Impaired Renal Function Disease
Impaired renal function disease, commonly known as kidney disease, refers to a condition where the kidneys are damaged and lose their ability to effectively filter waste products and excess fluid from the blood. This can lead to a buildup of harmful substances in the body, causing a range of health complications. The condition can manifest acutely, with a sudden decline in kidney function, or chronically, involving a gradual and progressive loss of function over months or years, with chronic kidney disease (CKD) being a major global health concern.
The kidneys are a pair of vital organs responsible for maintaining the body’s homeostasis. Their primary biological functions include filtering blood to remove metabolic waste products (such as urea and creatinine), regulating electrolyte balance (e.g., sodium, potassium, calcium), controlling blood pressure through hormone production, stimulating red blood cell production, and maintaining acid-base balance. Impaired renal function arises when damage to the nephrons, the microscopic filtering units within the kidneys, compromises these essential processes. This damage can stem from various underlying causes, including prolonged high blood pressure, diabetes mellitus, autoimmune disorders, infections, genetic factors, and the use of certain medications.
Clinically, impaired renal function often progresses silently in its early stages, as the kidneys can compensate for significant damage. As the disease advances, symptoms may emerge, including fatigue, swelling in the extremities, muscle cramps, nausea, loss of appetite, difficulty concentrating, and changes in urination patterns. Severe or end-stage renal disease (ESRD) can lead to life-threatening complications such as cardiovascular disease, anemia, bone disorders, nerve damage, and requires life-sustaining treatments like dialysis or kidney transplantation. Diagnosis typically involves blood tests to measure creatinine and estimate glomerular filtration rate (eGFR), urine tests to detect protein or blood, and imaging studies.
From a societal perspective, impaired renal function disease represents a significant public health burden. Chronic kidney disease affects a substantial portion of the global population, contributing to considerable morbidity, disability, and premature mortality. Its increasing prevalence is closely linked to the rising rates of risk factors such as diabetes and hypertension. The disease profoundly impacts the quality of life for affected individuals, often necessitating complex medical management, dietary restrictions, and the demanding regimen of dialysis. Furthermore, the economic costs associated with treating impaired renal function, particularly ESRD, are immense, placing considerable strain on healthcare systems and national economies worldwide. Public health efforts are therefore focused on prevention, early detection, and effective management of risk factors to mitigate the progression of the disease and its widespread societal consequences.
Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”Genetic association studies, particularly those investigating complex diseases like impaired renal function, often face limitations related to sample size and statistical power. For instance, studies on relatively rare conditions may possess only modest sample sizes, which can result in approximately 50% power to detect even moderate effect sizes for genetic variants[1]. This insufficient power increases the risk of Type II errors, meaning true genetic associations might be missed, thereby hindering the comprehensive identification of susceptibility loci. Consequently, the absence of a prominent association signal in such studies cannot definitively exclude the involvement of specific genes or pathways [2].
A critical aspect of robust genetic discovery is the need for independent replication to confirm initial associations [2]. While staged study designs are employed to manage the challenge of multiple statistical comparisons and potentially identify associations of moderate effect size[1], this approach still requires careful validation. Without thorough replication, particularly for findings that do not reach very low P values in initial discovery phases, there is a risk of reporting inflated effect sizes or spurious associations, which can complicate the interpretation of genetic risk factors for impaired renal function. Furthermore, incomplete coverage of common or rare genetic variations by array-based genotyping platforms can inherently reduce the power to detect significant associations, including those from less common, penetrant alleles [2].
Phenotypic Definition and Generalizability
Section titled “Phenotypic Definition and Generalizability”The clinical definition of a disease phenotype, such as impaired renal function, can introduce variability and challenges in genetic studies. When a phenotype is defined clinically, as opposed to through highly objective biomarkers, there is potential for heterogeneity in patient classification[1]. This variability can dilute genetic signals, making it more difficult to identify consistent and robust genetic associations, and subsequently impacting the precision with which specific genetic variants are linked to the disease. Such challenges underscore the importance of standardized and objective phenotyping across different study cohorts.
Generalizability of findings across diverse populations is another significant limitation. Genetic association studies are susceptible to population stratification, where differences in allele frequencies between distinct ancestral groups can lead to spurious associations if not adequately accounted for [3]. While methods like EIGENSTRAT correction are applied to mitigate this, residual stratification can still affect results. Therefore, findings from studies predominantly conducted in populations of specific ancestries may not be directly transferable or fully representative of the genetic architecture of impaired renal function in other populations, necessitating further research in diverse cohorts to determine the full range of associated phenotypes and variants [2].
Remaining Etiological Gaps and Predictive Value
Section titled “Remaining Etiological Gaps and Predictive Value”Despite the identification of numerous susceptibility loci for various complex diseases through genome-wide association studies, a substantial portion of the genetic contribution to conditions like impaired renal function often remains unexplained. The failure to detect prominent association signals for every relevant gene can stem from factors such as incomplete genomic coverage of both common and rare variants, thereby limiting the power to identify all causative alleles [2]. This suggests that the current understanding of the genetic architecture is incomplete, with many genetic factors and their interactions yet to be discovered.
Furthermore, the interplay between genetic predispositions and environmental factors, or gene-environment interactions, is often not fully elucidated in current association studies, yet these interactions are crucial for complex diseases. While genetic variants are identified, they have not yet, singly or in combination, consistently provided clinically useful prediction of disease risk[2]. This indicates a significant gap between identifying susceptibility loci and translating these findings into actionable clinical tools for risk prediction or personalized treatment strategies for impaired renal function, highlighting the need for more comprehensive etiological models.
Variants
Section titled “Variants”Genetic variations play a crucial role in influencing an individual’s susceptibility to various diseases, including conditions that lead to impaired renal function. These single nucleotide changes, or variants, can alter gene activity, protein function, or regulatory processes, contributing to disease development and progression. Understanding these variants helps to elucidate the complex genetic architecture underlying kidney health and disease.
The APOL1gene, which codes for Apolipoprotein L1, is strongly linked to several forms of chronic kidney disease, particularly in individuals of African descent. Variants such asrs9622363 and rs9622362 are part of common risk haplotypes (G1 and G2) that are associated with a significantly increased risk of focal segmental glomerulosclerosis (FSGS), HIV-associated nephropathy (HIVAN), and hypertension-attributed nephropathy. These specific DNA changes are believed to alter the APOL1 protein’s ability to form pores in cell membranes, leading to cellular toxicity and injury in kidney cells, thereby contributing to progressive renal failure[2]. The presence of these high-risk variants can accelerate the decline of kidney function, highlighting APOL1’s critical role in renal disease susceptibility.
Another important gene is UMOD, encoding uromodulin, also known as Tamm-Horsfall protein, the most abundant protein found exclusively in urine. The variant rs36060036 , located within an intron of the UMOD gene, can influence its expression or splicing. Uromodulin plays a vital role in kidney stone formation, electrolyte balance, and protecting against urinary tract infections. Mutations or variants affecting UMODfunction, including those that alter protein folding or secretion, are known to cause UMOD-associated kidney diseases such as familial juvenile hyperuricemic nephropathy and medullary cystic kidney disease type 2, both characterized by progressive renal impairment and often leading to end-stage renal disease[4].
The TCF7L2 gene, which produces Transcription Factor 7 Like 2, is a key regulator in the Wnt signaling pathway, essential for cell development and metabolism. The variant rs7903146 is one of the strongest genetic risk factors for type 2 diabetes, a major cause of chronic kidney disease (diabetic nephropathy)[5]. This intronic variant is thought to affect TCF7L2gene expression or splicing, influencing pancreatic beta-cell function and insulin secretion. By significantly increasing the risk of type 2 diabetes,rs7903146 indirectly contributes to the development and progression of diabetic nephropathy, a leading cause of impaired renal function worldwide [6].
Variants in genes like PDILT (Protein Disulfide Isomerase Like T) and HRH1 (Histamine Receptor H1) are also subjects of genetic association studies. The PDILT gene, encoding a protein disulfide isomerase, is involved in protein folding and quality control within cells, particularly in the endoplasmic reticulum. The intronic variant rs77924615 may influence PDILT expression, potentially impacting cellular stress responses or protein handling within kidney cells, which are crucial for maintaining renal health [2]. Similarly, HRH1 encodes the histamine H1 receptor, mediating various physiological processes including inflammation and vascular tone. The intronic variant rs74812151 could affect HRH1 function, potentially influencing inflammatory responses or hemodynamics within the kidneys, thereby playing a role in the pathogenesis of renal diseases [2]. While the direct mechanisms connecting these specific variants to renal function are still being explored, their involvement in fundamental cellular processes suggests a potential contribution to kidney disease susceptibility.
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs9622363 rs9622362 | APOL1 | apolipoprotein L1 measurement anemia, chronic kidney disease anemia (phenotype) phosphorus metabolism disease Abnormality of metabolism/homeostasis |
| rs77924615 | PDILT | glomerular filtration rate chronic kidney disease blood urea nitrogen amount serum creatinine amount protein measurement |
| rs36060036 | UMOD | CD27 antigen measurement corneodesmosin measurement trefoil factor 3 measurement tgf-beta receptor type-2 measurement thrombomodulin measurement |
| rs7903146 | TCF7L2 | insulin measurement clinical laboratory measurement, glucose measurement body mass index type 2 diabetes mellitus type 2 diabetes mellitus, metabolic syndrome |
| rs74812151 | HRH1 | impaired renal function disease |
Genetic Predisposition and Complex Inheritance
Section titled “Genetic Predisposition and Complex Inheritance”Impaired renal function disease, like many complex human conditions, can be significantly influenced by an individual’s genetic makeup. Research utilizing genome-wide association studies (GWAS) has been instrumental in identifying numerous susceptibility loci and inherited variants that contribute to the risk of various complex diseases[2]. These studies reveal a polygenic architecture where multiple genes, each potentially exerting a small effect, collectively increase an individual’s predisposition, often involving gene-gene interactions rather than simple Mendelian inheritance [2]. Such genetic factors can influence fundamental biological pathways, including those governing renal development, cellular function, or the kidney’s response to physiological stressors, thereby increasing the likelihood of developing impaired renal function disease.
Genetic Underpinnings of Complex Physiological Traits
Section titled “Genetic Underpinnings of Complex Physiological Traits”Understanding complex physiological conditions, such as impaired renal function disease, often involves unraveling the intricate interplay of genetic predispositions and environmental factors. Genome-wide association studies (GWAS) have emerged as a powerful tool for identifying genetic variants that contribute to the susceptibility of various common diseases[6]. These studies systematically survey the human genome to pinpoint specific loci, or regions of DNA, where variations are statistically associated with a particular trait or disease risk. The identification of such susceptibility loci provides crucial insights into the genetic architecture of conditions like cardiovascular disease outcomes[7], subclinical atherosclerosis[8], and even specific physiological responses like echocardiographic dimensions and endothelial function [9], by highlighting genes whose functions or regulatory elements may be compromised.
Molecular and Cellular Regulatory Networks
Section titled “Molecular and Cellular Regulatory Networks”At the molecular and cellular level, the proper functioning of organs relies on tightly regulated signaling pathways and metabolic processes. Key biomolecules, including critical proteins, enzymes, receptors, and hormones, orchestrate a vast array of cellular functions that maintain physiological balance. For instance, angiotensin II is a significant signaling molecule involved in various physiological processes, notably observed to antagonize cGMP signaling in vascular smooth muscle cells[9]. Such intricate molecular interactions are fundamental to normal physiological operation, and any dysregulation within these networks can disrupt cellular homeostasis and potentially lead to systemic consequences.
Homeostatic Disruptions and Pathophysiological Processes
Section titled “Homeostatic Disruptions and Pathophysiological Processes”Pathophysiological processes in complex diseases frequently arise from the disruption of homeostatic mechanisms, where the body’s ability to maintain a stable internal environment is compromised. Genetic variations can influence these processes by altering gene expression patterns, modifying protein function, or impacting regulatory networks, which may lead to cellular dysfunction. Initially, the body might mount compensatory responses to counteract these disruptions, but persistent stress or severe genetic predispositions can overwhelm these mechanisms. The study of conditions like hypertension, where context-dependent genetic effects are observed[9], illustrates how genetic factors can contribute to profound physiological imbalances that underpin disease progression.
Systemic and Organ-Level Interactions
Section titled “Systemic and Organ-Level Interactions”Complex diseases rarely affect a single cell type or organ in isolation, often involving intricate tissue interactions and systemic consequences that impact the entire organism. While specific organs may bear the brunt of the disease, their dysfunction can trigger a cascade of effects across different systems. For example, research into cardiovascular disease outcomes[7] and endothelial function [9]demonstrates how localized cellular changes, such as those affecting vascular smooth muscle cells, can have broader implications for cardiovascular health. Understanding these multi-level biological interactions, from genetic variants to molecular pathways and organ-system effects, is crucial for comprehending the full spectrum and progression of a disease.
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Regulatory Signaling in Vascular Homeostasis
Section titled “Regulatory Signaling in Vascular Homeostasis”The precise regulation of vascular tone is fundamental for maintaining stable renal function, a process primarily governed by complex signaling pathways. A significant interaction involves angiotensin II, a potent vasoconstrictor, which is known to antagonize cGMP signaling within vascular smooth muscle cells[9]. This molecular interaction plays a critical role in balancing blood vessel constriction and dilation, directly influencing renal perfusion and the filtration capacity of the kidneys. The activation of receptors by angiotensin II initiates an intracellular cascade that counteracts the effects of cGMP, thereby influencing cellular responses essential for vascular homeostasis.
This antagonism serves as a key regulatory mechanism, where an imbalance can lead to pathway dysregulation. For instance, an overactive angiotensin II pathway or a diminished cGMP response could shift the vascular state towards excessive vasoconstriction, contributing to elevated systemic blood pressure. Such sustained hemodynamic stress can detrimentally affect the renal microvasculature, progressively impairing kidney function. Therefore, a comprehensive understanding of the components and interactions within this signaling axis is crucial for elucidating the molecular basis of renal health and disease.
Genetic Modulators and Systemic Interactions
Section titled “Genetic Modulators and Systemic Interactions”Beyond individual molecular interactions, the overall health of the renal system is profoundly influenced by systems-level integration, where various pathways engage in crosstalk and form complex networks. Genetic factors significantly modulate these interactions, as evidenced by context-dependent genetic effects observed in conditions such as hypertension[10]. These genetic variations can influence the expression or activity of key signaling components, thereby altering the overall functional output of regulatory systems that govern blood pressure and renal hemodynamics. This hierarchical regulation underscores how genetic predispositions can modify physiological responses at a systemic level, impacting renal function.
The interplay between genetic background and environmental factors can lead to emergent properties at the organismal level, manifesting as susceptibility to diseases that affect renal function. For example, genetic variants influencing components of the angiotensin II-cGMP axis or related pathways could predispose individuals to hypertension, which is a primary driver of impaired renal function. Identifying these genetic modulators and understanding their impact on regulatory mechanisms is crucial for elucidating disease-relevant mechanisms and potentially informing future therapeutic strategies aimed at restoring renal homeostasis.
Clinical Relevance
Section titled “Clinical Relevance”Genetic Insights into Disease Risk and Progression
Section titled “Genetic Insights into Disease Risk and Progression”Genome-wide association studies (GWAS) are instrumental in identifying genetic loci associated with complex diseases, a methodology that holds significant promise for understanding impaired renal function. Research has successfully uncovered novel susceptibility genes for conditions such as coronary artery disease[6], [11], inflammatory bowel disease[12], and Parkinson disease[4]. Applying similar investigative approaches to impaired renal function could reveal underlying genetic predispositions, contributing to a deeper understanding of its pathogenesis and the biological pathways involved. These genetic discoveries are foundational for future advancements in clinical understanding and management.
Diagnostic and Prognostic Applications
Section titled “Diagnostic and Prognostic Applications”The findings from genome-wide association studies have demonstrated their potential to provide clinically useful prediction of disease[2]. For impaired renal function, genetic markers identified through GWAS could serve as valuable diagnostic tools, enabling earlier identification of individuals at risk or those presenting with subtle symptoms. Moreover, these genetic insights offer significant prognostic value, potentially predicting the trajectory of disease progression, the likelihood of complications, and long-term patient outcomes. This is akin to how genetic correlates have been explored for longevity and various age-related phenotypes[13], as well as for cardiovascular disease outcomes[7], guiding earlier interventions and tailored monitoring strategies for high-risk patient populations.
Comorbidity and Overlapping Phenotypes
Section titled “Comorbidity and Overlapping Phenotypes”Many complex diseases often co-occur or share common genetic underpinnings, leading to overlapping phenotypes. GWAS efforts have identified shared susceptibility loci across different conditions, such as those observed for various cardiovascular disease outcomes[7], subclinical atherosclerosis[8], and even echocardiographic dimensions [9]. For individuals with impaired renal function, understanding its genetic associations with related conditions or complications could illuminate syndromic presentations and common mechanistic pathways. This comprehensive view of genetic associations is crucial for a holistic approach to patient management, ensuring that not only the primary renal impairment but also its frequently associated comorbidities are effectively addressed.
Personalized Prevention and Treatment Strategies
Section titled “Personalized Prevention and Treatment Strategies”The identification of genetic risk variants through genome-wide association studies supports the evolution of personalized medicine. By stratifying individuals based on their unique genetic profiles, clinicians could identify those at highest risk for developing or progressing with impaired renal function, thereby enabling the implementation of targeted prevention strategies before irreversible damage occurs. While research has focused on identifying loci for diseases like Crohn’s disease[14], [15]or celiac disease[16], the underlying principle extends to tailoring treatment selection and monitoring strategies based on an individual’s genetic predisposition and predicted response. This approach facilitates more effective and individualized patient care, moving away from generalized treatment protocols.
Frequently Asked Questions About Impaired Renal Function Disease
Section titled “Frequently Asked Questions About Impaired Renal Function Disease”These questions address the most important and specific aspects of impaired renal function disease based on current genetic research.
1. My family has kidney problems. Will my kids definitely get it too?
Section titled “1. My family has kidney problems. Will my kids definitely get it too?”Not necessarily. While genetic factors certainly play a role in kidney disease risk, it’s not a guarantee your children will inherit it. Many genetic variants contribute, and their impact can vary. Lifestyle and environmental factors also strongly influence whether the disease develops, even with a family history.
2. Why did I get kidney disease even though I eat healthy and exercise?
Section titled “2. Why did I get kidney disease even though I eat healthy and exercise?”It can be frustrating when you do everything right. Even with a healthy lifestyle, genetic predispositions can significantly increase your risk for kidney disease. Some people inherit genetic variations that make their kidneys more vulnerable to damage, regardless of external factors, or make them more susceptible to conditions like high blood pressure or diabetes that lead to kidney issues.
3. Can a DNA test tell me if I’m at risk for kidney disease?
Section titled “3. Can a DNA test tell me if I’m at risk for kidney disease?”Genetic tests can identify some susceptibility loci for kidney disease. However, current genetic tests don’t yet provide a complete picture or consistently useful prediction of disease risk. Many genetic factors are still unknown, and gene-environment interactions are complex, so a test might only show a partial risk.
4. If my doctor says my kidneys are fine now, does that mean I’m safe from my family history?
Section titled “4. If my doctor says my kidneys are fine now, does that mean I’m safe from my family history?”Not entirely. Early stages of kidney disease often have no noticeable symptoms because your kidneys can compensate for significant damage. Even with a strong family history, regular monitoring, especially for risk factors like blood pressure and blood sugar, is crucial for early detection, as genetic factors can make you more prone to developing the condition later.
5. I’m from a specific ethnic background. Does that change my kidney disease risk?
Section titled “5. I’m from a specific ethnic background. Does that change my kidney disease risk?”Yes, it can. Genetic risk factors for kidney disease can differ among various ancestral populations. Findings from studies in one group might not fully apply to others due to population differences in gene frequencies. This means your ethnic background could influence your specific genetic predispositions and overall risk profile.
6. Why do some people develop severe kidney disease faster than others?
Section titled “6. Why do some people develop severe kidney disease faster than others?”The speed of progression can vary greatly due to a combination of genetic and environmental factors. Some individuals may have specific genetic variants that lead to more aggressive disease progression, or they might have underlying conditions like uncontrolled diabetes or hypertension that interact negatively with their genetic makeup, accelerating kidney damage.
7. Can I really prevent kidney disease if it’s “in my genes”?
Section titled “7. Can I really prevent kidney disease if it’s “in my genes”?”You can significantly influence your risk, even with a genetic predisposition. While you can’t change your genes, lifestyle choices like managing blood pressure, controlling diabetes, and maintaining a healthy diet can mitigate genetic risks. These actions can delay onset or reduce the severity of the disease by positively interacting with your genetic makeup.
8. My sibling has kidney issues, but mine are fine. Why the difference?
Section titled “8. My sibling has kidney issues, but mine are fine. Why the difference?”Even within the same family, genetic expression and environmental exposures differ. While you share many genes, specific genetic variants might be inherited differently or have varying penetrance between siblings. Additionally, individual lifestyle choices, diet, and exposure to other risk factors can lead to different outcomes, even with similar genetic backgrounds.
9. Why are early kidney problems so hard to spot, even if I have risk factors?
Section titled “9. Why are early kidney problems so hard to spot, even if I have risk factors?”Kidneys are remarkably resilient and can compensate for significant damage in the early stages without showing obvious symptoms. This “silent” progression makes early detection challenging. While genetic factors can contribute to vulnerability, the compensatory ability of the kidneys means symptoms often only appear when the disease is more advanced.
10. If I’m careful with my diet, can I overcome my genetic predisposition to kidney disease?
Section titled “10. If I’m careful with my diet, can I overcome my genetic predisposition to kidney disease?”Being careful with your diet is a powerful tool to manage your risk. While you can’t “turn off” your genetic predisposition, a healthy diet, alongside other lifestyle choices, can significantly modify how those genes express themselves and reduce their impact. This gene-environment interaction means you can often delay or lessen the severity of the disease, even with a genetic risk.
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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[3] Garcia-Barcelo, MM, et al. “Genome-wide association study identifies NRG1 as a susceptibility locus for Hirschsprung’s disease.”Proc Natl Acad Sci U S A, Feb. 2009.
[4] Pankratz, N. et al. “Genomewide association study for susceptibility genes contributing to familial Parkinson disease.”Hum Genet, vol. 124, no. 6, 2008, pp. 593-605.
[5] Saxena, R. et al. “Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels.”Science, vol. 316, no. 5829, 2007, pp. 1331-36.
[6] Samani, N. J. et al. “Genomewide association analysis of coronary artery disease.”N Engl J Med, vol. 357, no. 5, 2007, pp. 443-53.
[7] Larson, M. G. et al. “Framingham Heart Study 100K project: genome-wide associations for cardiovascular disease outcomes.”BMC Med Genet, vol. 8, no. S1, 2007, p. S5.
[8] O’Donnell, C. J., et al. “Genome-wide association study for subclinical atherosclerosis in major arterial territories in the NHLBI’s Framingham Heart Study.”BMC Med Genet, vol. 8, suppl. 1, 2007, p. S4.
[9] Vasan, R. S., et al. “Genome-wide association of echocardiographic dimensions, brachial artery endothelial function and treadmill exercise responses in the Framingham Heart Study.”BMC Med Genet, vol. 8, suppl. 1, 2007, p. S2.
[10] Kardia, Stephen L. “Context-dependent genetic effects in hypertension.”Current Hypertension Reports, vol. 2, no. 1, 2000, pp. 32-38.
[11] Erdmann, J., et al. “New susceptibility locus for coronary artery disease on chromosome 3q22.3.”Nat Genet, vol. 41, no. 3, 2009, pp. 280-2.
[12] Duerr, R. H., et al. “A genome-wide association study identifies IL23R as an inflammatory bowel disease gene.”Science, vol. 314, no. 5807, 2006, pp. 1921-3.
[13] Lunetta, K. L. et al. “Genetic correlates of longevity and selected age-related phenotypes: a genome-wide association study in the Framingham Study.” BMC Med Genet, vol. 8, no. S1, 2007, p. S2.
[14] Rioux, J. D., et al. “Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis.”Nat Genet, vol. 39, no. 5, 2007, pp. 596-604.
[15] Barrett, J. C., et al. “Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease.”Nat Genet, vol. 40, no. 7, 2008, pp. 955-62.
[16] Hunt, K. A., et al. “Newly identified genetic risk variants for celiac disease related to the immune response.”Nat Genet, vol. 40, no. 4, 2008, pp. 395-402.