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Background <p>Observational studies have shown a strong association between markers of iron status and gestational diabetes mellitus (GDM). This includes the association of increased levels of serum ferritin with GDM, and a lower incidence of GDM in pregnant women with anemia. However, randomized controlled trials of iron supplementation did not show conclusive evidence for the association of GDM with iron status, and evidence from observational studies is limited by confounders.</p> Objective <p>Our objective was to analyze the causal association of haemoglobin, serum ferritin, serum iron, total iron binding capacity, transferrin saturation, and liver iron with GDM through Mendelian Randomization to overcome the confounding factors generally seen in observational studies.</p> Methods <p>For the exposure variables, significantly and strongly associated genetic variants are selected from GWAS summary data of the European population from the blood cell consortium for haemoglobin, GWAS summary data of pre-menopausal women of Iceland, UK and Denmark from Bell et.al for serum iron markers, and GWAS summary data of European ancestry participants of UK-Biobank from Liu et. al for MRI derived liver iron levels. Wald’s ratios for the selected genetic variants were calculated as a ratio of association of the variants with gestational diabetes mellitus using GWAS summary data from the FinnGen cohort to the association of variants with the exposure variables. Inverse-variance weighted means (IVWM) of Wald’s ratios were used as the main analysis of Mendelian Randomization (MR). Other analyses with different assumptions were performed as sensitivity analysis.</p> Results <p>Main MR analysis and sensitivity analysis consistently showed the absence of causal effects of haemoglobin (IVWM = 0.96 (0.8 - 1.14), <i>p</i> =0.6), serum iron (IVWM= 0.99 (0.87 - 1.12), <i>p</i> =0.9), total iron binding capacity (IVWM = 1.01 (0.94 - 1.08), <i>p</i> =0.8), transferrin saturation (IVWM = 0.95 (0.78 - 1.17), <i>p</i> =0.7), ferritin (IVWM = 0.96 (0.81 - 1.14), <i>p</i> =0.7) and liver iron (IVWM = 0.97 (0.87 - 1.08), <i>p</i> =0.6) levels with gestational diabetes mellitus.</p> Conclusion <p>There is no causal relationship between iron parameters and gestational diabetes mellitus. It is unlikely that iron supplementation will increase the risk of gestational diabetes mellitus.</p>

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Genetic evidence against causal effects of haemoglobin and iron parameters on the risk of gestational diabetes mellitus: A two-sample Mendelian randomization study

  • 期刊论文

  • 发表日期：

    2025年7月12日

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  • Padmanaban Venkatesan,
  • Monica Peter,
  • Joe Varghese

摘要

Background

Observational studies have shown a strong association between markers of iron status and gestational diabetes mellitus (GDM). This includes the association of increased levels of serum ferritin with GDM, and a lower incidence of GDM in pregnant women with anemia. However, randomized controlled trials of iron supplementation did not show conclusive evidence for the association of GDM with iron status, and evidence from observational studies is limited by confounders.

Objective

Our objective was to analyze the causal association of haemoglobin, serum ferritin, serum iron, total iron binding capacity, transferrin saturation, and liver iron with GDM through Mendelian Randomization to overcome the confounding factors generally seen in observational studies.

Methods

For the exposure variables, significantly and strongly associated genetic variants are selected from GWAS summary data of the European population from the blood cell consortium for haemoglobin, GWAS summary data of pre-menopausal women of Iceland, UK and Denmark from Bell et.al for serum iron markers, and GWAS summary data of European ancestry participants of UK-Biobank from Liu et. al for MRI derived liver iron levels. Wald’s ratios for the selected genetic variants were calculated as a ratio of association of the variants with gestational diabetes mellitus using GWAS summary data from the FinnGen cohort to the association of variants with the exposure variables. Inverse-variance weighted means (IVWM) of Wald’s ratios were used as the main analysis of Mendelian Randomization (MR). Other analyses with different assumptions were performed as sensitivity analysis.

Results

Main MR analysis and sensitivity analysis consistently showed the absence of causal effects of haemoglobin (IVWM = 0.96 (0.8 - 1.14), p =0.6), serum iron (IVWM= 0.99 (0.87 - 1.12), p =0.9), total iron binding capacity (IVWM = 1.01 (0.94 - 1.08), p =0.8), transferrin saturation (IVWM = 0.95 (0.78 - 1.17), p =0.7), ferritin (IVWM = 0.96 (0.81 - 1.14), p =0.7) and liver iron (IVWM = 0.97 (0.87 - 1.08), p =0.6) levels with gestational diabetes mellitus.

Conclusion

There is no causal relationship between iron parameters and gestational diabetes mellitus. It is unlikely that iron supplementation will increase the risk of gestational diabetes mellitus.