Joint Disease
Joint disease encompasses a diverse group of conditions that affect the joints, the crucial connections between bones that enable movement and provide structural support. These diseases can manifest in various forms, from acute inflammatory responses to chronic degenerative processes, and are a leading cause of pain, impaired mobility, and reduced quality of life globally.
The biological basis of joint diseases is complex, often involving a delicate interplay of genetic predispositions, environmental triggers, and immune system dysregulation. Many inflammatory joint conditions, such as rheumatoid arthritis, have significant genetic components, with specific gene variations influencing immune responses. Degenerative conditions like osteoarthritis involve the breakdown of cartilage and underlying bone, a process that can also be influenced by genetic factors affecting cartilage health and repair mechanisms. Genome-wide association studies (GWAS) have been instrumental in identifying genetic loci, frequently in the form of Single Nucleotide Polymorphisms (SNPs), that are associated with susceptibility to a wide range of complex diseases, including those with joint manifestations[1]. These studies meticulously compare the genetic profiles of individuals with and without a disease to pinpoint common genetic variations that may confer an increased risk[2].
From a clinical perspective, understanding the genetic underpinnings of joint disease is paramount. Such knowledge can lead to the development of more accurate diagnostic tools, allowing for earlier identification and differentiation of various joint conditions. It also holds the promise of personalized treatment strategies, where therapies are tailored to an individual’s specific genetic profile, potentially improving efficacy and reducing adverse effects. Furthermore, genetic insights could contribute to preventative measures, identifying at-risk individuals before the onset of severe symptoms.
The social importance of joint disease is profound and far-reaching. These conditions significantly impact individuals’ ability to perform daily activities, maintain employment, and live independently, leading to substantial healthcare expenditures and a considerable burden on caregivers and society as a whole. Chronic pain and disability associated with joint diseases can also contribute to mental health challenges, including depression and anxiety. Ongoing research into the genetic basis of joint disease offers hope for developing more effective interventions, which could alleviate this societal burden, enhance the quality of life for millions, and promote healthier aging across populations.
Limitations
Section titled “Limitations”Research into complex conditions like joint disease, particularly through genome-wide association studies (GWAS), inherently faces several methodological and interpretive limitations. Acknowledging these constraints is crucial for a balanced understanding of current findings and for guiding future investigations.
Methodological and Statistical Considerations
Section titled “Methodological and Statistical Considerations”Initial genome-wide association studies for complex diseases often operate with limited genomic coverage and statistical power. For example, some discovery phases for similar conditions have been calculated to have only approximately 50% power to detect moderate effect sizes, such as an odds ratio of 2.0, even at a significance level of alpha < 0.05 [3]. This reflects the challenges in recruiting sufficiently large sample sizes for conditions where the phenotype is primarily defined clinically. Such power limitations can increase the risk of Type I errors or, conversely, may mask associations of moderate effect size, thereby requiring rigorous staged study designs and replication efforts to ensure the robustness of findings[3].
Replication studies are essential for confirming associations identified in initial GWAS, especially for loci exhibiting very low P values [1]. Without independent replication, there is a risk of reporting spurious associations that may arise from genotyping errors or random chance [3]. Furthermore, meticulous quality control is paramount in large datasets, as subtle systematic differences can obscure true associations [1]. The balance between stringent and lenient criteria for SNP exclusion is critical, as overly strict filters might discard genuine signals, while overly lenient ones risk swamping true findings with spurious results due to poor genotype calling. Therefore, systematic visual inspection of cluster plots for SNPs of interest remains an indispensable part of the quality control process [1].
Population Structure and Phenotype Definition
Section titled “Population Structure and Phenotype Definition”The interpretation of genetic association data must carefully consider the potential for population structure to confound inferences. While many studies employ statistical corrections, such as EIGENSTRAT, to account for population stratification [4], or demonstrate minimal confounding effects across most genomic regions [1], apparent associations in regions exhibiting strong geographical differentiation warrant cautious interpretation [1]. Beyond internal stratification, the generalizability of findings across diverse populations remains a significant challenge. Most studies may be predominantly based on cohorts of specific ancestries, potentially limiting the direct applicability of identified variants to other ethnic groups and highlighting the need for more diverse research populations.
Defining complex disease phenotypes, such as joint disease, particularly when diagnosis relies on clinical rather than purely genetic criteria, introduces inherent measurement concerns[3]. The clinical heterogeneity within a broad diagnosis of joint disease can obscure distinct genetic signals or lead to the identification of loci that are relevant only to specific sub-phenotypes. Moreover, there is evidence from other complex diseases that genetic effects can vary between males and females[1], suggesting that a single genetic association might not fully capture the disease’s manifestation across different sexes, thus necessitating sex-specific analyses where appropriate.
Incomplete Genetic Architecture and Predictive Value
Section titled “Incomplete Genetic Architecture and Predictive Value”Current genome-wide association studies, even with extensive coverage of common genetic variation, may not fully capture the complete genetic architecture of complex diseases like joint disease[1]. This limitation stems from several factors, including incomplete coverage of common variation by existing genotyping arrays and, more significantly, poor coverage of rare variants, including many structural variants, which reduces the power to detect rare, highly penetrant alleles [1]. Consequently, a failure to detect a prominent association signal for a particular gene does not conclusively exclude its involvement in disease pathogenesis[1]. It is widely recognized that much of the genetic susceptibility effects for complex diseases likely remain undiscovered, contributing to the phenomenon of “missing heritability.”
Despite the successful identification of numerous susceptibility loci for various complex diseases, the ability of these variants, either individually or in combination, to provide clinically useful prediction for joint disease remains limited[1]. The effect sizes of common variants typically identified in GWAS are often small, meaning that while they contribute to overall disease risk, they do not yet offer robust tools for personalized risk assessment or early diagnosis with high predictive accuracy. Future research needs to extend beyond mere statistical association to determine the functional range of associated phenotypes and to identify and characterize pathologically relevant variation that could lead to more impactful clinical applications[1].
Variants
Section titled “Variants”Genetic variations play a crucial role in influencing an individual’s susceptibility to joint diseases and related autoimmune conditions. These variations can affect immune responses, cellular functions, and the structural integrity of joint tissues. The following variants highlight diverse mechanisms through which genetic differences contribute to the complex etiology of joint disorders.
The HLA-B gene, with variants like rs146683910 , is a key component of the major histocompatibility complex (MHC) and is central to the immune system’s ability to present antigens to T cells. This process is fundamental for distinguishing self from non-self, and specific variations can predispose individuals to autoimmune conditions where the immune system mistakenly attacks the body’s own tissues, including joints. The broader HLA system, particularly the HLA-DRB1 locus, has long been recognized as a significant genetic factor in susceptibility to rheumatoid arthritis (RA), a chronic inflammatory joint disease characterized by the progressive destruction of synovial joints[1]. Furthermore, the human leukocyte antigen (HLA) system class II region also demonstrates a notable contribution to celiac disease susceptibility, underscoring its broad impact on immune-mediated disorders[1].
Variations in genes involved in cellular regulation and signaling pathways also significantly impact joint health. NCOA2 (Nuclear Receptor Coactivator 2), with variants such as rs558111321 , encodes a protein that acts as a coactivator for nuclear receptors and other transcription factors, influencing gene expression related to metabolism, development, and inflammation. Dysregulation of these pathways could affect chondrocyte function or immune cell activity within joints, similar to how other regulatory genes like PTPN2, a key negative regulator of inflammatory responses, are associated with RA and other inflammatory phenotypes [1]. ARHGAP22 (Rho GTPase Activating Protein 22), associated with rs576989219 , is involved in regulating Rho GTPase activity, which is critical for cell migration, adhesion, and cytoskeletal organization. These cellular processes are vital for maintaining joint integrity, cartilage repair, and controlling inflammatory cell infiltration in arthritic conditions, paralleling the role of genes such as CTLA-4 in T-lymphocyte regulation and RA susceptibility [1]. The gene MARK1 (MAP/microtubule affinity-regulating kinase 1), with variant rs148297397 , is involved in cell polarity and cytoskeletal dynamics, which are essential for tissue development and maintenance, including the complex architecture of joint tissues.
Genes directly or indirectly involved in maintaining the structural integrity of joints and cartilage are also important. The CDRT7 and CDRT8 genes, with variants like rs577262561 , are related to cartilage-derived retinoic acid-sensitive proteins, suggesting a direct role in cartilage development, maintenance, and repair. Given that rheumatoid arthritis and other joint diseases involve the degradation of cartilage, variations in these genes could influence susceptibility or progression by affecting cartilage resilience and regenerative capacity[1]. SYNE3 (Spectrin Repeat Containing Nuclear Envelope Protein 3), with variant rs577163016 , encodes a protein involved in linking the nuclear envelope to the cytoskeleton, influencing cell mechanics and tissue organization, which are fundamental to the robust structure of joint tissues. The importance of structural and regenerative components in joint health is further highlighted by associations with genes like KAZALD1, whose product is involved in bone regeneration[1]. Similarly, MYH13 and MYHAS (Myosin Heavy Chain 13 and associated genes), with variants like rs574455086 , are involved in muscle contraction and development. While primarily muscle-related, proper muscle function is crucial for joint stability and movement, and genetic variations could indirectly impact joint loading and long-term health.
Non-coding RNAs and pseudogenes, despite not encoding proteins, play significant regulatory roles that can indirectly impact joint disease.RNU6-283P, LINC02292, LINC02779, LINC00824, and MAFTRR (associated with rs368409746 ) are examples of these regulatory elements. Long intergenic non-coding RNAs (lincRNAs) such as LINC02292, LINC02779, and LINC00824 can modulate gene expression by affecting chromatin structure, transcription, or mRNA stability, potentially influencing inflammatory pathways or cell differentiation critical for joint tissue homeostasis. While the specific roles of these variants in joint disease are subjects of ongoing research, genome-wide association studies frequently identify novel loci, including those that may reside in non-coding regions, underscoring the broad genetic landscape influencing complex diseases[1]. PSMC1P12 (associated with rs531215209 ) is a pseudogene related to a proteasome subunit, and while pseudogenes often lose their protein-coding ability, they can still exert regulatory functions, such as acting as competing endogenous RNAs or influencing the expression of their functional counterparts. Such regulatory variations could subtly alter cellular responses to stress or inflammation, contributing to the complex etiology of joint disorders, and higher-density SNP arrays are continuously improving the ability to detect such associations [5].
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs146683910 | HLA-B - RNU6-283P | iritis spondylosis Back pain joint disease |
| rs558111321 | NCOA2 | joint disease |
| rs577163016 | LINC02292 - SYNE3 | joint disease |
| rs148297397 | LINC02779 - MARK1 | joint disease |
| rs577262561 | CDRT7 - CDRT8 | joint disease |
| rs539337875 | LINC00824 | joint disease |
| rs574455086 | MYH13, MYHAS | joint disease |
| rs531215209 | RNA5SP56 - PSMC1P12 | joint disease |
| rs368409746 | MAFTRR | joint disease |
| rs576989219 | ARHGAP22 | joint disease |
Classification, Definition, and Terminology
Section titled “Classification, Definition, and Terminology”Fundamental Definitions and Core Terminology
Section titled “Fundamental Definitions and Core Terminology”The term “joint disease” encompasses a broad spectrum of conditions affecting the body’s joints, each requiring precise definition for accurate understanding and study. Within this extensive category, “rheumatoid arthritis” stands as a key term, referring to a specific chronic inflammatory autoimmune disease primarily affecting the joints[6]. Establishing such precise definitions is critical for distinguishing different pathologies, guiding clinical practice, and facilitating focused research into underlying mechanisms and genetic predispositions. These definitions form the conceptual framework upon which more detailed classifications and diagnostic criteria are built.
Classification Systems and Diagnostic Criteria
Section titled “Classification Systems and Diagnostic Criteria”Formal classification systems are essential for categorizing joint-related conditions, ensuring consistency across clinical and research settings. For rheumatoid arthritis, the American Rheumatism Association 1987 revised criteria serve as a foundational nosological system for its classification[6]. These criteria provide specific diagnostic parameters, guiding clinicians and researchers in identifying individuals with the disease. Furthermore, the evaluation and comparison of different methods for disease classification in rheumatoid arthritis underscore an ongoing effort to refine these systems for improved accuracy and utility[7]. This iterative process highlights the dynamic nature of disease classification, moving towards more robust and universally applicable standards.
Clinical and Research Significance of Classification
Section titled “Clinical and Research Significance of Classification”The rigorous classification and definition of joint conditions like rheumatoid arthritis hold significant clinical and scientific importance. Such standardized approaches enable comprehensive epidemiological studies, allowing for accurate assessments of disease incidence and prevalence within populations, as exemplified by research into the incidence of rheumatoid arthritis in the United Kingdom[8]. Moreover, precise classification is fundamental for genetic research, facilitating the identification of susceptibility loci by enabling the study of affected family members and sibling pairs [9]. This ensures that genetic association studies are conducted on well-defined patient cohorts, enhancing the reliability and interpretability of findings related to disease etiology.
The development of joint disease is a multifactorial process, influenced by a complex interplay of genetic predispositions, environmental factors, and age-related changes. Understanding these causal pathways is crucial for prevention and treatment strategies.
Genetic Predisposition and Polygenic Risk
Section titled “Genetic Predisposition and Polygenic Risk”Genetic factors play a significant role in determining an individual’s susceptibility to joint disease. Research, often utilizing genome-wide association studies (GWAS), has identified numerous inherited variants, such as single nucleotide polymorphisms (SNPs), that are associated with an increased risk for various complex diseases[3]. These studies indicate that many conditions, including those affecting joint health, are polygenic, meaning they are influenced by multiple genes, each contributing a small effect to the overall risk [1]. For instance, specific susceptibility loci have been identified for conditions like inflammatory bowel disease (Crohn’s disease) and Kawasaki disease, which can sometimes have joint manifestations, underscoring the complex genetic architecture underlying these traits[10]. The collective impact of these genetic variants, rather than a single gene defect, shapes an individual’s inherited predisposition to disease[11].
Environmental and Lifestyle Influences
Section titled “Environmental and Lifestyle Influences”While genetic factors provide a foundation for disease susceptibility, environmental and lifestyle influences are critical modulators in the development of joint disease. The manifestation of complex conditions often involves an interaction between an individual’s genetic makeup and various external factors. Although specific environmental triggers for joint disease are not detailed in the provided research, the broader understanding of complex diseases suggests that elements such as lifestyle choices, dietary patterns, and specific environmental exposures can significantly impact disease risk. These environmental factors can activate or suppress disease pathways in genetically predisposed individuals, highlighting the importance of gene-environment interactions in the etiology of many conditions.
Developmental Factors and Age-Related Changes
Section titled “Developmental Factors and Age-Related Changes”The progression and onset of joint disease can also be influenced by developmental factors and changes that occur with age. While the provided studies do not detail early life influences or epigenetic mechanisms like DNA methylation and histone modifications specifically for joint disease, age itself is recognized as a significant factor in the manifestation of various complex conditions. For example, genetic associations have been investigated in relation to the age of onset for diseases such as late-onset Alzheimer’s disease and Parkinson’s disease[12]. This indicates that the impact of genetic predispositions and other causal factors can evolve throughout an individual’s lifespan, influencing when a disease becomes clinically apparent or its severity over time.
Biological Background
Section titled “Biological Background”Joint diseases encompass a wide spectrum of conditions that affect the integrity and function of joints, leading to symptoms such as pain, stiffness, and reduced mobility. These conditions arise from a complex interplay of genetic predispositions, environmental factors, and disruptions in various biological pathways at molecular, cellular, and tissue levels. Understanding these underlying mechanisms is crucial for elucidating disease pathogenesis and developing effective therapeutic strategies.
Genetic Underpinnings of Joint Health and Disease Susceptibility
Section titled “Genetic Underpinnings of Joint Health and Disease Susceptibility”Joint diseases, like many complex traits, exhibit a significant genetic component, with individuals inheriting varying susceptibilities. Genome-wide association studies (GWAS) have been instrumental in identifying numerous susceptibility loci across the genome that contribute to the risk of various inflammatory and autoimmune conditions, offering insights into shared biological pathways relevant to joint health [1]. These genetic variants, often single nucleotide polymorphisms (SNPs), can reside within or near genes, influencing their function, expression patterns, or the efficiency of regulatory elements that control when and where genes are turned on or off[13]. Such genetic predispositions can alter the production or activity of critical proteins and enzymes, thereby perturbing the delicate balance required for maintaining healthy joint tissues.
For example, specific gene alleles, such as those related to the GAB2gene, have been shown to modify disease risk in the presence of other genetic factors likeAPOE epsilon4carriers in conditions like Alzheimer’s, illustrating how genetic interactions can modulate disease susceptibility[14]. Similarly, the identification of IL23Ras a susceptibility gene for inflammatory bowel disease highlights the role of specific genetic variations in key immune signaling pathways, which can have broader implications for inflammatory processes affecting joints[15]. These genetic insights underscore the complex interplay between inherited factors and disease development, paving the way for a deeper understanding of the molecular basis of joint diseases.
Cellular and Molecular Pathways in Joint Pathogenesis
Section titled “Cellular and Molecular Pathways in Joint Pathogenesis”The health of joints relies on intricate cellular functions and finely tuned molecular pathways that govern tissue maintenance and repair. Disruptions in these fundamental processes can initiate or exacerbate joint disease. For instance, the process of autophagy, a critical cellular mechanism for recycling damaged cellular components and maintaining homeostasis, has been implicated in the pathogenesis of inflammatory conditions such as Crohn’s disease[13]. Impaired autophagy can lead to the accumulation of cellular debris, triggering inflammatory responses and contributing to tissue damage, which can manifest in joints.
Beyond autophagy, various signaling pathways and metabolic processes are crucial for cartilage integrity and synovial tissue function. Cellular regulatory networks involving enzymes, receptors, and transcription factors orchestrate the cellular response to stress, injury, and inflammation. Dysregulation in these networks, potentially influenced by genetic variants, can lead to chronic inflammation, degradation of structural components like collagen and proteoglycans, and ultimately, the progressive deterioration characteristic of many joint diseases.
Immune System Dysregulation and Inflammatory Responses
Section titled “Immune System Dysregulation and Inflammatory Responses”A critical driver in many forms of joint disease is the dysregulation of the immune system and subsequent chronic inflammatory responses. The immune system, normally protective, can mistakenly target joint tissues, leading to inflammation and damage, as seen in autoimmune conditions[16]. Genetic risk variants have been identified that are related to the immune response in diseases like celiac disease, indicating a shared genetic predisposition for immune-mediated pathologies[17]. Such variants can impact the function of key biomolecules, including receptors and signaling proteins, that regulate immune cell activation and inflammatory mediator production.
A prime example is the IL23Rgene, identified as a susceptibility locus for inflammatory bowel disease, which is known to be involved in T-cell differentiation and the production of pro-inflammatory cytokines[15]. Abnormalities in the IL-23/Th17 pathway, regulated by IL23R, can drive persistent inflammation, leading to tissue destruction not only in the gut but potentially in distant sites like joints. Understanding these immune-related pathways and the genetic factors that influence them is crucial for deciphering the mechanisms underlying inflammatory joint diseases and developing targeted therapies.
Tissue Homeostasis and Pathophysiological Disruptions
Section titled “Tissue Homeostasis and Pathophysiological Disruptions”Joints are complex structures comprising cartilage, bone, synovium, and ligaments, all of which must maintain a delicate homeostatic balance for proper function. Pathophysiological processes in joint disease involve the disruption of this balance, leading to progressive damage. While the provided research focuses on cardiovascular, gastrointestinal, and neurological conditions, the principles of tissue-level disruption and systemic consequences are broadly applicable. For instance, chronic inflammation, driven by genetic and environmental factors, can lead to the breakdown of cartilage and bone within the joint, causing pain, stiffness, and loss of mobility.
The interplay between different tissues within a joint, such as the synovial membrane and articular cartilage, is crucial. Inflammation in the synovium can release destructive enzymes and cytokines that degrade cartilage, demonstrating significant tissue interactions. Although not directly about joint disease, studies on subclinical atherosclerosis in major arterial territories highlight how systemic inflammatory processes can affect specific organ systems, a concept that extends to how systemic inflammation or autoimmune responses can target and damage joints[5]. Understanding these multifaceted disruptions, from molecular signals to tissue-level changes, is vital for comprehending the progression of joint diseases and developing strategies to restore tissue homeostasis.
Frequently Asked Questions About Joint Disease
Section titled “Frequently Asked Questions About Joint Disease”These questions address the most important and specific aspects of joint disease based on current genetic research.
1. My mom has bad joints; will I get them too?
Section titled “1. My mom has bad joints; will I get them too?”Yes, there’s a strong chance you could have a genetic predisposition if it runs in your family. Many inflammatory joint conditions like rheumatoid arthritis, and degenerative ones like osteoarthritis, have significant genetic components. Genome-wide association studies (GWAS) have identified specific genetic variations that influence your risk, meaning you might inherit a higher susceptibility.
2. Can exercise really overcome my family’s joint problems?
Section titled “2. Can exercise really overcome my family’s joint problems?”While genetics play a significant role in predisposing you to joint conditions by affecting things like cartilage health and immune responses, lifestyle factors are also crucial. Regular, appropriate exercise can strengthen the muscles around your joints, improve flexibility, and help manage weight, potentially mitigating some of the genetic risks you might carry.
3. Why do I have joint pain, but my healthy friends don’t?
Section titled “3. Why do I have joint pain, but my healthy friends don’t?”Joint disease often involves a complex interplay of genetic predispositions, environmental triggers, and immune system factors. You might have specific genetic variations that increase your susceptibility to certain joint conditions, even if your lifestyle seems similar to your friends’. These genetic factors can influence your body’s immune responses or how your cartilage and bones are maintained.
4. Could a DNA test tell me if my joint pain will get worse?
Section titled “4. Could a DNA test tell me if my joint pain will get worse?”Yes, understanding your genetic profile can lead to more accurate diagnostic tools, allowing for earlier identification and differentiation of various joint conditions. Genetic insights could help identify individuals at risk before severe symptoms, potentially guiding personalized treatment strategies. However, current genetic understanding is still evolving and doesn’t fully predict individual disease progression.
5. Does my ethnic background affect my risk of joint disease?
Section titled “5. Does my ethnic background affect my risk of joint disease?”Yes, it can. Most genome-wide association studies (GWAS) have primarily focused on cohorts of specific ancestries, which means the identified genetic variants may not directly apply to other ethnic groups. This highlights the need for more diverse research populations to fully understand how genetic risks might vary across different ethnic backgrounds.
6. Is it true that joints just get bad as I age, no matter what?
Section titled “6. Is it true that joints just get bad as I age, no matter what?”While degenerative conditions like osteoarthritis often become more prevalent with age, genetics play a significant role inhowyour joints age. Genetic factors influence your cartilage health and repair mechanisms, meaning some individuals are more predisposed to age-related joint breakdown than others. Understanding these genetic factors can help promote healthier aging.
7. Could a special diet or therapy work better for my specific joint pain?
Section titled “7. Could a special diet or therapy work better for my specific joint pain?”Yes, understanding your unique genetic profile holds the promise of personalized treatment strategies. Therapies could be tailored to your specific genetic makeup, potentially improving efficacy and reducing adverse effects compared to a one-size-fits-all approach. This is a key goal of genetic research in joint disease.
8. Do men and women experience joint disease differently because of genetics?
Section titled “8. Do men and women experience joint disease differently because of genetics?”Yes, there’s evidence from other complex diseases that genetic effects can vary between males and females. This suggests that a single genetic association might not fully capture how joint disease manifests across different sexes, indicating that sex-specific analyses are important for a complete understanding.
9. Can I prevent joint disease if it runs in my family?
Section titled “9. Can I prevent joint disease if it runs in my family?”While genetic predispositions are significant, genetic insights could contribute to preventative measures by identifying at-risk individuals before the onset of severe symptoms. Knowing your genetic risk factors could guide earlier interventions or lifestyle adjustments to potentially delay or reduce the severity of joint disease, though full prevention isn’t always possible.
10. Why do some people seem to recover from joint injuries faster than me?
Section titled “10. Why do some people seem to recover from joint injuries faster than me?”Your genetic makeup can influence your body’s repair mechanisms and immune responses, which are critical for healing after joint injuries or in managing conditions. Genetic factors affecting cartilage health and repair, for instance, could contribute to differences in how quickly and effectively individuals recover, even from similar injuries.
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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[5] O’Donnell, Christopher J., et al. “Genome-wide association study for subclinical atherosclerosis in major arterial territories in the NHLBI’s Framingham Heart Study.”BMC Med Genet, 2007. PMID: 17903303.
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[7] MacGregor, AJ, et al. “A comparison of the performance of different methods of disease classification for rheumatoid arthritis. Results of an analysis from a nationwide twin study.”J. Rheumatol., vol. 21, 1994, pp. 1420–1426.
[8] Symmons, DP, et al. “The incidence of rheumatoid arthritis in the United Kingdom: results from the Norfolk Arthritis Register.”Br. J. Rheumatol., vol. 33, 1994, pp. 735–739.
[9] Worthington, J, et al. “The Arthritis and Rheumatism Council’s National Repository of Family Material: pedigrees from the first 100 rheumatoid arthritis families containing affected sibling pairs.”Br. J. Rheumatol., vol. 33, 1994, pp. 970–976.
[10] Barrett, Jeffrey C., et al. “Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease.”Nature Genetics, vol. 40, no. 7, 2008, pp. 955-62.
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[12] Beecham, GW et al. “Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease.”Am J Hum Genet, PMID: 19118814.
[13] Rioux, John D., et al. “Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis.”Nature Genetics, vol. 39, no. 5, 2007, pp. 596-604.
[14] Reiman, Eric M., et al. “GAB2 alleles modify Alzheimer’s risk in APOE epsilon4 carriers.” Neuron, vol. 54, no. 5, 2007, pp. 713-22.
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[16] Nature. “Paths to understanding the genetic basis of autoimmune disease.”Nature, vol. 435, 2005, pp. 584-9.
[17] Hunt, Karen A., et al. “Newly identified genetic risk variants for celiac disease related to the immune response.”Nature Genetics, vol. 40, no. 4, 2008, pp. 395-402.