Causal relationship between peripheral immune cell phenotypes and recurrent miscarriage: a two-way Mendelian...

Recurrent miscarriage is a multifactorial condition, with immune dysregulation proposed as a potential contributing factor. This study investigates the causal relationship between immune cell phenotypes and miscarriage risk using Mendelian randomization (MR).

We performed a two-sample MR analysis using genome-wide association study (GWAS) summary statistics from publicly available datasets. The exposure data for immune cell phenotypes were obtained from the ebi-a-GCST90001599 dataset in the IEU GWAS database, which included over 3,000 individuals of predominantly European ancestry from multiple cohorts within the UK Biobank. The outcome data for miscarriage risk were sourced from the UKB-B-419 dataset in the MRC-IEU GWAS database, which analysed the number of spontaneous miscarriages in 78,700 individuals of predominantly European ancestry from the United Kingdom. The primary MR analysis was conducted using inverse-variance weighted (IVW) regression, complemented by Wald ratio and MR-Egger regression methods to assess robustness. MR-PRESSO was used to test for pleiotropy, while sensitivity analyses evaluated instrument validity and heterogeneity.

MR-Egger regression did not provide statistically significant evidence for a causal association between immune cell phenotypes and miscarriage risk. However, IVW and Wald ratio analyses identified statistically significant associations between specific immune cell profiles and miscarriage risk. A higher proportion of HLA DR+ CD4+ and CD8+ T cells was associated with an increased risk of miscarriage (p < 0.005), while a higher absolute lymphocyte count was linked to a decreased risk (p = 0.011). Additionally, elevated levels of TCRgd T cells and FSC-A on CD4+ T cells were potentially protective against miscarriage (p < 0.01). Conversely, lower proportions of granulocytes and FSC-A on myeloid dendritic cells were associated with an increased miscarriage risk (p < 0.05). MR-PRESSO detected significant pleiotropy (global test p < 0.001), suggesting that some genetic variants may influence other traits, potentially biasing the initial MR estimates.

Our findings suggest a complex interplay between immune cell composition and miscarriage risk, providing new insights into the immunological mechanisms contributing to pregnancy loss. These results highlight the need for further research to confirm these associations and explore potential therapeutic targets for immune-related pregnancy complications.