# Human blood cell traits and sporadic lymphangioleiomyomatosis: results from mediation joint multi-omics and eQTL Mendelian randomization analysis

## TL;DR

This study explores how blood cell traits might genetically influence the risk of a rare lung disease called sporadic lymphangioleiomyomatosis using advanced genetic analysis methods.

## Contribution

The study is the first to use mediation and multi-omics Mendelian randomization with sc-eQTL data to investigate blood cell traits in sLAM pathogenesis.

## Key findings

- Higher basophil count is genetically linked to increased sLAM risk.
- Transitional B cells mediate 36% of the effect of basophil count on sLAM.
- 12 genes across immune cell types are suggested to have causal relationships with sLAM via basophil regulation.

## Abstract

To investigate the genetic causality between Human blood cell (HBC) traits and sporadic lymphangioleiomyomatosis (sLAM) by mediation joint multi-omics and eQTL Mendelian randomization analysis.

Quality control processes were followed to select eligible instrumental variables strongly associated with 35 kinds of HBC traits. Independent cohort of European ancestry with sLAM and lung function genome-wide association study (GWAS) summary statistics were used separately. We utilized a two-step MR approach to explore potential mediators and evaluate the proportion of effect mediated in the associations linking HBC trait candidates to sLAM. Finally MR analysis integrating single cell expression quantitative trait loci (sc-eQTL) from 14 immune cell types with GWAS of sLAM was conducted.

Increased level of basophil count was positively associated with higher risk of sLAM (BASO#; OR = 3.878, 95%CI:1.137–13.221, P = 0.030). No evidences of horizontal pleiotropy were observed. The multivariable MR still demonstrated that BASO# was genetically associated with the risk of sLAM after adjustment for other blood traits in the same category(OR = 5.918, 95% CI:1.275–27.468 P = 0.023) and estradiol (OR = 3.814, 95% CI:1.130-12.874, P = 0.031) respectively. No evidence for associations between basophil traits (BASO# and basophil percentage of white cells: BASO%) and lung functions containing forced vital capacity (FVC) and forced expiratory volume in 1 s/forced vital capacity(FEV1/FVC). The estimated degree of transitional B cell absolute count mediated the effect of BASO# on sLAM by 36%, while no mediating factors, including immune cells, inflammatory proteins, VEGF-related proteins were found. We identified 12 genes in 14 immune cell types that may have a putative causal relationship with sLAM by mediating through the regulation of BASO#, such as EGFL8, PAX8, KANSL1-AS and L3MBTL3. L3MBTL3 was implicated across several immune cell types.

For the first time, this study leverages mediation analysis and multi-omics MR integrated with sc-eQTL data to elucidate the roles of HBC traits, immune cells, inflammatory proteins, VEGF-related proteins and immune cell-specific genes in the pathogenesis of sLAM among the European populations.

The online version contains supplementary material available at 10.1186/s13023-026-04224-6.