Pancytopenia

Introduction

Pancytopenia is a medical condition characterized by a significant reduction in all three major blood cell lines: red blood cells (leading to anemia), white blood cells (leading to leukopenia, often specifically neutropenia), and platelets (leading to thrombocytopenia). This broad deficiency in blood components can arise from various underlying causes, ranging from bone marrow disorders and autoimmune conditions to infections and exposure to certain drugs or toxins. The severity and prognosis of pancytopenia depend heavily on its etiology and the degree of cytopenias.

Biological Basis

The biological basis of pancytopenia primarily involves dysfunction or damage to the bone marrow, the body's main site of blood cell production. Hematopoietic stem cells within the bone marrow are responsible for differentiating into all types of blood cells. When these stem cells are impaired, destroyed, or crowded out by abnormal cells, the production of erythrocytes, leukocytes, and platelets can be severely compromised, leading to pancytopenia. Genetic factors can play a role in predisposing individuals to certain bone marrow failure syndromes or in influencing the response to environmental triggers that cause pancytopenia.

Clinical Relevance

Clinically, pancytopenia presents with a diverse set of symptoms reflecting the deficiencies in each blood cell line. Anemia can cause fatigue, weakness, and shortness of breath. Leukopenia increases susceptibility to severe infections, particularly bacterial and fungal. Thrombocytopenia leads to an increased risk of bleeding and bruising. Diagnosis involves blood tests to confirm the reduction in cell counts, followed by bone marrow examination to identify the underlying cause. Treatment strategies are highly dependent on the diagnosis and may include supportive care (e.g., blood transfusions, growth factors), immunosuppressive therapy, or chemotherapy, and in some cases, stem cell transplantation. Understanding the genetic underpinnings of such complex conditions, including those affecting the hematopoietic system, is a crucial area of research. ^[1] Studies have identified significant gene associations with traits related to the hematopoietic system, highlighting the role of genetics in these conditions. ^[1]

The social importance of pancytopenia stems from its potential for severe morbidity and mortality, significantly impacting patients' quality of life and requiring extensive medical resources. The condition often necessitates prolonged hospital stays, frequent medical interventions, and can lead to chronic health issues or life-threatening complications. Research into the genetic architecture of diseases, including those affecting the hematopoietic system, can help identify individuals at risk, develop targeted therapies, and improve diagnostic accuracy, ultimately reducing the burden of such conditions on individuals and healthcare systems. ^[1]

Population Specificity and Generalizability

The genetic insights into pancytopenia, derived predominantly from the Taiwanese Han population, inherently limit the direct generalizability of these findings to other diverse ancestral groups. Genetic risk factors for diseases are profoundly influenced by an individual's ancestry, and the underrepresentation of non-European populations in genetic studies often hinders the discovery of rare variants that may have higher minor allele frequencies in specific populations. Consequently, effect sizes and the predictive power of polygenic risk scores (PRSs) observed in this cohort may not translate accurately to individuals of different ethnic backgrounds, necessitating ancestry-specific genetic architectures for robust PRS models. ^[1] For example, a variant in the SELENOI gene showed a notable difference in effect size between the Taiwanese Han population and a European cohort, underscoring the population-specific nature of genetic associations. ^[1] This highlights a critical knowledge gap concerning the broader applicability of identified genetic markers for pancytopenia across global populations.

Phenotypic Ascertainment and Data Limitations

The reliance on a hospital-centric electronic medical record (EMR) database introduces specific biases and limitations in phenotypic ascertainment. A significant challenge is the absence of truly "sub-healthy" individuals in the control group, as virtually all participants have at least one documented diagnosis, potentially skewing the baseline health status comparison. ^[1] Furthermore, diagnostic recording can be influenced by physician decisions to order specific tests, potentially leading to the documentation of unconfirmed diagnoses. While the study implemented a criterion of three or more diagnoses for case inclusion to mitigate false positives, this approach might still introduce a degree of misclassification or phenotype aggregation, which could obscure nuanced genetic associations for conditions like pancytopenia. ^[1] Future research would benefit from stricter, more comprehensive phenotyping criteria that integrate diagnosis with medication history and laboratory test results for clearer outcomes.

Incomplete Genetic and Environmental Modeling

Understanding the genetic architecture of complex diseases such as pancytopenia is often hampered by the interplay of multiple genes and environmental factors, a limitation frequently encountered in genome-wide association studies (GWASs). ^[1] While the study adjusted for key confounders like age, sex, and principal components of ancestry, numerous other clinical and environmental factors—such as body mass index, blood pressure, various biomarkers, lifestyle choices (e.g., exercise, diet, alcohol consumption, and smoking)—were not comprehensively integrated into the models. ^[1] The observed modest predictive power of PRS models, with AUC values often below 0.7 for PRS alone and rarely exceeding 0.9 even with age and sex adjustments, indicates that a substantial portion of the heritability and disease risk remains unexplained by the current genetic and clinical features. ^[1] This suggests significant remaining knowledge gaps regarding gene-environment interactions and the full spectrum of factors contributing to the etiology of pancytopenia.

Variants

Variants within the PNPLA3 gene, specifically rs738409 and rs3747207, are primarily recognized for their roles in lipid metabolism and liver disease. The PNPLA3 gene encodes patatin-like phospholipase domain-containing protein 3, an enzyme involved in triglyceride hydrolysis in adipocytes and hepatocytes. The rs738409 C>G variant, leading to an I148M amino acid change, is a well-studied genetic risk factor for increased liver fat content, non-alcoholic fatty liver disease (NAFLD), inflammation, and fibrosis, progressing to cirrhosis and hepatocellular carcinoma. ^[1] Similarly, rs3747207 is also associated with metabolic and liver phenotypes. While not directly causing pancytopenia, severe chronic liver disease, particularly cirrhosis with portal hypertension, can lead to splenomegaly and subsequent hypersplenism, a condition where the enlarged spleen prematurely sequesters and destroys blood cells, resulting in pancytopenia. ^[1] Thus, these PNPLA3 variants could indirectly contribute to pancytopenia through their profound impact on liver health.

The variant rs867931530 is located within the RPH3AL gene, which encodes Rabphilin 3A like, a protein thought to be involved in exocytosis and synaptic vesicle trafficking. While the precise function of RPH3AL in hematopoiesis or its direct link to pancytopenia is not extensively documented, proteins involved in cellular transport and signaling can subtly influence various physiological processes, including the complex pathways governing blood cell production. ^[1] As an intronic variant, rs867931530 might affect gene expression or splicing rather than directly altering the protein's amino acid sequence. Its contribution to conditions like pancytopenia would likely be as part of a polygenic risk profile or through indirect mechanisms affecting cellular health and function within the bone marrow microenvironment. ^[1]

The DNMT3A gene, associated with the rs147001633 variant, plays a crucial role in de novo DNA methylation, an epigenetic modification essential for gene regulation and cell differentiation. DNMT3A is particularly important for the normal function and maintenance of hematopoietic stem cells. ^[1] Mutations in DNMT3A, especially at the R882 hotspot, are frequently observed in various hematological malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndromes, as well as in clonal hematopoiesis of indeterminate potential (CHIP). These conditions often present with pancytopenia due to impaired production or increased destruction of blood cells in the bone marrow. Although rs147001633 is an intronic variant, it could potentially influence DNMT3A expression or be in linkage disequilibrium with other functional variants that contribute to hematopoietic dysfunction and, consequently, pancytopenia. ^[1]

Finally, the rs76393800 variant is located within the MAML3 gene, which encodes Mastermind-like transcriptional coactivator 3. This protein is a key component of the Notch signaling pathway, a highly conserved cell-to-cell communication system critical for embryonic development, cell fate determination, proliferation, and differentiation in many tissues, including the hematopoietic system. ^[1] The Notch pathway plays a vital role in regulating hematopoietic stem cell self-renewal and lineage commitment. While the specific impact of the intronic rs76393800 variant on MAML3 function or Notch signaling is not well-defined, dysregulation of this pathway has been implicated in various cancers and developmental disorders. Impaired Notch signaling or altered MAML3 activity could theoretically disrupt normal hematopoiesis, leading to a reduction in multiple blood cell lineages and contributing to pancytopenia. ^[1]

Key Variants

RS ID	Gene	Related Traits
rs738409 rs3747207	PNPLA3	non-alcoholic fatty liver disease serum alanine aminotransferase amount Red cell distribution width response to combination chemotherapy, serum alanine aminotransferase amount triacylglycerol 56:6 measurement
rs867931530	RPH3AL	pancytopenia
rs147001633	DNMT3A	myeloproliferative disorder myeloid leukemia leukemia polycythemia vera erythrocyte volume
rs76393800	MAML3	pancytopenia

Clinical Identification and Diagnostic Approaches

Conditions affecting the hematopoietic system, such as pancytopenia, are identified within clinical research cohorts through a rigorous process involving the extraction of data from patient electronic medical records (EMRs). ^[1] Diagnostic information is primarily captured using International Classification of Diseases (ICD) codes, specifically ICD-9-CM and ICD-10-CM, which are subsequently matched with relevant PheCodes. ^[1] A definitive diagnosis is typically established when PheCode criteria are met on at least three distinct occasions, ensuring a robust and consistent definition for case identification in large-scale studies. ^[1] This systematic approach allows for the comprehensive classification and study of various clinical phenotypes, including those impacting the hematopoietic system.

Phenotypic Variability and Demographic Influences

The clinical presentation of conditions affecting the hematopoietic system can exhibit significant inter-individual variation, often influenced by demographic factors such as age and sex. ^[1] In research analyses, adjustments for age and sex are routinely incorporated into regression models to account for their potential confounding effects on disease associations. ^[1] For instance, studies have observed slight differences in mean age between male (47.89 ± 21.72 years) and female (46.37 ± 21.07 years) participants within cohorts, and sex has been identified as a statistically significant factor in predicting disease risk in various polygenic risk score models. ^[1] This underscores the importance of considering demographic context when evaluating the phenotypic diversity and heterogeneity of hematopoietic conditions.

Severity Assessment and Diagnostic Significance

The diagnostic significance of conditions impacting the hematopoietic system is established through their systematic classification within large-scale studies, where cases are defined by meeting specific PheCode criteria on multiple occasions. ^[1] This stringent definition helps to accurately differentiate true disease states from control groups, thereby enhancing the diagnostic value of the identified clinical phenotypes. ^[1] While specific prognostic indicators for pancytopenia are not detailed, the comprehensive collection of longitudinal patient electronic medical records, including laboratory results and medical procedures, provides foundational data for future investigations into disease progression and severity ranges. ^[1] Such detailed clinical data, when integrated with genetic insights, enables a deeper understanding of disease mechanisms and the identification of potential red flags for severe presentations.

Causes of Pancytopenia

Pancytopenia, a condition characterized by a reduction in all three major blood cell lines (red blood cells, white blood cells, and platelets), arises from a complex interplay of genetic predispositions, environmental exposures, and acquired cellular changes. Understanding these diverse causal factors is crucial for effective diagnosis and management.

Genetic Underpinnings of Hematopoiesis

The development of pancytopenia is often influenced by an individual's genetic makeup, encompassing both rare Mendelian forms and common polygenic contributions to hematopoietic function. Large-scale genome-wide association studies (GWAS) have identified numerous genetic loci associated with various hematological parameters, highlighting the complex polygenic basis of blood traits and diseases. ^[2] For instance, research has uncovered genetic factors influencing eight quantitative traits in Asian populations and identified 22 loci linked to eight hematological parameters through meta-analyses, indicating that baseline blood cell counts and their regulation are significantly shaped by genetic variations . ^{[3], [4], [5]} These studies provide insight into how inherited variants can impact blood cell differentiation and overall hematopoietic capacity.

Specific genetic variations can predispose individuals to pancytopenia by affecting critical pathways involved in blood cell production and maturation. Genetic analysis of quantitative traits in Japanese populations has linked particular cell types to complex human diseases, providing mechanisms by which genetic alterations can compromise the hematopoietic system. ^[6] Furthermore, studies on mosaic loss of chromosome Y have highlighted genetic effects on blood cell differentiation, illustrating the intricate genetic architecture that governs the development and maintenance of blood cells. ^[7]

Environmental Influences and Therapeutic Challenges

Environmental factors play a substantial role in the etiology of pancytopenia, especially through exposure to certain substances or therapeutic agents. Medical treatments, such as pegylated interferon and ribavirin therapy used for chronic hepatitis C, are known to induce adverse hematological effects, including thrombocytopenia, which is a component of pancytopenia. This drug-induced suppression of blood cell production represents a direct environmental trigger that can significantly reduce blood cell counts. ^[8]

Beyond specific therapeutic interventions, broader environmental exposures, lifestyle choices, and dietary factors can indirectly affect hematopoietic function. While direct causal links to pancytopenia can be intricate, these elements may contribute to physiological stress or nutritional deficiencies that impair bone marrow activity. Geographic influences and socioeconomic conditions can also impact an individual's exposure to environmental toxins or access to adequate nutrition and healthcare, collectively influencing the bone marrow's ability to produce sufficient blood cells.

Interactions Between Genes and Environment

Pancytopenia often results from a complex interplay where genetic predispositions interact with environmental triggers. Gene-environment interactions describe how an individual's genetic background can modify their susceptibility to environmental factors, influencing the likelihood and severity of developing conditions like pancytopenia. ^[9] This interaction is particularly evident in adverse drug reactions, where specific genetic variants determine an individual's sensitivity to medication-induced hematological toxicity.

A clear example is the observation that variants in the ITPA and DDRGK1 genes are associated with thrombocytopenia in patients receiving pegylated interferon and ribavirin therapy for chronic hepatitis C. This interaction illustrates how genetic factors can render individuals more vulnerable to medication-induced reductions in platelet counts, a key feature of pancytopenia. Such findings underscore the importance of considering both genetic and environmental factors when assessing risk and tailoring treatments. ^[8]

Pancytopenia can also stem from developmental factors, age-related biological changes, and other acquired forms of cellular dysregulation within the hematopoietic system. Early life influences and epigenetic modifications, such as alterations in DNA methylation and histone modifications, can profoundly affect gene expression patterns essential for proper blood cell development and function throughout an individual's life. These epigenetic changes can lead to long-term alterations in bone marrow reserve and overall cellular health, potentially predisposing individuals to pancytopenia.

Moreover, aging itself is a significant contributing factor, as the hematopoietic stem cell compartment can undergo changes, including the emergence of clonal hematopoiesis. This condition is associated with dysregulation of the immune system and can impact the overall production of blood cells, leading to reduced counts. ^[10] Various comorbidities, such as chronic inflammatory diseases or other systemic illnesses, can also indirectly impair bone marrow function. Additionally, numerous medications, beyond those specifically mentioned for hepatitis C, can contribute to pancytopenia through direct suppression of bone marrow activity or immune-mediated destruction of blood cell precursors.

Biological Background

Pancytopenia is a hematological disorder characterized by a significant reduction in all three major blood cell lines: red blood cells (anemia), white blood cells (leukopenia), and platelets (thrombocytopenia). This multifaceted condition stems from disruptions in the complex biological processes that govern blood cell production and maintenance. Understanding the molecular, cellular, and genetic underpinnings of hematopoiesis is crucial for comprehending the diverse etiologies and pathophysiological mechanisms contributing to pancytopenia.

Hematopoiesis and Cellular Differentiation

Pancytopenia signifies a profound deficiency across the erythrocyte, leukocyte, and platelet lineages, all of which originate from hematopoietic stem cells (HSCs) residing primarily in the bone marrow. The process of hematopoiesis involves the precise differentiation of HSCs into various progenitor cells, which then mature into the diverse specialized blood cell types. ^[7] Any disruption along this intricate developmental pathway—from the initial proliferation of stem cells to the final maturation of specific cell types—can lead to a reduction in blood cell counts, resulting in pancytopenia when all three lineages are simultaneously affected.

The harmonious production of different blood cell components relies on tightly regulated molecular signaling and cellular functions within the bone marrow microenvironment. For instance, the development of megakaryocytes, which are precursors to platelets, and erythroid cells, which mature into red blood cells, are interconnected processes. Research indicates that defective megakaryopoiesis is often accompanied by abnormal erythroid development. ^[11] This highlights the delicate balance and intricate tissue interactions necessary for healthy hematopoiesis, where a disturbance in one lineage can have systemic consequences impacting others.

Genetic Regulation of Blood Cell Production

Genetic mechanisms are fundamental to governing hematopoiesis and are frequently implicated in the development of pancytopenia. The proper functioning of genes, the activity of their regulatory elements, and precise gene expression patterns are essential for maintaining adequate blood cell levels. Key transcription factors, such as RUNX1 and GATA2, are critical regulators of hematopoietic differentiation. ^[7] RUNX1, for example, plays a role in repressing the erythroid gene expression program during megakaryocytic differentiation, illustrating its importance in lineage commitment and balancing blood cell production. ^[12] Similarly, mutations in GATA2 have been associated with various hematopoietic deficiencies, including conditions like MonoMAC syndrome. ^[13]

Beyond these specific genes, a broader spectrum of genetic influences, encompassing both polygenic and monogenic bases, affects various blood traits and diseases. ^[14] Genome-wide association studies (GWAS) have successfully identified numerous genetic loci that impact hematological parameters, underscoring the complex genetic architecture underlying blood cell production. ^[4] Variants within genes like ITPA and DDRGK1 have been specifically linked to thrombocytopenia, a component of pancytopenia, particularly in the context of certain therapeutic interventions. ^[8] These genetic and epigenetic regulatory networks are crucial for dictating hematopoietic cell fate and function.

Molecular Pathways and Key Biomolecules

The molecular and cellular pathways that orchestrate hematopoiesis involve a sophisticated network of critical proteins, enzymes, receptors, and hormones. Signaling pathways meticulously control cellular proliferation, differentiation, and survival. Erythropoietin (EPO), a vital hormone, is a prime example, crucial for erythropoiesis; while gain-of-function mutations in EPO can lead to an excess of red blood cells, its deficiency or dysregulation can contribute to anemia, a hallmark of pancytopenia. ^[15] Transcription factors like FLI-1 also demonstrate the complexity of these regulatory networks; while indispensable for megakaryocyte development, FLI-1 simultaneously acts as a suppressor of erythroid differentiation, maintaining the delicate balance required for normal blood cell production. ^[16]

Essential metabolic processes and cellular functions within hematopoietic cells are equally critical. DNA polymerases, such as POLN, are fundamental for DNA repair and replication, processes that are indispensable for the rapid proliferation and differentiation of blood cells. ^[17] Any impairment in these basic cellular functions can severely compromise the production of all blood cell lineages. Furthermore, the emergence of clonal hematopoiesis, where a select group of hematopoietic stem cells acquires mutations and expands, can lead to broader immune system dysregulation and potentially contribute to the overall failure of hematopoiesis. ^[10]

Pathophysiological Mechanisms and Systemic Consequences

Pancytopenia stems from diverse pathophysiological processes that disrupt the fundamental homeostatic balance of blood cell production. These disease mechanisms can range from primary bone marrow failure, where stem cells are unable to produce sufficient blood cells, to increased peripheral destruction of mature blood cells, or their abnormal sequestration within organs. For instance, mosaic loss of chromosome Y (mLOY) has been identified as a genetic factor influencing blood cell differentiation, showing an increased effect size on platelet count and also impacting red blood cell and white blood cell counts. ^[7] Such chromosomal abnormalities highlight how significant genetic alterations can profoundly affect the entire hematopoietic system.

The systemic consequences of pancytopenia are far-reaching, impacting multiple organs and overall physiological function. A deficiency in red blood cells leads to anemia, impairing the body's oxygen transport capacity; low white blood cell counts (leukopenia) severely compromise the immune system, increasing vulnerability to infections; and reduced platelets (thrombocytopenia) predispose individuals to bleeding disorders. These widespread disruptions underscore the critical interconnectedness of the hematopoietic system with the body's general health, demonstrating the severe impact that its failure can have on an individual's well-being.

Frequently Asked Questions About Pancytopenia

These questions address the most important and specific aspects of pancytopenia based on current genetic research.

1. My family has this condition; will I get it too?

While not strictly inherited like some conditions, genetic factors can definitely play a role in whether you develop pancytopenia or how your body responds to triggers. Some bone marrow failure syndromes linked to pancytopenia have a genetic basis, meaning a predisposition can be passed down. Knowing your family history is important, and it's worth discussing with your doctor to understand your personal risk.

2. Does my ethnic background change my risk for this?

Yes, your ethnic background can influence your risk. Genetic risk factors for conditions like pancytopenia can differ significantly across various ancestral groups. For example, research on the Taiwanese Han population has identified specific genetic associations that might not apply the same way to individuals of other ancestries, highlighting the need for diverse genetic studies.

3. Can my lifestyle choices, like diet, help prevent this?

Lifestyle choices and environmental factors can certainly play a role in your overall health and how your body functions, including blood cell production. While genetic studies for pancytopenia often don't fully account for specific lifestyle details like diet or exercise, it's generally understood that a healthy lifestyle supports bone marrow function. However, pancytopenia can also arise from genetic predispositions or other causes unrelated to lifestyle.

4. Could a liver problem cause my blood counts to drop?

Yes, surprisingly, a severe liver problem can indirectly lead to pancytopenia. If you have chronic liver disease, especially cirrhosis with portal hypertension, your spleen can become enlarged. This enlarged spleen, a condition called hypersplenism, can then prematurely destroy red blood cells, white blood cells, and platelets, causing your blood counts to drop. Genetic variations in genes like PNPLA3 are linked to liver disease and can contribute to this pathway.

5. Why does this condition affect people so differently?

The severity and specific symptoms of pancytopenia vary greatly because its underlying causes are diverse, ranging from bone marrow disorders to infections or drug exposure. Your unique genetic makeup can also influence how your body's bone marrow responds to these different triggers and how severe your condition becomes. This complex interplay of factors leads to individual differences in how the condition presents and progresses.

6. I'm always tired; could it be a blood cell problem?

Yes, persistent fatigue and weakness are common symptoms of anemia, which is a key component of pancytopenia. When your body doesn't produce enough red blood cells, your tissues don't get enough oxygen, leading to tiredness and shortness of breath. If you're experiencing ongoing fatigue, it's important to talk to your doctor to investigate the cause.

7. Why do I get sick with infections so often?

Frequent infections, especially bacterial or fungal ones, can be a sign of low white blood cell counts, specifically neutropenia, which is part of pancytopenia. Your white blood cells are crucial for fighting off pathogens, so a deficiency leaves you more vulnerable. If you're constantly falling ill, it's a good idea to have your blood counts checked.

8. I bruise easily; is that a sign of this condition?

Easy bruising and an increased risk of bleeding can indeed be a symptom of thrombocytopenia, which is a reduction in platelets and a component of pancytopenia. Platelets are essential for blood clotting, so when their numbers are low, your body has difficulty stopping bleeding. If you notice unusual bruising or bleeding, you should consult a doctor.

9. Can a genetic test tell me my personal risk for this?

While genetic research is advancing rapidly, current polygenic risk score models for complex conditions like pancytopenia often have modest predictive power. They might indicate a general predisposition, but they don't provide a definitive "yes" or "no" answer for your individual risk. Such tests are still a crucial area of research, but often don't fully account for all genetic and environmental factors.

10. Does my overall health influence my chances of getting this?

While genetics and specific triggers are primary causes, your overall health can play a role in your body's resilience and its ability to maintain healthy blood cell production. Factors like body mass index, blood pressure, and other biomarkers, though not always fully integrated into genetic risk models, are part of a complex picture. Maintaining good general health can support your body's systems, but pancytopenia can still develop due to specific underlying issues.

This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.

Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.

References

[1] Liu TY et al. "Diversity and longitudinal records: Genetic architecture of disease associations and polygenic risk in the Taiwanese Han population." Sci Adv, 2025.

[2] Sankaran, V. G., et al. "The polygenic and monogenic basis of blood traits and diseases." Cell, vol. 182, 2020, pp. 1214–1231.e11.

[3] Kamatani, Y., et al. "Genome-wide association study of hematological and biochemical traits in a Japanese population." Nat Genet, vol. 42, 2010, pp. 210–5.

[4] Soranzo, N., et al. "A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium." Nat Genet, vol. 41, 2009, pp. 1182–90.

[5] Cho, Y. S., et al. "A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits." Nat Genet, vol. 41, 2009, pp. 527–34.

[6] Kanai, M., et al. "Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases." Nat Genet, vol. 50, 2018, pp. 390–400.

[7] Terao, C. "GWAS of mosaic loss of chromosome Y highlights genetic effects on blood cell differentiation." Nat Commun, 2019.

[8] Tanaka, Y., et al. "Genome-wide association study identified ITPA/DDRGK1 variants reflecting thrombocytopenia in pegylated interferon and ribavirin therapy for chronic hepatitis C." Hum Mol Genet., vol. 20, no. 17, 2011, pp. 3507-16.

[9] Virolainen, S. J., et al. "Gene-environment interactions and their impact on human health." Genes Immun, vol. 24, 2023, pp. 1–11.

[10] Belizaire, R., et al. "Clonal haematopoiesis and dysregulation of the immune system." Nat Rev Immunol, 2023.

[11] Kawada, H., et al. "Defective megakaryopoiesis and abnormal erythroid development in Fli-1 gene-targeted mice." Int. J. Hematol., vol. 73, 2001, pp. 463–468.

[12] Kuvardina, O. N., et al. "RUNX1 represses the erythroid gene expression program during megakaryocytic differentiation." Blood, vol. 125, 2015, pp. 3570–3579.

[13] Camargo, J. F., et al. "MonoMAC syndrome in a patient with a GATA2 mutation: case report and review of the literature." Clinical Infectious Diseases: an Official Publication of the Infectious Diseases Society of America, vol. 57, 2013, pp. 697–699.

[14] Sakaue, S., et al. "The polygenic and monogenic basis of blood traits and diseases." Cell, vol. 182, 2021, pp. 1214–1231.e11.

[15] Zmajkovic, J., et al. "A gain-of-function mutation in EPO in familial erythrocytosis." N. Engl. J. Med., vol. 378, 2018, pp. 924–930.

[16] Athanasiou, M., et al. "FLI-1 is a suppressor of erythroid differentiation in human hematopoietic cells." Leukemia, vol. 14, 2000, pp. 439–445.

[17] Marini, F., et al. "POLN a nuclear PolA family DNA polymerase homologous to the DNA cross-link sensitivity protein Mus308." J Biol Chem, vol. 278, 2003, pp. 32014–32019.