Causal Relationship Between Sex Hormone Binding Globulin and Obstetrical Disorders: A Two-Sample Bidirectional...

Area of Science:

• Reproductive Endocrinology
• Maternal-Fetal Medicine
• Genetic Epidemiology

Background:

• Obstetrical disorders pose significant risks to maternal and fetal well-being.
• Sex hormone-binding globulin (SHBG) influences pregnancy through hormonal, metabolic, and inflammatory pathways.
• The causal role of SHBG in obstetrical disorders requires elucidation.

Purpose of the Study:

• To investigate the causal relationship between genetically predicted Sex hormone-binding globulin (SHBG) levels and 12 obstetrical disorders.
• To determine if higher SHBG levels are associated with a reduced risk of specific pregnancy complications.

Main Methods:

• Mendelian randomization (MR) study utilizing cis-protein quantitative trait loci (cis-pQTLs) for SHBG.
• Analyses performed in FinnGen and UK Biobank (UKBB) datasets, followed by meta-analyses.
• Inverse variance weighting (IVW) as the primary analysis method, with sensitivity analyses for robustness.

Main Results:

• Elevated SHBG levels were associated with significantly reduced risks of gestational diabetes (OR=0.835), hyperemesis gravidarum (OR=0.823), gestational hypertension (OR=0.917), and early-pregnancy hemorrhage (OR=0.853).
• Meta-analysis confirmed a causal role of SHBG in reducing gestational diabetes risk.
• Co-localization analyses identified shared genetic loci for SHBG with gestational diabetes, hyperemesis, early hemorrhage, preterm delivery, and postpartum hemorrhage.

Conclusions:

• Sex hormone-binding globulin (SHBG) causally reduces the risk of multiple obstetrical disorders, including gestational diabetes, hypertension, hyperemesis, miscarriage, and preterm delivery.
• These findings underscore the clinical significance of SHBG in obstetrical pathophysiology.
• Targeting SHBG may offer novel therapeutic strategies for preventing pregnancy complications.