Epidemiology and genetics of rheumatic diseases

3 Epidemiology and genetics of rheumatic diseases



Matthew A. Brown


Cases relevant to this chapter


68, 76, 80, 92, 95, 98



Essential facts




1. Musculoskeletal disorders are common, with osteoarthritis affecting 80% of the population over 75 years of age and 12% of the population between 25 and 74 years of age.


2. There is a genetic component to most musculoskeletal disorders, and the genetic risk of common musculoskeletal conditions is determined by multiple genes.


3. HLA-DRB1 is the major risk gene for anti-cyclic citrullinated peptide antibody (ACPA) positive rheumatoid arthritis, but appears not be involved in ACPA-negative disease.


4. Ankylosing spondylitis has very high heritability and familiality, due to the presence of HLA-B27, but only 1–5% of HLA-B27 carriers actually develop disease.


5. Many genes have been implicated in osteoporosis, but the risk of fracture remains predominantly non-genetic.


All common rheumatic diseases have a substantial genetic component, which is not surprising given the importance of a functional musculoskeletal system in survival in times of hardship, and the inverse relationship between risk factors for autoimmunity and immunity. Genes do not, however, operate in isolation; they interact with one another and with environmental factors. Much is already known about environmental factors involved in rheumatic diseases, and the genes involved are steadily being identified.



Heritability and familiality of rheumatic diseases


The relative magnitude of the genetic and environmental contributions to variation in the risk for developing a disease can be documented by measuring heritability in twins or families, or demonstrating familiality, which is the tendency of a condition to recur in families compared with the frequency in the general population. A weakness of both of these approaches is that they generally assume similar sharing of environmental risk factors for a disease, which is difficult to prove. Studies of concordance rates of twins or non-twin siblings raised either together or separately can at least partially address this question, although even such studies do not control for environmental sharing before the siblings are separated (e.g. in utero), and identifying sufficient numbers of families raised separately is very difficult unless the disease is common.


Heritability reflects the proportion of a population’s risk of a disease or variance of a trait that is explained by genetic factors. Where everyone in the population is exposed to an environmental risk factor, any variation in the trait influenced by that risk is not due to exposure to that environmental factor, but rather is genetic. For example, ankylosing spondylitis (AS) has a heritability greater than 90% in twins, but it is likely that an unknown environmental factor plays a significant role in its causation. A similar situation exists in osteoporosis, where the variation in bone density in the general population is high, but numerous environmental risk factors are known to be important. For example, poor dietary calcium intake causes low bone density, but in the range of intakes prevalent in the population there is little effect on bone density compared with the influence of genes, and thus the heritability is high.


The familiality of a condition compared with the general population, termed the ‘recurrence risk ratio’, is an important statistic in determining the difficulty of mapping genes, as it is related to the heritability, number of genes involved, their population frequencies and individual magnitudes of effect. The most frequently quoted statistic to assess familiality is the sibling recurrence risk ratio, λS, which is the recurrence rate in siblings of cases, compared with the population frequency of the disease. Demographic details for common rheumatic diseases are given in Table 3.1, and heritability and sibling recurrence risk ratios are shown in Table 3.2.



Table 3.1 Demographic details of common rheumatic diseases

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Table 3.2 Heritability, familiality (assessed by the sibling recurrence risk ratio) of common rheumatic diseases











































Disease Heritability (%) Sibling Recurrence Risk Ratio
Hip osteoarthritis    
Radiographic 58  
Requiring joint replacement 27 1.9
Osteoporosis    
Twins 80–90  
Families 40–80 5
Rheumatoid arthritis 60 5–10
Systemic lupus erythematosus 60 14
Ankylosing spondylitis 97 52–82

Evidence for a role for genetic factors in a condition can also come from the finding of families with monogenic inheritance of the disease. Although in some conditions such as rheumatoid arthritis (RA) and AS no clearly monogenic causes have been established, other conditions, such as chondrocalcinosis, osteoporosis, osteoarthritis, systemic lupus erythematosus (SLE) and Paget’s disease, can be caused by a single gene mutation. Such monogenic traits tend to be rare, because natural selection prevents the disease-causing mutation from becoming common in the community.



Rheumatoid arthritis


Despite case reports linking environmental exposure to infections, such as human parvovirus, Epstein–Barr virus and hepatitis B, there is no convincing evidence of a relationship between any triggering infective factor and RA. Cigarette smoking is clearly a risk factor for ACPA-positive RA, and it has been estimated that 35% of ACPA-positive RA is attributable to cigarette smoking. Genetic factors have an established role in severe disease, but genetic associations and heritability in less severe cases are much weaker. Nonetheless, strong established associations exist with MHC (major histocompatibility complex) and non-MHC genes (Figs 3.1 & 3.2 show some of the genetic sequences present on chromosome 6).


image

FIGURE 3.1 MHC region of chromosome 6


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FIGURE 3.2 Detailed map of genes present on short arm of chromosome 6



The MHC


The MHC is the major locus in all common inflammatory rheumatic diseases. It is situated on chromosome 6 (6p21.3), extends over 3.6 million base-pairs and is divided into three regions: class I, II and III. The class I region, at the telomeric end of the MHC, contains the HLA class I genes, HLA-A, -B and -C, and extends over 2000 kilobases (kb). In the HLA class II region are the HLA-DR, -DP and -DQ loci, encoding the α and β chains of the various HLA class II molecules. The class III region lies between the class I and II regions and contains the tumour necrosis factor (TNF), complement and heat-shock protein genes. The MHC is a highly gene-dense region containing about 224 genes, 40% of which are predicted to have immunoregulatory functions. Approximately 30% of the genetic risk for RA is encoded within the MHC.


Gregersen and colleagues first proposed the unifying ‘shared epitope’ (SE) hypothesis, demonstrating that RA is associated with specific HLA-DRB1 (DRB1) alleles that encode a conserved sequence of amino acids termed the SE, which comprise residues 70–74 in the third hypervariable region (HVR3) of the DRβ1 chain. HLA-DRB1 is associated with ACPA-positive, but not ACPA-negative, RA, suggesting significant differences in aetiopathogenesis between the two RA subsets. Gene–environment interaction is involved, with cigarette smoking markedly increasing the risk of RA in ACPA-positive individuals, but not ACPA-negative disease.



Non-MHC genes and RA


Rapid progress has been made using the genome-wide association study approach to identify non-MHC genes associated with RA, with over 30 genes now known to be associated with the disease. The genes involved generally fall into one of a few pathways involved, as discussed below.



T-cell differentiation/activation genes


PTPN22 was the first non-MHC gene to be confirmed to be associated with RA. It encodes a 110-kDa cytoplasmic protein tyrosine phosphatase (Lyp) that is thought to function as a down-regulator of T-cell receptor-dependent responses through interaction with a negative regulatory kinase, Csk. This gene is also associated with a variety of other autoimmune diseases including type 1 diabetes (T1DM), SLE, Addison’s disease and Hashimoto’s thyroiditis. PTPN22 is not associated with RA in Asians, because the key associated variant (rs2476601, R620W) is not polymorphic in Asian populations.


STAT4, another T-cell activation gene significantly associated with RA, is also associated with other organ-specific autoimmune diseases including T1DM and SLE. STAT4 (signal transducer and activator of transcription 4) is a transcription factor that is phosphorylated by Janus kinase (JAK) proteins in response to various pro-inflammatory stimuli leading to its translocation to the nucleus, where it stimulates interferon-γ secretion and T helper type 1 (Th1) lymphocyte differentiation. The recent demonstration that JAK inhibitors are effective in treatment of RA confirms the importance of this system in RA.


CTLA4 is a protein involved in co-stimulation regulation of T-cell activation. Polymorphisms of CTLA4 are associated with autoimmune thyroid disease, T1DM, and coeliac disease, and RA. PRKCQ, another RA-associated gene, encodes a protein kinase C isoform that is involved in linking T-cell receptor signalling with T-cell differentiation and survival in addition to being involved in nuclear factor (NF)-κB activation.


It is likely that many of the other genes already known to be associated with RA operate by mechanisms involving T-cell differentiation/activation. Although the key disease-associated variants at the RA-associated loci IL2/IL21, IL2RA and IL2RB have yet to be pinpointed, given the known role of IL-2 in driving T-cell differentiation/activation, it is likely that these loci operate through this mechanism.

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Jul 12, 2016 | Posted by in RHEUMATOLOGY | Comments Off on Epidemiology and genetics of rheumatic diseases

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