In the present study, a two-sample Mendelian Randomization (MR) approach was utilized to evaluate the potential causal linkage between 10 autoimmune diseases and anemia. Although several observational studies have investigated the association between autoimmune diseases and anemia, the underlying causal dynamics remain intricate and elusive. This MR study elucidates, for the first time, a causal relationship between pertinent autoimmune diseases and an elevated risk of anemia.
The association between autoimmune diseases and anemia is progressively corroborated by evidence, potentially bearing significant ramifications for the early appraisal and prevention of anemia's incidence and severity. This may favorably influence the alleviation of anemia's repercussions and potential adverse clinical outcomes. Numerous studies have unequivocally delineated such associations. For instance, a Swedish population study discerned a notable correlation between malignant anemia and the presence of 14 disparate autoimmune diseases (AIDs) within the Swedish populace38. Of 34 patients who underwent esophagogastroduodenoscopy (EGD) or gastrectomy due to malignant anemia, 32 were diagnosed with autoimmune or immunological diseases39. A dual-center, retrospective analysis of 188 patients with malignant anemia disclosed a prevalent association with autoimmune thyroiditis40. A retrospective examination spanning two decades revealed that as many as 29.4% of 34 neonatal lupus erythematosus cases were accompanied by anemia41. Similarly, another retrospective investigation ascertained that the anemia incidence rate soared to 51.24% among 1057 patients afflicted with rheumatoid arthritis42.
The mechanistic association between autoimmune diseases and anemia is mediated through multiple intricate biological processes43. Initially, immune dysregulation can instigate enduring inflammatory responses, known to disrupt iron metabolism and utilization, consequently precipitating anemia. Inflammatory cells and cytokines, namely tumor necrosis factor-αand interferon-γ,may restrain erythropoiesis, thereby contributing to anemia44. Secondly, specific immune disorders such as systemic lupus erythematosus (SLE)4546 may exhibit autoimmunity that directly targets red blood cells or their progenitors, culminating in hemolytic anemias like autoimmune hemolytic anemia (AIHA)47. Within AIHA, autoantibodies mark an individual's red blood cells for enhanced clearance via Fc receptor (FcR)-mediated phagocytosis, underscoring the immunological mediation of hemolytic anemia in autoimmune scenarios48.Thirdly,certain pharmacological interventions for immune disorders may impair bone marrow functionality or precipitate other anemia-inducing side effects. Fourthly, autoimmune reactions can devastate or impair cells within the stomach essential for vitamin B12 absorption, causing pernicious anemia. Lastly, specific forms of immune disorders may induce bone marrow suppression, impacting erythropoiesis. These mechanisms elucidate the complex interplay between autoimmune reactions and anemia, laying a groundwork for further examination in Mendelian randomization discussions.
Our bi-variate Mendelian randomization analysis intimates that Type 1 Diabetes, Multiple Sclerosis, and Rheumatoid Arthritis exert deleterious effects on anemia, with multivariable MR substantiating the detrimental interrelation among Type 1 Diabetes, Multiple Sclerosis, and anemia. These adverse associations may be mediated through mechanisms pertinent to immune responses49, chronic inflammation, and drug interactions. In Type 1 Diabetes, the autoimmune apparatus erroneously targets pancreatic β-cells, a dysregulation similarly manifested in certain anemic conditions50. Multiple Sclerosis, being an immune-mediated malady, may harbor shared immunoregulatory aberrations or pathways with autoimmune responses manifest in anemia51. Type 1 Diabetes may incite chronic inflammation, adversely impacting erythropoiesis and iron metabolism, thereby precipitating anemia. Microvascular complications and renal maladies are prevalent in individuals with Type 1 Diabetes, potentially further impeding erythropoiesis and blood circulation52. Chronic inflammation, a recurrent comorbidity in Multiple Sclerosis and an inherent characteristic of the chronic inflammatory disorder Rheumatoid Arthritis, may detrimentally affect bone marrow function and iron metabolism, exacerbating anemia53. Lastly, pharmaceuticals employed to ameliorate Type 1 Diabetes, Multiple Sclerosis, and Rheumatoid Arthritis may engage in interactions with drugs modulating anemia, consequently altering red blood cell counts.
In framing the Mendelian randomization discourse, an examination of the shared biological and physiological mechanisms, alongside potential genetic and environmental determinants, may elucidate the complexities and intersections among Type 1 diabetes, multiple sclerosis, and rheumatoid arthritis in relation to anemia. This endeavor could unveil novel perspectives and avenues for ensuing clinical research and therapeutic interventions.
In summation, our investigation boasts several merits. Initially, a comprehensive strategy was deployed to ascertain the causal ramifications of 10 autoimmune diseases on anemia susceptibility. In contrast to conventional epidemiological inquiries, the two-sample Mendelian Randomization (MR) approach furnishes a superior tier of evidence for causal associations, given its diminished vulnerability to potential biases and confounders, contingent upon the satisfaction of primary assumptions. Secondly, we procured the most recent Genome-Wide Association Study (GWAS) summary statistics for Type 1 diabetes, multiple sclerosis, and rheumatoid arthritis, in addition to anemia outcomes, to orchestrate the principal multivariable MR analysis, thereby bolstering the credibility of our conclusions. Thirdly, the effect estimates harvested from diverse data sources exhibited consistency, as evidenced by the robust methodologies employed in the sensitivity analysis to negate multiple pleiotropy. Collectively, we amalgamated assorted data resources, numerous statistical techniques, and multivariable MR analysis to scrutinize the causal nexus between autoimmune diseases and anemia. Our findings corroborate the presence of independent causal linkages between the augmented risk of anemia and Type 1 diabetes, multiple sclerosis, and rheumatoid arthritis.
Nonetheless, several limitations warrant consideration. Firstly, despite diligent endeavors to amass the most current Genome-Wide Association Study (GWAS) summary statistics for autoimmune diseases and anemia for the principal Mendelian Randomization (MR) analysis, the data predominantly emanate from European ancestry, mandating a judicious interpretation of our study findings. We advocate for ensuing research in diverse ethnic populations, given the potential variability in genetic structures across ethnicities. Secondly, the absence of unmeasured confounding factors between genetic variables and anemia risk was noted. Independent GWAS data were garnered for two-sample MR analysis to the greatest extent feasible. Yet, theoretically, confounding between genetic variables and outcomes may persist. Consequently, our study findings ought to be construed with circumspection. Future prospective cohort studies, boasting larger sample sizes, would be more propitious and may engender more compelling causal inferences.