic fatty liver disease Absolute neutrophil count
BUN Indicator of protein metabolism and renal excretion;
Reflective of kidney function and hydration status;
Correlated with dietary protein intake and catabolic states;
Influenced… 		Convenient Potential risk factor 31925909 Nitrogen metabolism Blood Urea Nitrogen
FABP4 Adipokine involved in fatty acid transport and metabolism;
Associated with insulin resistance and obesity;
Reflective of adipocyte function and lipolysis;
Lipid transport protein… 		Convenient Promising potential risk factor 29016489, 32747382, 34368366, 27147422, 38593305, 18511927, 34880500 PPAR signaling pathway, Adipocytokine signaling pathway Fatty Acid-Binding Protein 4
FPG Glucose homeostasis monitoring；
Diabetes mellitus diagnosis；
Prognostic evaluation in metabolic disorders；
Indicator of hepatic glucose output 		Convenient The most promising risk factor 23193214, 30877716, 20175116 Insulin secretion, Glycolysis / Gluconeogenesis, 2-Oxocarboxylic acid metabolism, Insulin signaling pathway Fasting Plasma Glucose
FT3 Active thyroid hormone regulating metabolic rate;
Influential in energy expenditure and protein synthesis;
Indicator of thyroid function alongside FT4 and TSH;
Essential for… 		Convenient Promising potential risk factor 29889229, 34453541, 39345886, 33486811 Thyroid hormone signaling pathway Free Triiodothyronine
FT3 to FT4 ratio Balance of active thyroid hormones;
Indicator of thyroid gland output and peripheral conversion;
Reflective of metabolic rate and energy homeostasis;
Linked to cardiac function… 		Convenient Promising potential risk factor 29889229, 34453541 Thyroid hormone signaling pathway Free Triiodothyronine to Thyroid Hormone ratio
FT4 Indicator of thyroid hormone production;
Reflective of thyroid gland function and metabolic rate;
Central regulator of energy expenditure and protein synthesis;
Partner with TSH… 		Convenient Potential risk factor 27583471, 33310125, 30935929, 34453541 Thyroid hormone signaling pathway Thyroid Hormone
GGT Cleaves the gamma-glutamyl bond of periplasmic glutathione (gamma-Glu-Cys-Gly), glutathione conjugates, and other gamma-glutamyl compounds. The metabolism of glutathione releases free glutamate and… Convenient Potential risk factor 24795397, 38546139, 30333792, 35021057 Glutathione metabolism, Taurine and hypotaurine metabolism, Arachidonic acid metabolism Gamma-Glutamyl Transferase
HbA1c Long-term glycemic control indicator;
Key measure for diabetes diagnosis and management;
Therapeutic efficacy monitoring tool;
Less influenced by daily glucose fluctuations;… 		Convenient Potential risk factor 25190675, 31794807, 33132213, 24912095, 26351946 African trypanosomiasis, map05144 Hemoglobin A1c
HDL-C Facilitator of reverse cholesterol transport;
Cardioprotective factor against atherosclerosis;
Correlated with metabolic health and insulin sensitivity;
Modifiable by lifestyle… 		Convenient Potential risk factor 38085430, 28436169, 39075387 Cholesterol metabolism, Lipid and atherosclerosis High Density Lipoprotein Cholesterol
HOMA-IR Index of insulin resistance assessment;
Correlates with beta-cell function and glucose metabolism;
Predictive of type 2 diabetes and metabolic syndrome risk;
Reflective of… 		Convenient Potential risk factor 37075929, 26754418, 18382910 Glycolysis / Gluconeogenesis, Insulin resistance, AMPK signaling pathway, Insulin signaling pathway, 2-Oxocarboxylic acid metabolism, PPAR signaling pathway, Type II diabetes mellitus, Non-alcoholic fatty liver disease, Adipocytokine signaling pathway, FoxO signaling pathway, Diabetic cardiomyopathy, Regulation of lipolysis in adipocytes, PI3K-Akt signaling pathway, MAPK signaling pathway Homeostatic Model Assessment for Insulin Resistance
hsa-miR-122-5p A promising avenue for studying the early effect of impaired glucose metabolism on placental development.
Influencing the insulin and AMPK signaling pathways and contributing to the early… 		Complex Potential risk factor 35926094, 31058973 Cholinergic synapse, GABAergic synapse, Dilated cardiomyopathy, Glucagon signaling pathway, Circadian entrainment, HIF-1 signaling pathway, Thyroid cancer, Adherens junction, JAK-STAT signaling pathway, Notch signaling pathway, Carbohydrate digestion and absorption, Calcium signaling pathway, Fat digestion and absorption
hsa-miR-144-3p The MALAT1/hsa-miR-144-3p/IRS1 axis was predicted to be the key axis and was identified as being associated with GDM for the first time. Complex Biology interesting risk factor Cholinergic synapse, GABAergic synapse, Dilated cardiomyopathy, Glucagon signaling pathway, Circadian entrainment, HIF-1 signaling pathway, Adherens junction, JAK-STAT signaling pathway, Notch signaling pathway, Calcium signaling pathway
hsa-miR-20a-5p Controls insulin signaling, may be useful if incorporated into miRNA panels or risk assessment algorithms to identify GDM;
This miRNAs is associated with insulin resistance and abnormal… 		Complex Promising potential risk factor 29556924, 25887942 Cholinergic synapse, GABAergic synapse, Dilated cardiomyopathy, Glucagon signaling pathway, Circadian entrainment, HIF-1 signaling pathway, Thyroid cancer, Adherens junction, JAK-STAT signaling pathway, Notch signaling pathway, Carbohydrate digestion and absorption, Calcium signaling pathway, Fat digestion and absorption
hsa-miR-210-3p Hypoxia-inducible regulator affecting mitochondrial function;
Promotes angiogenesis under low oxygen conditions;
Associated with tumor adaptation to hypoxic stress 		Complex Potential risk factor 28783527, 31058973 Cholinergic synapse, GABAergic synapse, Glucagon signaling pathway, Circadian entrainment, HIF-1 signaling pathway, Adherens junction, JAK-STAT signaling pathway
hsa-miR-320d Serum hsa-miR-320d had differential expressions between healthy controls and T2DM patients. Complex Biology interesting risk factor Cholinergic synapse, GABAergic synapse, Notch signaling pathway
Leptin Central regulator of appetite and satiety;
Key mediator of energy homeostasis and body weight;
Indicator of adipose tissue mass;
Potential link between obesity and inflammation;… 		Convenient Potential risk factor 35985429, 14990416, 31836012, 9732873 Adipocytokine signaling pathway, JAK-STAT signaling pathway, PI3K-Akt signaling pathway, Insulin signaling pathway , Type II diabetes mellitus Leptin
MPV Parameter reflecting platelet size and activity;
Associated with thrombosis risk and platelet reactivity;
Indicator of bone marrow megakaryocyte function;
Influenced by… 		Convenient Potential risk factor 24897392, 32594791 Platelet activation, Complement and coagulation cascades Mean platelet volume
PAPP-A Metalloproteinase which specifically cleaves IGFBP-4 and IGFBP-5, resulting in release of bound IGF. Cleavage of IGFBP-4 is dramatically enhanced by the presence of IGF, whereas cleavage of IGFBP-5… Convenient Potential risk factor 26362726, 39175575, 28323969, 37033400, 36837599, 27155776 MAPK signaling pathway, PI3K-Akt signaling pathway Pregnancy Associated Plasma Protein A
PLT Essential for blood clot formation;
Indicator of thrombopoiesis and hemostatic capacity;
Reflective of bone marrow function and megakaryocyte activity;
Influenced by infections,… 		Convenient Potential risk factor 32594791, 33795771 Platelet activation, Complement and coagulation cascades, AGE-RAGE signaling pathway in diabetic complications Platelet Count
RBP4 Transporter of vitamin A (retinol) in bloodstream;
Linked to insulin resistance and adipose tissue dysfunction;
Reflective of liver function and nutritional status;
Modulator of… 		Convenient Potential risk factor 34537998, 30428456, 23153527, 16034410 Retinol metabolism Retinol-Binding Protein 4
S100A8 RAGE receptor binding；
Toll-like receptor binding；
long-chain fatty acid binding；
fatty acid binding；
monocarboxylic acid binding；
calcium-dependent protein binding 		Complex Potential risk factor 33045922, 31363816, 21738950 IL-17 signaling pathway S100 Calcium Binding Protein A8
S100A9 RAGE receptor binding；
Toll-like receptor binding；
long-chain fatty acid binding；
fatty acid binding；
monocarboxylic acid binding；
calcium-dependent protein binding 		Complex Potential risk factor 23709000, 31448371, 31363816, 21738950 IL-17 signaling pathway S100 Calcium Binding Protein A9
SF Stores iron in a soluble, non-toxic, readily available form. Important for iron homeostasis. Has ferroxidase activity. Iron is taken up in the ferrous form and deposited as ferric hydroxides after… Convenient Potential risk factor 16644640, 37547304, 39523925, 28580448 Ferroptosis, Mineral absorption Serum Ferritin
TG Major energy reservoir;
Cardiovascular risk factor;
Central component of lipoprotein metabolism;
Reflective of dietary and hepatic regulation 		Convenient Potential risk factor 16188575, 34407277, 38085430, 18401346, 36518243 Fatty acid degradation, Insulin signaling pathway, PPAR signaling pathway Triglyceride
TG to HDL-C ratio Combined ratio indicating lipid abnormality;
Reflective of atherogenic dyslipidemia and insulin resistance;
Associated with increased cardiovascular risk;
Useful in diagnosing… 		Convenient Potential risk factor 26981541, 37843770, 38616992 Cholesterol metabolism, Lipid and atherosclerosis High Density Lipoprotein Cholesterol
t-PA Catalyst for fibrinolysis and clot breakdown;
Key regulator of thrombolytic pathways;
Reflective of endothelial function and vascular health;
Associated with thrombosis risk when… 		Convenient Potential risk factor 20876721, 30205647, 10527036, 18235054 Complement and coagulation cascades, Platelet activation Tissue Plasminogen Activator
TyG Marker of insulin resistance;
Correlated with metabolic syndrome and cardiovascular risk;
Derived from fasting TG and glucose levels;
Reflective of ectopic fat accumulation and… 		Convenient Potential risk factor Glycolysis / Gluconeogenesis, Insulin signaling pathway, Insulin resistance Fatty acid metabolism Triglyceride glucose index
Visfatin Critical enzyme in NAD+ biosynthesis;
Modulator of cellular energy homeostasis and metabolism;
Associated with inflammation, aging, and metabolic dysregulation;
Potential… 		Convenient Potential risk factor 21325104, 31836012, 17392604, 17237424 Nicotinate and nicotinamide metabolism, NOD-like receptor signaling pathway Visfatin
Vit B12 Essential cofactor in DNA synthesis and neurological function;
Reflective of dietary intake and absorption in terminal ileum;
Deficiency associated with megaloblastic anemia and… 		Convenient Potential risk factor 33158950, 36501046 One carbon pool by folate , Propanoate metabolism, Vitamin digestion and absorption Vitamin B12
VitE Antioxidant protecting cell membranes from oxidative damage;
Reflective of dietary intake and fat absorption capacity;
Associated with immune function and cardiovascular health;
… 		Convenint Potential risk factor 35458191 Vitamin digestion and absorption Vitamin E
WBC Primary component of immune defense;
Protection against infections and foreign pathogens;
Indicator of inflammation and infection status;
Reflective of stress or immune… 		Convenient Potential risk factor 24612458, 35909297 Leukocyte transendothelial migration, Cytokine-cytokine receptor interaction White Blood Cell Count

Notes:

1) 34 potential risk factors, were identified by manual mapping of multiple molecular pathways, and target relationship.

2) The results were from the enrichment of KEGG mapping, including pathway, function, disease, literatures related to gestational diabetes mellitus and complexity of clinical examination, respectively.

3) These risk factors (RFs) were mined from original studies before the 16th gestational weeks in gestational diabetes mellitus or rigorously identified from high-throughput expression data;

4) The most promising RFs (mpRFs) are related with multiple risk factors in gestational diabetes mellitus, reported as biomarkers for gestational diabetes mellitus in original researches and playing key roles in the progress and prognosis of gestational diabetes mellitus.

And the biologically interesting risk factors (BIRFs) may play different important roles in gestational diabetes mellitus development.