ENOrphanet Journal of Rare Diseases | Genetic Association Between Basophil Count and Sporadic Lymphangioleiomyomatosis
Date: February 21, 2026
Classification: Frontiers
Recommend:
This study, for the first time, reveals the potential causal role of basophil count in sporadic lymphangioleiomyomatosis (sLAM) through multi-omics Mendelian randomization analysis, and identifies regulatory mechanisms of multiple immune cell-specific genes.
Literature Overview
The article titled 'Human blood cell traits and sporadic lymphangioleiomyomatosis: results from mediation joint multi-omics and eQTL Mendelian randomization analysis', published in the journal *Orphanet Journal of Rare Diseases*, systematically reviews and summarizes the use of mediation joint multi-omics and expression quantitative trait loci (eQTL) Mendelian randomization (MR) analysis to investigate the genetic causal relationship between human blood cell (HBC) traits and sporadic lymphangioleiomyomatosis (sLAM). The study evaluates the association between 35 HBC traits and sLAM risk, identifying a significant causal link between elevated basophil count (BASO#) and increased sLAM risk. It further explores the mediating roles of immune cells, inflammatory proteins, and VEGF-related proteins in this pathway. By integrating single-cell eQTL data, the study reveals potential regulatory roles of multiple immune cell-specific genes in sLAM pathogenesis. These findings provide new insights into the immune microenvironment regulation in sLAM and suggest basophils as potential biomarkers or therapeutic targets. Focusing on European populations, this study highlights the value of multi-omics integration in rare disease research. With comprehensive content and rigorous logic, it lays a theoretical foundation for future functional validation and clinical translation.Background Knowledge
Lymphangioleiomyomatosis (LAM) is a multisystem disorder primarily affecting women of reproductive age, characterized by multiple cystic lung lesions leading to progressive dyspnea and declining pulmonary function. LAM is classified into sporadic LAM (sLAM) and tuberous sclerosis complex-associated LAM (TSC-LAM). The pathogenesis of sLAM remains incompletely understood. Although somatic mutations in the TSC2 gene are known in some patients, not all carry such mutations, suggesting involvement of additional factors. Estrogen is believed to play a role in LAM pathogenesis, but its exact mechanism remains unclear. LAM cells exhibit smooth muscle-like features and can infiltrate the lungs, kidneys, and lymphatic system, forming cystic structures and leading to complications such as pneumothorax and chylothorax. Currently, mTOR inhibitors are the primary treatment, but relapse after discontinuation is common, and lung transplantation may eventually be required. Therefore, identifying novel pathogenic mechanisms and therapeutic targets is crucial. In recent years, the role of the immune system in the tumor microenvironment has received increasing attention, particularly the regulatory functions of inflammatory cells such as basophils, B cells, and T cells in tumor progression. Previous studies have shown that basophils promote the development and recurrence of various tumors and are associated with poor prognosis. However, their role in sLAM has not been systematically investigated. Mendelian randomization (MR), a genetic epidemiological method, uses genetic variants as instrumental variables to infer causal relationships between exposure and outcome, effectively avoiding confounding bias and reverse causality in traditional observational studies. MR analysis combined with single-cell eQTL data can further reveal cell type-specific gene regulatory networks, enhancing the accuracy of causal inference. This study leverages this cutting-edge approach to systematically explore the causal relationship and biological mechanisms between blood cell traits and sLAM, filling a research gap and providing important clues for future functional studies and clinical interventions.
Methods and Experiments
The study employs a three-stage Mendelian randomization (MR) analytical framework. Stage one performs a two-sample MR analysis to evaluate the genetic causal relationship between 35 human blood cell (HBC) traits and sLAM, using GWAS summary statistics from European populations. Stage two conducts mediation MR analysis to explore the mediating roles of 91 inflammatory proteins, 731 immune cell phenotypes, and 5 VEGF-related factors in the association between HBC traits and sLAM. Stage three integrates single-cell expression quantitative trait loci (sc-eQTL) data to analyze the upstream regulatory effects of gene expression in 14 immune cell types on sLAM. All analyses follow the STROBE-MR guidelines, using multiple MR methods (e.g., IVW, weighted median, MR-Egger regression) for causal effect estimation, with multiple testing correction (FDR < 0.05). Sensitivity analyses include Cochran’s Q test for heterogeneity, MR-Egger intercept test for horizontal pleiotropy, and leave-one-out analysis to exclude outliers.Key Conclusions and Findings
Research Significance and Outlook
This study is the first to systematically reveal the potential causal role of basophils in sLAM pathogenesis, expanding our understanding of LAM's immune pathological mechanisms. The findings suggest basophils may serve not only as disease biomarkers but also as novel therapeutic targets. The mediating role of transitional B cells highlights that B cell immune tolerance dysregulation may play a key role in the sLAM microenvironment. Furthermore, the identified immune cell-specific genes provide candidate targets for future functional studies, aiding in deciphering cell type-specific regulatory networks in LAM. The multi-omics MR integration strategy offers a methodological paradigm for rare disease research, applicable to other complex diseases.
Despite its significance, the study has limitations. First, the analysis is limited to European populations, lacking data from other ethnic groups, which limits generalizability. Second, due to the rarity of sLAM, the GWAS sample size is small, potentially affecting statistical power. Future studies should validate these findings in larger, more diverse cohorts and perform functional validation using experimental models (e.g., co-culture systems, animal models). Additionally, the precise molecular mechanisms by which basophils regulate transitional B cells and genes like L3MBTL3 remain to be elucidated. Clinically, assessing whether basophil count can be used for early screening or prognosis in sLAM would have significant translational value. In summary, this study provides new insights into the immune mechanisms of sLAM and lays a theoretical foundation for developing novel diagnostic and therapeutic strategies.
Conclusion
By integrating multi-omics data and Mendelian randomization analysis, this study systematically reveals the potential causal role of basophil count in sporadic lymphangioleiomyomatosis (sLAM). The findings show that elevated basophil count significantly increases sLAM risk, and this effect is independent of pulmonary impairment and common confounding factors. Mechanistically, the absolute count of transitional B cells mediates approximately 36% of the effect, suggesting that B cell immune tolerance dysregulation may contribute to disease progression. Further integration of single-cell eQTL data identifies 12 immune cell-specific genes (e.g., L3MBTL3, EGFL8) that may influence sLAM pathogenesis through regulation of basophils, revealing novel upstream regulatory pathways. Additionally, the study finds basophils can affect estradiol levels, but the VEGF pathway is not confirmed as a mediator. These findings not only expand our understanding of the immune microenvironment in sLAM but also provide new insights for early diagnosis and treatment. Although limited to European populations and sample size, this study lays an important foundation for subsequent functional validation and clinical translation, suggesting that targeting basophils and their associated pathways may represent a novel therapeutic direction for sLAM. Future research should validate these findings in diverse populations and explore the biological functions of the identified genes.
