TY  - JOUR
T1  - Potential Genetic Causal Associations of Systemic Lupus Erythematosus with Five Hematologic Disorders in the European-ancestry Population: A Bidirectional Two-sample Mendelian Randomization Study 
AU  - Guo, Tianyang
AU  - Zhou, Hui
AU  - Zhang, Lili
AU  - Chen, Rong
JF  - Exploratory Research and Hypothesis in Medicine
VL  - 11
IS  - 3
SN  - 2472-0712
SP  - e00013
EP  - e00013
Y1  - 2026-07-30
DO  - 10.14218/ERHM.2026.00013
UR  - https://www.xiahepublishing.com/2472-0712/ERHM-2026-00013
AB  - Background and objectives 
Observational studies indicate frequent associations between systemic lupus erythematosus (SLE) and various hematologic disorders, yet causal inferences are limited by confounding and reverse causality. We therefore applied a bidirectional Mendelian randomization (MR) design to assess potential genetic causal associations of SLE with specific hematologic conditions.
Methods
We used European-ancestry GWAS summary statistics for SLE (5,201 cases, 9,066 controls) and five hematologic outcomes (vitamin B12 deficiency anemia (B12DA), myelodysplastic syndrome (MDS), immune thrombocytopenia (ITP), agranulocytosis (AGC), iron deficiency anemia (IDA)) from FinnGen. The primary analysis used inverse-variance weighting, supplemented by MR-Egger and weighted median methods, with comprehensive sensitivity analyses, including heterogeneity tests, pleiotropy assessment, and leave-one-out analysis.
Results
Bidirectional MR analysis revealed that genetically predicted SLE increased the risk of B12DA (odds ratio (OR) = 1.08, P < 0.001), and genetically predicted B12DA was associated with an increased risk of SLE (OR = 2.22, P = 1.6 × 10−29). The MDS → SLE association was nominally significant (P = 0.023) but did not survive Bonferroni correction (P < 0.005) and was inconsistent across MR methods. No significant genetic associations were found between SLE and ITP, AGC, or IDA in either direction (all P > 0.005).
Conclusions
This bidirectional MR study provides genetic evidence that SLE increases the risk of B12DA, whereas the reverse direction (B12DA → SLE) should be interpreted cautiously because it was based on only five instruments and was not supported by the Steiger directionality test. No robust genetic associations were found for ITP, AGC, IDA, or MDS. Clinically, monitoring B12DA in SLE patients may be warranted, although screening recommendations await prospective validation.