Association of PPARγ2 Pro12Ala polymorphism with gestational diabetes mellitus risk: A systematic review and meta-analysis

Abstract

Gestational diabetes mellitus (GDM) is a prevalent pregnancy complication that poses significant risks to both mothers and their offspring, with genetic susceptibility believed to play a role in its pathogenesis. This study examined the association between the Pro12Ala (Pro [C]→Ala [G]) polymorphism in the peroxisome proliferator-activated receptor γ2 (PPARγ2) gene and the risk of developing GDM. A systematic literature search was conducted across databases including PubMed/Medline, Web of Science, Embase, and the Cochrane Library, identifying clinical studies that evaluated the relationship between the PPARγ2 Pro12Ala variant and GDM. Strict inclusion criteria ensured that all case groups comprised exclusively women diagnosed with GDM. Data on study characteristics, sample sizes, and allele frequencies were extracted, and meta-analyses were performed using RevMan 5.3 and Stata with Hartung-Knapp random-effects models. Fifteen studies were included in the analysis. The Pro12Ala polymorphism showed no significant association with GDM risk across allelic (Ala [G] vs. Pro [C]), dominant (CG+GG vs. CC), and recessive (GG vs. CG+CC) models (allelic: OR=0.90, 95% CI=0.75–1.08, p=0.26; dominant: OR=0.92, 95% CI=0.74–1.13, p=0.42; recessive: OR=0.82, 95% CI=0.54–1.25, p=0.33; all p>0.05). Subgroup analyses by ethnicity indicated a potential protective association of the Ala (G) allele with GDM in East Asian populations, while no significant associations were found in European or Middle Eastern populations; ethnicity was identified as a significant effect modifier (p<0.05). There were no meaningful differences in subgroups categorized by study quality and sample size. Sensitivity analyses confirmed the robustness of the findings, and small-study effects detected by Egger’s test did not substantially alter the pooled estimates. In conclusion, the PPARγ2 Pro12Ala polymorphism was not significantly associated with GDM risk in the general population. The potentially protective trend observed in East Asian women warrants cautious interpretation due to concerns regarding multiple testing, allele-frequency variation, and limited statistical power.