Familial Glucocorticoid Deficiency
Introduction
Familial glucocorticoid deficiency (FGD) is a rare, inherited endocrine disorder characterized by the adrenal glands' inability to produce sufficient cortisol, a vital glucocorticoid hormone, despite normal production of other adrenal hormones like aldosterone. This condition typically manifests in infancy or early childhood and can lead to life-threatening adrenal crises if not promptly diagnosed and treated.
Biological Basis
The underlying biological basis of FGD involves genetic mutations that impair the adrenal cortex's ability to respond to adrenocorticotropic hormone (ACTH). ACTH is a pituitary hormone that stimulates cortisol production. Key genes implicated in this pathway include MC2R, which encodes the ACTH receptor, and MRAP, encoding the Melanocortin 2 Receptor Accessory Protein, which is essential for MC2R function. Mutations in these genes disrupt the signaling cascade, preventing the adrenal glands from synthesizing adequate cortisol even when ACTH levels are high. Research indicates that inherited genetic variants can be associated with glucocorticoid sensitivity and glucocorticoid receptor gene expression, highlighting the role of genetic factors in individual responses to these hormones. [1] Genome-wide association studies (GWAS) have identified various genetic variants that influence physiological responses to glucocorticoid therapy, demonstrating how specific genetic profiles can affect drug efficacy and individual hormone function. [2] For instance, certain single nucleotide polymorphisms (SNPs) like rs6924808, rs10481450, rs1353649, rs12438740, and rs2230155 have been linked to varying levels of response to glucocorticoid intervention, with different genotypes exhibiting distinct dose-response patterns. [2]
Clinical Relevance
Clinically, FGD presents with symptoms such as recurrent hypoglycemia, seizures, poor feeding, and failure to thrive, often appearing in infancy. Affected individuals may also exhibit hyperpigmentation due to elevated ACTH levels stimulating melanocytes. Early diagnosis is crucial to prevent acute adrenal crises, which are medical emergencies. Management involves lifelong glucocorticoid replacement therapy, typically with hydrocortisone, to substitute the missing cortisol. Understanding the specific genetic variants involved can aid in precise diagnosis, predict disease severity, and guide personalized treatment strategies. The impact of genetic variations on individual responses to glucocorticoid treatment underscores the importance of pharmacogenomics in optimizing therapeutic outcomes. [2]
Social Importance
The social importance of understanding familial glucocorticoid deficiency extends to improving patient outcomes, facilitating genetic counseling, and advancing public health. Early and accurate diagnosis through genetic testing can prevent severe complications and ensure affected individuals receive appropriate, timely treatment, enabling a better quality of life. For families, genetic counseling helps in understanding the inheritance patterns, assessing risks for future pregnancies, and making informed reproductive decisions. Furthermore, research into the genetic basis of glucocorticoid sensitivity contributes to a broader understanding of endocrine disorders and the development of more targeted therapies, potentially benefiting a wider population with conditions affected by glucocorticoid function.
Methodological and Statistical Power Constraints
Genetic investigations into familial glucocorticoid deficiency face inherent methodological and statistical limitations that can impact the comprehensiveness and interpretability of findings. Studies often contend with insufficient statistical power, particularly for detecting uncommon or rare genetic variants, which may be crucial in conditions like familial glucocorticoid deficiency. [3] For instance, post-hoc power calculations in some genome-wide association studies (GWAS) have revealed detection power as low as 1% for uncommon variants, indicating that many potentially significant associations may be overlooked. [3] Furthermore, small sample sizes, especially for specific sub-analyses or in replication cohorts, can lead to imprecise estimates of genetic effects and may prevent variants from reaching statistical significance, even if they hold true biological relevance. [4] This limitation underscores the challenge in identifying the full spectrum of genetic contributions to familial glucocorticoid deficiency, particularly when complex genetic architectures or variants with modest effect sizes are involved.
The reliance on specific statistical models, such as additive genetic models, can also limit the discovery of variants that exhibit non-additive effects, including dominant, recessive, or heterodominant patterns. [4] While additive models are often the most sensitive for initial discovery, variants with non-additive associations might only become significant with larger sample sizes or when tested with alternative models. Moreover, achieving robust replication of genetic findings remains a critical challenge, requiring sufficiently powered replication cohorts to confirm initial discoveries and prevent the overestimation of effect sizes observed in discovery phases. [5] The absence of comprehensive DNA collection from non-trial family participants in many clinical trials further restricts the use of family-based study designs, which could otherwise offer increased power and better control for confounding factors in complex genetic analyses. [2]
Challenges in Phenotypic Characterization and Generalizability
Defining and measuring complex phenotypes such as familial glucocorticoid deficiency accurately across diverse study populations presents significant challenges, impacting the generalizability of genetic findings. Variability in diagnostic criteria, assay methodologies, or clinical definitions of the condition can introduce heterogeneity that obscures true genetic associations or leads to inconsistent results across cohorts. [5] While efforts to standardize measurements are crucial, subtle differences may still exist, potentially affecting the precise characterization of the trait and its genetic underpinnings.
Furthermore, many large-scale genetic studies, including GWAS, are predominantly conducted in populations of specific ancestries, such as those from European or East Asian descent. [6] This demographic imbalance limits the generalizability of findings to more diverse global populations, as allele frequencies, linkage disequilibrium patterns, and genetic effects can vary substantially across different ancestral groups. Consequently, genetic variants identified in one population may not be directly transferable or have the same effect size in another, potentially leading to an incomplete understanding of familial glucocorticoid deficiency worldwide. Such ascertainment biases necessitate caution when extrapolating results and highlight the need for more inclusive and globally representative genetic research to fully capture the genetic diversity influencing the condition.
Environmental Confounders and Complex Genetic Architectures
Studies of familial glucocorticoid deficiency must also contend with the influence of environmental factors and the inherent complexity of genetic architectures, which can confound the identification of direct genetic associations. Human genetic studies, by their nature, cannot control for numerous demographic and environmental variables, such as age, sex, lifestyle choices (e.g., alcohol consumption, smoking status), socioeconomic status, and even seasonal variations, all of which can act as confounders. [2] While statistical models incorporating covariates can mitigate some of these effects, their precision can be limited by sample size, and residual confounding may persist, potentially masking or distorting true genetic signals.
Moreover, complex traits like familial glucocorticoid deficiency are influenced not only by individual genetic variants but also by intricate gene-environment interactions and shared environmental effects among relatives. [6] The current understanding may not fully capture these complex interplay, contributing to what is known as "missing heritability"—the gap between the heritability estimated from family studies and that explained by identified genetic variants. The absence of certain candidate genes from top association hits does not preclude their role in the condition, as their contributions might be small, involve complex interactions, or be missed by current analytical approaches, thereby indicating remaining knowledge gaps in the complete genetic landscape of familial glucocorticoid deficiency. [5]
Variants
Genetic variants near or within specific genes can play a role in modulating cellular processes, including those critical for hormone regulation and sensitivity, which may have implications for conditions like familial glucocorticoid deficiency. Familial glucocorticoid deficiency (FGD) is a rare inherited disorder characterized by the adrenal glands' inability to produce sufficient cortisol, leading to a range of symptoms from hypoglycemia to seizures. Investigating single nucleotide polymorphisms (SNPs) and their associated genes provides insight into the complex genetic architecture underlying such conditions. [1]
The variant rs530430768 is located in a region encompassing the MYL10 and CUX1 genes. MYL10 (Myosin Light Chain 10) encodes a component of myosin, a protein crucial for muscle contraction and various cellular processes like cell motility and cytokinesis. CUX1 (Cut Like Homeobox 1) is a transcription factor, meaning it regulates the expression of other genes by binding to specific DNA sequences. [1] Variants like rs530430768 in regulatory regions or within these genes could potentially alter the function of these proteins or their expression levels, thereby influencing cellular signaling pathways that might indirectly affect adrenal gland development or the cellular response to glucocorticoids. [7] Such disruptions could contribute to the impaired cortisol production or action seen in familial glucocorticoid deficiency.
Another variant, rs141172114, is associated with LINC02714, a long intergenic non-coding RNA (lincRNA). LincRNAs are a class of RNA molecules that do not encode proteins but play crucial roles in regulating gene expression through various mechanisms, including chromatin remodeling, transcriptional interference, and post-transcriptional control. [8] A variant such as rs141172114 could affect the expression, stability, or function of LINC02714, subsequently altering the regulatory networks it controls. If LINC02714 normally influences genes involved in adrenal steroidogenesis or the cellular machinery that responds to glucocorticoids, then a functional change due to this variant could contribute to the pathogenesis of familial glucocorticoid deficiency. [2]
Similarly, rs138782561 is found in a genomic region associated with MMADHC-DT and LINC01818. MMADHC-DT is a readthrough transcript or a pseudogene related to MMADHC, a gene involved in cobalamin (vitamin B12) metabolism. While direct links to glucocorticoid deficiency are not always evident, broad metabolic pathways can impact cellular health and stress responses, which are relevant to endocrine function. [9] LINC01818 is another lincRNA, and as with LINC02714, variants within or near it could modulate gene expression patterns critical for physiological processes. Alterations in these non-coding regions or readthrough transcripts, as influenced by rs138782561, might affect the precise regulation of genes involved in adrenal function or glucocorticoid sensitivity, potentially contributing to the genetic susceptibility or manifestation of familial glucocorticoid deficiency. [10]
There is no information about the signs and symptoms of familial glucocorticoid deficiency in the provided context. Therefore, this section cannot be written.
Key Variants
| RS ID | Gene | Related Traits |
|---|---|---|
| rs530430768 | MYL10 - CUX1 | familial glucocorticoid deficiency chronic primary adrenal insufficiency |
| rs141172114 | LINC02714 | familial glucocorticoid deficiency |
| rs138782561 | MMADHC-DT - LINC01818 | familial glucocorticoid deficiency |
Causes
Familial glucocorticoid deficiency is a complex condition influenced by a combination of genetic predispositions, environmental factors, and how these elements interact. The underlying causes can range from specific inherited genetic variants that directly impair glucocorticoid function to more subtle polygenic influences and external modifiers.
Genetic Predisposition and Inheritance
Familial glucocorticoid deficiency often stems from inherited genetic variants that directly impact glucocorticoid synthesis, signaling, or sensitivity. Studies have identified specific single nucleotide polymorphisms (SNPs) that are significantly associated with an individual's physiological response to glucocorticoids. For instance, variants such as rs6924808 on chromosome 6, rs10481450 on chromosome 8, rs1353649 on chromosome 11, and rs12438740 and rs2230155 on chromosome 15 have been linked to varying responses to glucocorticoid therapy, where a mutant allele may lead to a more pronounced or delayed effect compared to the wild-type allele. [11] These variants can influence the expression of genes involved in glucocorticoid pathways, thereby altering the body's ability to produce or respond to these crucial hormones. [1]
Beyond single-gene defects, familial glucocorticoid deficiency can also involve a polygenic architecture, where multiple common genetic variations collectively contribute to risk or modify disease severity. Even in conditions with a clear Mendelian basis, common polymorphisms can interact with rare pathogenic variants to influence the overall clinical presentation. [12] The cumulative effect of these many variants, each with a small effect size, can explain a significant portion of trait variance, as observed in studies simulating phenotypes with polygenic effects. [6] The mode of inheritance for such complex traits can involve both additive and non-additive genetic associations, including recessive models, further highlighting the intricate genetic landscape underlying familial conditions. [10]
Environmental Factors and Gene-Environment Interactions
Environmental factors play a significant role in modulating physiological processes, and by extension, can influence the manifestation or severity of familial glucocorticoid deficiency. While specific environmental causes for glucocorticoid deficiency are not detailed, analogous situations, such as vitamin D deficiency, illustrate the impact of external elements. Factors like aging, obesity, skin color, dietary intake, exposure to ultraviolet B sunlight, geographical latitude, and dietary supplement intake are known to affect vitamin D levels, highlighting how lifestyle and environmental exposures can influence the availability and metabolism of crucial biological compounds. [9] This suggests a broader principle that environmental elements could similarly impact glucocorticoid status.
The interplay between an individual's genetic makeup and their environment can be critical in determining the penetrance and expressivity of familial glucocorticoid deficiency. Genetic predispositions do not always act in isolation; environmental triggers can modulate their effects. For instance, the impact of genetic variants associated with vitamin D levels can vary significantly by season, demonstrating a direct gene-environment interaction. [13] This indicates that an individual's genetic background may confer a particular susceptibility that is only fully expressed or exacerbated under specific environmental conditions, suggesting a complex interaction between inherited risk and external factors in familial glucocorticoid deficiency. [12]
Pharmacogenomic Influences and Disease Modifiers
An individual's genetic profile can significantly influence their response to glucocorticoid medications, which can in turn affect the management and apparent severity of familial glucocorticoid deficiency. Pharmacogenomic studies have identified specific genetic variants that dictate how effectively a person responds to glucocorticoid interventions. For example, several SNPs, including rs6924808, rs10481450, rs1353649, and rs12438740, are associated with varied physiological responses to glucocorticoid therapy, with different genotypes exhibiting distinct dose-response patterns. [11] These genetic differences in drug target pathways, such as those involving the glucocorticoid receptor, can lead to individuals requiring different doses or showing varied clinical outcomes, thereby modifying the overall impact and perception of their glucocorticoid status. [14]
Beyond primary genetic and environmental factors, other physiological changes and conditions can act as modifiers in familial glucocorticoid deficiency. Age-related changes, for instance, are recognized as factors that can influence levels of vital biological compounds, as seen with vitamin D. [9] While the specific impact of aging on glucocorticoid deficiency is not detailed, it suggests that the body's changing physiology over time could modify the severity or presentation of an underlying familial predisposition. The overall genetic background and the presence of other health conditions, though not explicitly detailed as comorbidities for this specific trait, are broadly acknowledged as factors that can influence the expression and severity of complex diseases. [12]
Glucocorticoid Signaling and Receptor Function
Glucocorticoids are a class of steroid hormones critical for regulating a wide array of physiological processes, including metabolism, immune response, and stress adaptation. Their cellular effects are primarily mediated by the glucocorticoid receptor, a key biomolecule that acts as a ligand-activated transcription factor. Upon binding to glucocorticoids, the activated receptor translocates to the nucleus, where it modulates gene expression, thereby influencing various cellular functions and regulatory networks. [14] Familial glucocorticoid deficiency arises from disruptions in this intricate signaling pathway, leading to impaired cellular responses and a spectrum of clinical manifestations. Studies highlight a correlation between inherited genetic variants and the expression levels of the glucocorticoid receptor gene, underscoring the molecular basis of individual sensitivity to these hormones. [1]
Genetic Determinants of Glucocorticoid Sensitivity
The sensitivity to glucocorticoids is significantly influenced by an individual's genetic makeup, with inherited genetic variants playing a crucial role in determining cellular and systemic responses. Genome-wide association studies (GWAS) have successfully identified numerous genetic loci associated with varying physiological responses to glucocorticoid therapy, revealing a complex interplay of genetic mechanisms. [2] For instance, specific single nucleotide polymorphisms (SNPs) such as rs6924808 on chromosome 6, rs10481450 on chromosome 8, rs1353649 on chromosome 11, and rs12438740 and rs2230155 on chromosome 15 have been linked to significant variations in glucocorticoid responsiveness. [2] These variants, often found in high linkage disequilibrium, can impact gene expression patterns, including that of the glucocorticoid receptor, thereby directly affecting how cells and tissues react to glucocorticoids. [1]
Pathophysiological Manifestations and Therapeutic Response
The genetic variants underlying familial glucocorticoid deficiency contribute to diverse pathophysiological processes and variable therapeutic outcomes. Different genotypes can exhibit distinct dose-response patterns; for example, homozygotes for certain mutant alleles may not respond to glucocorticoid treatment until a specific dose level is reached, while genotypes with the wild-type allele might appear more resistant to increasing doses. [2] This genetic influence means that some SNPs explain a broad variation in response, while others account for a narrower range, affecting sensitivity to low doses or only becoming apparent at higher therapeutic levels. [2] Ultimately, the presence of specific mutant alleles can lead to a pronounced increase in physiological function, such as lung function following glucocorticoid treatment, compared to wild-type counterparts, highlighting the critical role of genetic background in mediating systemic consequences and compensatory responses. [2]
Genetic Modifiers and Disease Complexity
Familial glucocorticoid deficiency, as a Mendelian disorder, can exhibit a wide spectrum of severity, suggesting a significant role for genetic background effects and environmental factors in modifying its presentation. [12] The interplay between rare pathogenic variations, which often cause the core Mendelian trait, and more common polymorphisms can profoundly influence disease severity and progression. [12] Investigating these modifier effects in rare disorders is challenging due to their low prevalence, often necessitating advanced genetic mapping techniques, large biobank datasets, or the use of model organisms to uncover the full extent of genetic influences on homeostatic disruptions and their developmental processes. [12] While specific examples for familial glucocorticoid deficiency are not detailed here, the general principle of heritability and genetic background shaping health outcomes is well-established. [9]
Genetic Modifiers of Glucocorticoid Receptor Sensitivity
Genetic variations can significantly alter an individual's sensitivity to glucocorticoids, impacting the efficacy of treatment for conditions like familial glucocorticoid deficiency. Polymorphisms within the NR3C1 gene, which encodes the glucocorticoid receptor, are known to influence both therapeutic outcomes and the incidence of toxic side effects, as observed in studies of acute lymphoblastic leukemia (ALL) patients. [1] These variations can affect receptor expression, function, or downstream signaling, thereby modulating the cellular response to glucocorticoid hormones and exogenous medications.
Beyond the primary receptor, other genes contribute to the overall glucocorticoid response profile. For instance, suggestive single nucleotide polymorphisms (SNPs) such as rs904419, rs1995178, rs6549238, and rs6798211 have been identified within the 3p14.1 region, annotated to the FRMD4B gene, and are associated with sensitivity to prednisolone and dexamethasone. [1] The expression levels of FRMD4B have shown a correlation with glucocorticoid sensitivity, suggesting its role in modulating cellular responsiveness. In contrast, TGFBR3 gene expression did not demonstrate similar significant differences in sensitivity, highlighting the specificity of genetic influences on glucocorticoid pathways.
Pharmacodynamic Variability in Glucocorticoid Response
Genetic variants profoundly influence the pharmacodynamic response to glucocorticoid treatment, affecting how individuals respond to different drug doses. Studies have identified several loci with genome-wide significance for dose-dependent responses to glucocorticoids, including rs6924808 on chromosome 6, rs10481450 on chromosome 8, rs1353649 on chromosome 11, and rs12438740 and rs2230155 on chromosome 15. [2] For most of these variants, mutant alleles tend to enhance pulmonary function by 30-300% after glucocorticoid treatment compared to wild-type alleles, indicating a more robust therapeutic effect. Conversely, a specific mutant homozygote at rs37972 has been associated with a significant decrease (120-330%) in lung function, underscoring the potential for reduced efficacy or adverse outcomes in certain genetic backgrounds. [2]
The pattern of genetic effects on drug response can vary significantly; some SNPs, like rs6924808, are sensitive to low doses of the drug, while others, such as rs10481450 and rs12438740, only exhibit variability after a certain dose level is reached. [2] These genotype-specific differences translate into distinct pharmacodynamic parameters, including maximal effect (Emax), half-maximal effective concentration (EC50), and sigmoidicity (H), which collectively define the dose-response curve for each genetic profile. [2] Many of the identified significant SNPs demonstrate a recessive effect, meaning that individuals homozygous for the mutant alleles are primarily responsible for the observed variability in the glucocorticoid response. [2]
Clinical Implications for Personalized Glucocorticoid Therapy
The high heritability of glucocorticoid response attributed to individual genetic variants offers a strong foundation for personalized medicine. Understanding how specific genotypes influence pharmacodynamic parameters, such as Emax, EC50, and H, can guide clinicians in developing tailored dosing strategies to optimize therapeutic efficacy and mitigate potential adverse reactions. [2] For example, identifying individuals with variants associated with enhanced response might allow for lower starting doses, while those with variants linked to decreased response, like rs37972, might require alternative treatment approaches or closer monitoring. [2]
Integrating these pharmacogenomic insights into clinical practice can lead to more informed drug selection and personalized prescribing. The validation of these significant SNPs in multiple independent clinical trials reinforces their potential utility in predicting patient response to glucocorticoids. [2] By leveraging genetic information, healthcare providers can move towards a more precise approach to managing familial glucocorticoid deficiency, potentially improving patient outcomes through evidence-based, individualized treatment plans.
Frequently Asked Questions About Familial Glucocorticoid Deficiency
These questions address the most important and specific aspects of familial glucocorticoid deficiency based on current genetic research.
1. Why isn't my baby growing well, despite eating?
Your baby's poor feeding and failure to thrive could be a sign of familial glucocorticoid deficiency. This condition means their body can't make enough cortisol, a hormone vital for metabolism and energy. Without enough cortisol, they might experience recurrent low blood sugar (hypoglycemia), which impacts their ability to grow and develop properly. Genetic mutations in genes like MC2R and MRAP are often the cause.
2. Why is my child's skin getting darker?
A darkening of your child's skin, called hyperpigmentation, can be a symptom of familial glucocorticoid deficiency. This happens because when the adrenal glands don't produce enough cortisol, the pituitary gland tries to compensate by releasing more ACTH. High levels of ACTH can stimulate melanocytes, the cells that produce skin pigment, leading to a darker complexion. It's an important clue for diagnosis.
3. Will my children definitely inherit this condition?
If familial glucocorticoid deficiency runs in your family, the inheritance pattern depends on the specific genetic mutation involved. It's an inherited disorder, meaning genetic variants are passed down. Genetic counseling can help you understand the risks for future pregnancies and assess the likelihood of your children inheriting the condition, based on your family's genetic profile.
4. Do I really need to take this medicine my whole life?
Yes, if you have familial glucocorticoid deficiency, lifelong glucocorticoid replacement therapy, typically with hydrocortisone, is crucial. Your adrenal glands are unable to produce sufficient cortisol naturally, and cortisol is a vital hormone for many bodily functions. Taking your medicine consistently substitutes this missing hormone, preventing serious health complications like adrenal crises.
5. Why might my medicine dose be different from others?
Your specific medicine dose might vary because genetic factors influence how your body responds to glucocorticoid therapy. Research shows that inherited genetic variants, including specific single nucleotide polymorphisms (SNPs) like rs6924808, can affect your glucocorticoid sensitivity and how efficiently your body uses the medication. This personalized response is why pharmacogenomics is important for optimizing your treatment.
6. Why is it so urgent to diagnose this early?
Early diagnosis is critically important because familial glucocorticoid deficiency can lead to life-threatening adrenal crises if untreated. These are medical emergencies that can cause severe hypoglycemia, seizures, and even death. Prompt diagnosis and lifelong treatment ensure your child receives the necessary cortisol replacement, preventing these acute complications and enabling a better quality of life.
7. Is genetic testing worth it for my family?
Yes, genetic testing can be very valuable for your family. It provides a precise diagnosis by identifying the specific genetic mutations, such as those in MC2R or MRAP, that cause familial glucocorticoid deficiency. This information helps guide personalized treatment strategies and allows for genetic counseling, which is essential for understanding inheritance patterns and making informed family planning decisions.
8. Does my family's background affect my risk?
Your family's ethnic background can potentially influence your risk and how genetic findings apply to you. Many large-scale genetic studies have predominantly focused on populations of European or East Asian descent. This means that genetic variants and their effects might differ in other ancestral groups, highlighting the need for more diverse research to fully understand the condition worldwide.
9. Could my child's seizures be from this, not something else?
Yes, your child's seizures could indeed be a symptom of familial glucocorticoid deficiency. This condition often causes recurrent hypoglycemia, or dangerously low blood sugar, especially in infancy or early childhood. Severe hypoglycemia can trigger seizures, making it a critical symptom that points towards a potential diagnosis of this underlying endocrine disorder.
10. Can healthy living reduce my family's risk?
Unfortunately, healthy living alone cannot reduce your family's risk of developing familial glucocorticoid deficiency if there's a genetic predisposition. This condition is caused by specific inherited genetic mutations, such as those in MC2R or MRAP, that directly impair the adrenal glands' ability to produce cortisol. While a healthy lifestyle is always beneficial, it doesn't alter the fundamental genetic cause of this disorder.
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
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[10] Pankratz, N et al. "Genomewide association study for susceptibility genes contributing to familial Parkinson disease." Hum Genet, 2008.
[11] Wang, Y. "Pharmacodynamic genome-wide association study identifies new responsive loci for glucocorticoid intervention in asthma." Pharmacogenomics Journal, vol. 16, no. 5, 2016, pp. 411-420.
[12] Blair, D. R., et al. "Common genetic variation associated with Mendelian disease severity revealed through cryptic phenotype analysis." Nat Commun, vol. 13, no. 1, 2022, p. 35760791.
[13] Amin, H. A., et al. "No evidence that vitamin D is able to prevent or affect the severity of COVID-19 in individuals with European ancestry: a Mendelian randomisation study of open data." BMJ Nutr Prev Health, vol. 4, no. 1, 2021, pp. 195-201.
[14] Condreay, L. D., et al. "Pharmacogenetic investigation of efficacy response to mepolizumab in eosinophilic granulomatosis with polyangiitis." Rheumatol Int, vol. 40, no. 4, 2020, pp. 605-13.