Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymatic X-linked human disorder and it primarily affects red blood cells (1). An estimated 400 million people worldwide carry a mutation in the G6PD gene associated with enzyme deficiency, with marked ethnic and geographic differences (2, 3). G6PD deficiency is prevalent in Africa, Asia and the Middle East. In the United States, about 14% of African-American men are affected (4, 5). There are numerous alleles of different severities and geographic propensities (6). Most individuals with G6PD deficiency remain asymptomatic or experience mild symptoms throughout their lives but may develop hemolysis under certain circumstances such as neonatal jaundice, consumption of specific medications, or following an infection.

Several studies have suggested that G6PD-deficient individuals may be more predisposed to specific autoimmune diseases (7, 8), infections (9–11) and diabetes mellitus (12, 13). Associations were found between G6PD deficiency and cardiovascular risk (14–17) in conflicting directions. Regarding malignancy, key studies have reported lower rates of cancer in G6PD-deficient patients, in particular for cancers of endodermal origin (colorectal, gastric and liver malignancies) (18, 19), but a protective effect of G6PD against cancer was not found for other types of cancer and notably hematologic malignancies (20, 21). We recently reported that individuals with G6PD deficiency had an increased risk of COVID-19 infection and severity, with higher rates of hospitalization and diagnosed long COVID (22).

To date, there is no large-scale study showing the association of G6PD deficiency with infectious and immune-related diseases altogether. This large-scale observational study addresses this knowledge gap.

To our knowledge, this is the first large-scale epidemiologic analysis to assess the association between G6PD deficiency and the long-term risk of immune system associated diseases. We show G6PD deficient patients have globally higher rates of acute infectious diseases, and in particular staphylococcal infections, suggesting a predisposition to infections. The link between G6PD deficiency and infections has been previously recognized in infancy, with lack of G6PD activity identified as a risk factor for neonatal sepsis in males (10). This study is the first to show this association on a large scale and for a wide range of infectious diseases.

Another finding from our study is a higher rate of allergic diseases in G6PD-deficient subjects. No systematic review of allergic comorbidity in G6PD deficiency was found in the literature. However, a retrospective case-control study showed that G6PD deficiency is an independent risk factor for asthma (24) and G6PD was noticeably downregulated in asthmatic children (25). In asthma, the level of reduced glutathione is significantly increased, and G6PD-deficient subjects’ insufficient production of NADPH may contribute to asthma pathogenesis (26). Moreover, the chronic depletion of nitric oxide in G6PD deficient subjects may affect the basal bronchodilator tone (27). In our cohort, we also found an association between asthma and G6PD deficiency (OR=1.08, P=.043), but much more stronger associations were present for other conditions such as allergic conjunctivitis (OR=1.25, P<.001), food allergy (OR=1.23, P<.001), and contact dermatitis (OR=1.19, P<.001).

The most striking finding of our study are the much-elevated rates of autoimmune diseases and chronic inflammatory conditions in G6PD deficient individuals. We notably observed markedly elevated rates of scleroderma (OR=6.87, P<.001), SLE (OR=4.56, P<.001), dermatomyositis (OR=3.56, P<.001), Sjögren’s syndrome (OR=2.80), rheumatoid arthritis (OR=2.41, P<.001) and ankylosing spondylitis (OR=2.52, P=.001) in individuals affected with G6PD deficiency. These findings were corroborated with elevated rates of positive autoimmune serology in G6PD deficiency and higher rates of treatment with medications commonly used to treat autoimmune conditions. This is consistent with a previous study reporting lower levels of G6PD enzymatic activity in patients with rheumatoid arthritis and Sjögren’s syndrome, which in many cases was subclinical and of acquired origin (28).

We also observed significantly higher rates of organ-specific inflammatory diseases such as Hashimoto’s thyroiditis (OR=1.26, P=.001) and Graves’ disease (OR=1.46, P=.001), and particularly elevated rates of pernicious anemia (OR=18.7, P<.001). We corroborated these findings with higher rates of individuals with positive anti-gastric parietal cells and anti-TPO antibodies in the G6PD group. Findings of increased rate of autoimmune thyroid disorders in G6PD patients are consistent with a recently published case-control study from North Sardinia, which identified an odds ratio of 1.36 (95% CI 1.11 to 1.60) for these disorders for G6PD patients (8).

We also observed higher rates of inflammatory bowel disease (OR=1.34, P=.05) and psoriasis (OR=1.19, P=.02) among G6PD deficient patients. Interestingly, we observed markedly higher rates for diseases for which the pathological basis is poorly understood, notably hidradenitis suppurativa (OR=2.57, P<.001) and fibromyalgia (OR=1.98, P<.001). These strong associations with G6PD deficiency suggest that metabolic pathway alterations, as those present in G6PD deficiency, may play a major role in these pathologies.

G6PD deficient individuals differed markedly from the rest of the population for commonly prescribed laboratory tests. They display diminished white blood cells counts, particularly monocytes and neutrophils. Interestingly, activated monocytes and neutrophils produce reactive oxygen species (ROS), which could be particularly harmful to G6PD-deficient cells and could lead to increased cell death. We also observed markedly increased levels of iron, ferritin, and transferrin saturation, with diminished transferrin levels. Immunoglobulins A and G levels were increased in G6PD patients and C4 complement decreased, suggesting a possible activation of the complement system in G6PD deficiency, presumably through the classical pathway and with the production of circulating immune complexes (29). Indeed, immune dysregulation may play a role in the pathogenesis of autoimmune and infectious diseases in G6PD deficiency, presumably through dysregulated NADPH homeostasis and ROS imbalances (30).

G6PD deficiency has been associated with a proinflammatory state with over-expression of IL-8, IL-4, IL-5, and IL-9 cytokines, and increased chemotaxis of eosinophils and Th2 immune polarization (31, 32). Oxidative stress had been suggested in the pathogenesis of human SLE and Sjögren syndrome (33, 34). Oxidative stress in G6PD deficient subjects contributes to developing novel epitopes by oxidizing proteins and lipids and producing anti-DNA antibodies (35, 36). Oxidative stress may also play a role in the sustained activation of lymphocytes and cause autoimmune responses by modulation of T and B cell homeostasis, leading to a loss in immunological tolerance (37, 38). These may be some of the reasons for the observed higher rates of autoimmune diseases. Their roles in food allergy, atopic and allergic contact dermatitis should be elucidated in further research. Autoimmune diseases in G6PD deficient patients may be triggered by activation of TGF-β/NADPH oxidases/ROS signaling, the expression of ICAM-1 and VCAM-1, and the adhesion of leukocytes to the endothelial cells with endothelial to mesenchymal transition (31, 39).

Several mechanisms could explain higher susceptibility to infections in individuals with G6PD deficiency. NADPH is critical for the regeneration of glutathione, reactive oxygen species (ROS) and plays an essential role in the production of reactive nitrogen species and nitric oxide (40). Immune inflammation in airway epithelial cells induces G6PD activity with the concomitant increase of glutathione, ROS, nitrotyrosine, and NADPH oxidase 2 (NOX2) (41). Experimental models have shown that G6PD inhibition suppresses airway inflammation induced by lipopolysaccharides and the ROS derived from NOX2 (42). Dysregulated redox systems and NF-κB signaling in G6PD-deficient cells have been associated with increased susceptibility to coronavirus and enterovirus infection (43, 44). G6PD-deficient individuals also produce lower levels of pro-inflammatory cytokines, IL-6, and IL-1β in peripheral mononuclear cells (45), and their granulocytes display diminished bactericidal activity and increased susceptibility to infection (46). Reduced expression of prostaglandin E2 and cyclooxygenase-2 (47), defective neutrophil extracellular trap (NET) formation (48), and impaired inflammasome activation have also been observed in the neutrophils of G6PD-deficient individuals (49).

In our study, we did not find a significant association between G6PD deficiency and malignancy. Earlier studies have observed decreased cancer risk in G6PD deficient patients, in particular for cancers of endodermal origin (colorectal, gastric and liver), but these findings were not replicated in other studies, notably for hematologic malignancies. In this large cohort of G6PD deficient individuals, carefully matched by multiple factors, we did not find evidence for an association between G6PD deficiency and the overall rate of both solid and hematologic cancers during a mean follow-up of 14.3 years, but the lack of statistical association could be due to the relatively low rate of malignancy (~4%) diagnosed in this relatively young cohort. It is remarkable that even though G6PD deficiency is associated with several chronic inflammatory diseases, this does not translate into cancer risk. This may be explained by the fact that G6PD deficiency is associated with multiple changes in metabolic and cellular states (6) with some changes being pro-tumorigenic and other changes being anti-tumorigenic.

In conclusion, G6PD deficiency is a condition which appears to be associated with increased susceptibility to autoimmune, infectious and allergic diseases. Additional studies are warranted to confirm these observations and investigate the mechanisms underlying the higher prevalence of these conditions in G6PD deficiency. Some of the novel associations we report with G6PD deficiency are for poorly understood conditions such as fibromyalgia or hidradenitis suppurativa, and this may suggest new directions for investigating the pathological basis of these diseases.

The data analyzed in this study is subject to the following licenses/restrictions: Access to raw patient data is restricted to researchers approved by the institutional ethics committee. Requests to access these datasets should be directed to aisrael@leumit.co.il.

This study was approved by the ethics committee of Leumit Health Services (LEU 02-23) with a waiver of informed consent. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements.

AI and EMa: designed research, performed research, collected, analyzed and interpreted the data, performed statistical analysis, and wrote the initial draft of the manuscript; AAS, DO, EMe, IG, AG-C, MB, ER, and SV: analyzed and interpreted data and wrote the manuscript. All authors contributed to the article and approved the submitted version.