The genetics of complex autoimmune diseases: non-MHC susceptibility genes

Susceptibility to complex autoimmune diseases (AIDs) is a multigenic phenotype affected by a variety of genetic and environmental or stochastic factors. After over a decade of linkage analyses, the identification of non-major histocompatibility complex (non-MHC) susceptibility alleles has proved to be difficult, predominantly because of extensive genetic heterogeneity and possible epistatic interactions among the multiple genes required for disease development. Despite these difficulties, progress has been made in elucidating the genetic mechanisms that influence the inheritance of susceptibility, and the pace of gene discovery is accelerating. An intriguing new finding has been the colocalization of several AID susceptibility genes in both rodent models and human linkage studies. This may indicate that several susceptibility alleles affect multiple AIDs, or alternatively that genomic organization has resulted in the clustering of many immune system genes. The completion of the human genome sequence, coupled with the imminent completion of the mouse genome, should yield key information that will dramatically enhance the rate of gene discovery in complex conditions such as AID susceptibility.     

Genetic variants of the HLA-A, HLA-B and AIF1 loci show independent associations with type 1 diabetes in Norwegian families

The main genetic predisposition to type 1 diabetes (T1D) is known to be conferred by the HLA-DRB1, -DQA1 and -DQB1 genes in the major histocompatibility complex (MHC). Other genetic factors within this complex are known to contribute, but their identity has often been controversial. This picture is shared with several other autoimmune diseases (AIDs). Moreover, as common genetic factors are known to exist between AIDs, associations reported with other AIDs may also be involved in T1D. In this study, we have used these observations in a candidate gene approach to look for additional MHC risk factors in T1D. Using complementary conditional methods (involving conditional logistic regression and family-based haplotype tests) and analyses of linkage disequilibrium (LD) patterns, we confirmed association for alleles of the HLA-A and HLA-B genes and found preliminary evidence for a novel association of a single-nucleotide polymorphism (rs2259571) in the AIF1 gene, independent of the DRB1-DQA1-DQB1 genes and of each other. However, no evidence of independent associations for a number of previously suggested candidate polymorphisms was detected. Our results illustrate the importance of a comprehensive adjustment for LD effects when performing association studies in this complex.     

单核苷酸多态性与自身免疫性疾病相关性的研究进展

自身免疫性疾病的发生是遗传和环境因素共同作用的结果,在遗传学研究中,HL4基因被认为对自身免疫性疾病的易感性影响最大,而连锁分析发现多个非HLA区域也与自身免疫性疾病的发生相关,而且单核苷酸多态性与疾病的相关性是近年来研究的热点,这不仅为我们进一步了解这类复杂疾病的发病机制提供了线索,而且有可能会有利于发现新的防御及干预措施.本文综述了PTPN22、IL-23R、STAT4、CD226几个热点非HLA基因的单核苷酸多态性与自身免疫性疾病易感性的研究进展.     

Non-HLA associations with autoimmune diseases

Susceptibility to autoimmune diseases (AID) has been associated with multiple combinations of genes and environmental or stochastic factors. The strongest influence on susceptibility to autoimmunity is the major histocompatibility complex (MHC), in particular HLA; however, linkage analyses among multiple affected family members have established that non-MHC chromosomal susceptibility regions also influence the susceptibility towards AID. Besides HLA, three non-HLA genes have been convincingly associated with different AID: Citotoxic T lymphocyte-associated antigen 4 (CTLA4), Protein Tyrosine Phosphatase (PTPN22) and Tumor Necrosis Factor-alpha (TNF), indicating that autoimmune phenotypes could represent pleiotropic outcomes of non-specific diseases' genes that underline similar immunogenetic mechanisms. Identification of genes that generate susceptibility will enhance our understanding of the mechanisms that mediate these complex diseases and will allow us to predict and/or prevent them as well as to discover new therapeutic interventions.     

Sex, MHC and complement C4 in autoimmune diseases

Autoimmune diseases are estimated to affect 10-50 million people in the United States, and untold millions worldwide. Nearly 80% of all people with autoimmune diseases are women, and a strong association of these diseases with MHC genes has been known for some time. However, very little is known about what causes autoimmune diseases or the factors that lead to disease recurrence. The sex-associated differences in multiple sclerosis (MS) and the mouse model of MS, experimental autoimmune encephalomyelitis (EAE), are associated with MHC genetic background, sex hormone levels and cytokine production. The implication of these factors has aided the identification of new autosomal genetic susceptibility loci. Complete deficiencies of early complement components are strongly associated with systemic lupus erythematosus (SLE) but the role of complement proteins in SLE is not yet clear. Recent data suggest that quantitative and qualitative diversities of the MHC-linked complement C4 among different ethnic groups can be important in the susceptibility and disease severity of SLE.     

CTLA-4 (CD152) and its involvement in autoimmune disease

Autoimmune diseases (AID) are inherited as complex genetic diseases. Different Autoimmune diseases have been found to cluster in families and are believed to share some common etiological factors. With the exception of major histocompatibility complex (MHC) genes contributing susceptibility to these diseases have been difficult to identify. CD152 has emerged as one such candidate unifying several autoimmune diseases. We here review the evidence that CD152 constitutes a general susceptibility factor for multiple autoimmune diseases and discuss how CD152 and other co-stimulatory pathways may contribute to autoimmune pathogenesis.     

CTLA-4 (CD152) and its involvement in autoimmune disease

Autoimmune diseases (AID) are inherited as complex genetic diseases. Different Autoimmune diseases have been found to cluster in families and are believed to share some common etiological factors. With the exception of major histocompatibility complex (MHC) genes contributing susceptibility to these diseases have been difficult to identify. CD152 has emerged as one such candidate unifying several autoimmune diseases. We here review the evidence that CD152 constitutes a general susceptibility factor for multiple autoimmune diseases and discuss how CD152 and other co-stimulatory pathways may contribute to autoimmune pathogenesis.     

Epigenetics changes associated to environmental triggers in autoimmunity

Autoimmune diseases (AIDs) are chronic conditions initiated by the loss of immunological tolerance to self-antigens and represent a heterogeneous group of disorders that affect specific target organs or multiple organs in different systems. While the pathogenesis of AID remains unclear, its aetiology is multifunctional and includes a combination of genetic, epigenetic, immunological and environmental factors. In AIDs, several epigenetic mechanisms are defective including DNA demethylation, abnormal chromatin positioning associated with autoantibody production and abnormalities in the expression of RNA interference (RNAi). It is known that environmental factors may interfere with DNA methylation and histone modifications, however, little is known about epigenetic changes derived of regulation of RNAi. An approach to the known environmental factors and the mechanisms that alter the epigenetic regulation in AIDs (with emphasis in systemic lupus erythematosus, the prototype of systemic AID) are showed in this review.     

Genetic factors in pemphigus

Epidemiological studies performed in different ethnic populations and family studies, notably based on a partial phenotype of the autoimmune process, indicate that genetic factors are involved in the occurrence of pemphigus. However, the precise heritability remains uncertain in the absence of twin concordance rate studies. Among the different strategies available to identify genetic factors participating in autoimmune disease susceptibility, only population studies based on case-control design have been performed in pemphigus. These studies consistently showed that MHC locus, in particular HLA class II alleles, are associated with pemphigus vulgaris and pemphigus foliaceus. Other genes of the MHC locus may also participate in disease susceptibility as shown by studies using microsatellite markers across different regions of the MHC. It is likely that other non-MHC genes are involved in the pathogenesis of pemphigus. In particular, involvement of a polymorphic variant of desmoglein 1 gene was shown to be associated with pemphigus foliaceus and to interact in an epistatic manner with MHC class II genes to contribute to the autoimmune process. Other candidate genes to which a role can be assigned in the disease pathogenesis should be considered to design case-control or family-based association studies. Genome scan studies which require a large number of multiplex families to reach statistical power, should also be considered in the endemic form of pemphigus foliaceus because of the high number of familial cases.     

Celiac disease: strongly heritable, oligogenic, but genetically complex

Celiac disease, or gluten-sensitive enteropathy, is a small intestinal disorder which affects up to 1:250 people in the United States. Disease development has a strong genetic component, with a sibling relative risk (lambda(s)) of 30. One susceptibility locus is the MHC region, with a particular association with the HLA-DQ alleles DQA1*0501 and DQB1*0201. However, haplotype sharing studies suggest that genes within the MHC complex contribute no more than 40% to the sibling familial risk of disease. This means that the stronger genetic risk is likely to be conferred by a small number of non-HLA-linked genes. Genome-wide linkage studies, plus linkage and association studies of candidate loci have been used to try to identify these genes. However, these studies have either failed to detect loci, or produced inconsistent results. Such difficulties in identifying susceptibility genes are encountered when investigating any complex genetic disorder. Information from the Human Genome Project, coupled with new technology for high throughput single nucleotide polymorphism typing may help to identify the non-HLA determinants of celiac disease in the future.     

Epidemiology of autoimmune reactions induced by vaccination

In order for vaccinations to 'work', the immune system must be stimulated. The concern that immunizations may lead to the development of autoimmune disease (AID) has been questioned. Since AID occur in the absence of immunizations, it is unlikely that immunizations are a major cause of AID. Epidemiological studies are needed, however, to assess whether immunizations may increase the risk in some susceptible individuals. This paper discusses the evidence for and against vaccination as a risk factor for AID. Evidence for immunizations leading to AID come from several sources including animal studies, single and multiple case reports, and ecologic association. However more rigorous investigation has failed to confirm most of the allegations. Unfortunately the question remains difficult to address because for most AIDs, there is limited knowledge of the etiology, background incidence and other risk factors for their development. This information is necessary, in the absence of experimental evidence derived from controlled studies, for any sort of adequate causality assessment using the limited data that are available. Several illustrative examples are discussed to highlight what is known and what remains to be explored, and the type of epidemiological evidence that would be required to better address the issues. Examples include the possible association of immunization and multiple sclerosis (and other demyelinating diseases), type 1 diabetes mellitus, Guillain-Barre Syndrome, idiopathic thrombocytopenic purpura, and rheumatoid arthritis.     

Novel genetic association between the corneodesmosin (MHC S) gene and susceptibility to psoriasis.

Psoriasis is an inflammatory skin disease of unknown origin, but with a clear genetic component. The strongest genetic association has been found with the major histocompatibility complex (MHC) region, and specifically between susceptibility to familial early onset psoriasis and human leukocyte antigen (HLA)-Cw6. The basis of this association of the HLA-C locus with disease pathogenesis is, however, not clear, and it is possible that other genes, or a combination of genes, in the HLA region are of functional importance. The MHC S gene is expressed specifically in keratinocyte differentiation and, being located 160 kb telomeric of HLA-C, is a plausible candidate gene. We analysed the allelic distribution of two polymorphisms in the MHC S gene (at +619 and +1243) in a case-control association study. We could confirm a significant association between psoriasis and HLA-Cw6 [odds ratio (OR) = 7.75]. No association was found between disease (or any subtypes) and the MHC S gene polymorphism at position +619, despite its close proximity to HLA-C and the strong linkage disequilibrium between the loci. However, a significant trend with the rarer allele at MHC S (+1243) and psoriasis was detected in the overall data set (OR = 2. 66; P = 2 [times] 10(-)9). This effect was most pronounced in the type 1a (early onset) psoriatics (OR = 3.43). Furthermore, homozygosity for the associated allele at MHC S (+1243) increased the risk of disease over that for carriage of HLA-Cw6 alone (OR = 9. 38), suggesting that allele 2 of MHC S (+1243) provides an additional risk in psoriasis susceptibility. The strong association found here, coupled with the biological involvement of the MHC S gene product corneodesmosin in skin physiology, implicates this locus (or a haplotype across HLA-C and MHC S ) in the impaired desquamation characteristic of psoriasis.     

Familial clustering of autoimmune diseases in patients with type 1 diabetes mellitus

We investigated the familial aggregation of autoimmune diseases (AIDs) among first-degree relatives (FDR) of patients with type 1 diabetes mellitus (T1D). Relatives of 98 T1D patients defined according to the guidelines diagnosis of the American Diabetes Association and 113 matched controls without any AID, were interviewed using a questionnaire that sought information about demographic and medical characteristics including a list of 18 AIDs. Genetic analysis was performed using the program ASSOC and by calculating recurrent risk ratios. In cases, 25.5% of the families had at least one member having an AID, while in controls there were 9% (odds ratio [OR]: 3.96, 95% confidence interval [CI]=1.74-9.0, p=0.0006). An AID was registered in 8.3% of 312 FDR of patients as compared with 2.4% of 362 FDR in controls (OR: 3.56, 95% CI=1.64-7.73, p=0.0008). The most frequent AIDs registered in FDR of cases were autoimmune thyroid disease (AITD) and T1D, which disclosed coefficients of aggregation. These results indicate that AIDs cluster within families of T1D patients adding further evidence to consider that clinically different autoimmune phenotypes may share common susceptibility gene variants, which may act pleiotropically as risk factors for autoimmunity.     

The haplotype block, NFKBIL1-ATP6V1G2-BAT1-MICB-MICA, within the class III-class I boundary region of the human major histocompatibility complex may control susceptibility to hepatitis C virus-associated dilated cardiomyopathy

Cardiomyopathy is a heart muscle disease with impaired stretch response that can result in severe heart failure and sudden death. A small proportion of hepatitis C virus (HCV)-infected patients may be predisposed to develop dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). The molecular mechanisms involved in the predisposition remain unknown due in part to the lack of information on their genetic background. Because the human leukocyte antigen (HLA) region has a pivotal role in controlling the susceptibility to HCV-induced liver disease, we hypothesized that particular HLA alleles and/or non-HLA gene alleles within the human major histocompatibility complex (MHC) genomic region might control the predisposition to HCV-associated DCM (HCV-DCM) and/or HCV-associated HCM (HCV-HCM). Here, we present mapping results of the MHC-related susceptibility gene locus for HCV-associated cardiomyopathy by analyzing microsatellite and single nucleotide polymorphism markers. To delineate the susceptibility locus, we genotyped 44 polymorphic markers scattered across the entire MHC region in a total of 59 patients (21 HCV-DCM and 38 HCV-HCM) and 120 controls. We mapped HCV-DCM susceptibility to a non-HLA gene locus spanning from NFKBIL1 to MICA gene loci within the MHC class III-class I boundary region. Our results showed that HCV-DCM was more strongly associated with alleles of the non-HLA genes rather than the HLA genes themselves. In addition, no significant association was found between the MHC markers and HCV-HCM. This marked difference in the MHC-related disease susceptibility for HCV- associated cardiomyopathy strongly suggests that the development of HCV- DCM and HCV-HCM is under the control of different pathogenic mechanisms.     

T cell receptor recognition of self and foreign antigens in the induction of autoimmunity

The major histocompatibility complex (MHC) on human chromosome 6 represents the most important genetic locus for a number of common human autoimmune diseases. Specific alleles that differ from closely related alleles by only one or a few amino acids in the peptide binding groove are frequently strongly associated with disease susceptibility, raising the important question of which peptide presentation events are critical in disease initiation and progression. This review will cover a number of topics pertinent to this fundamental question, including MHC linked disease susceptibility to autoimmune diseases, molecular mechanisms for the role of MHC molecules in autoimmune diseases as well as the recognition of self and microbial peptides by self-reactive T cell receptors (TCRs).     

Bleomycin hydrolase and a genetic locus within the MHC affect risk for pulmonary fibrosis in mice

Susceptibility to pulmonary fibrosis following environmental insults or cytotoxic cancer therapies has a genetic component. In mouse strains differing in susceptibility to bleomycin-induced lung fibrosis, we show highly significant linkage to only two loci. The first locus on chromosome 17 in the major histocompatibility complex (MHC), LOD = 17.4, named Blmpf1, is highly significant in both males and females, and accounts for approximately 20% of the phenotypic variance. We confirmed the presence of Blmpf1 in MHC congenic mice and narrowed the region to 2.7 cM in a reduced MHC congenic strain. The second locus on chromosome 11, LOD = 5.6, named Blmpf2, is significant in males only. A model including an interaction between Blmpf1 and Blmpf2 best fit the data in males. We confirmed Blmpf2 in a chromosome substitution strain, C57BL/6J-11(C3H), and found that its presence reduces the severity of fibrosis. Functional studies of bleomycin hydrolase activity indicate that this enzyme modulates bleomycin-induced pulmonary fibrosis, suggesting that it may be a candidate gene for Blmpf2. The data suggest sex-specific models of susceptibility to bleomycin-induced lung fibrosis, with an interaction between Blmpf2 and Blmpf1 for the more susceptible males and Blmpf1 as the major locus in females. A putative mechanism for the interaction between the two loci in males is that bleomycin hydrolase functions as an MHC class I epitope-processing protease.     

Non-major histocompatibility complex rheumatoid arthritis susceptibility genes

Recent results from genetic and treatment studies have shed new light on chronic inflammatory and autoimmune diseases such as rheumatoid arthritis (RA). In particular, genome-wide association studies (GWAS) have provided supportive evidence that RA is a disease with a strong genetic background. Interestingly, a series of candidate genes have been identified outside of the classical major histocompatibility (MHC) locus, which had long been regarded as the major contributor to the pathogenesis of this disease. Among these genes, PTPN22 plays an outstanding role. CD40, STAT4, PRM1, and TNFAIP3 also seem to be of relevance. Interestingly, there is a significant overlap between RA susceptibility genes and those of other autoimmune diseases such as systemic lupus erythematosus (SLE) and type 1 diabetes, which suggests common pathogenic mechanisms. Genetic analyses may not only provide new insights into the pathogenesis of RA, but may also open new avenues for therapeutic approaches, because overactive immune-signaling pathways might specifically be addressed by biologic therapies. However, the predictive value of many of the recent findings of large-scale genetic analyses in identifying new genetic polymorphisms remains low. We describe the current knowledge about the role of non-MHC genes in the pathogenesis of rheumatoid arthritis.     

Comparative United States autoimmune disease rates for 2010–2016 by sex,geographic region,and race

PurposeAIDs may disproportionately impact specific racial groups, but autoimmune (AID) prevalence information by minority racial group is sparse for many AIDs. The objective of this analysis was to supplement previously published AID prevalence rates by providing information on race rate ratios (minority race populations compared to Caucasian populations) in the United States. Preliminary to estimating race rate ratios, contemporary US-specific, health care utilization-based AID prevalence rates and female-to-male ratios were estimated and compared to previously published AID prevalence rates.MethodsWe used a large national electronic medical record database of 52 million individuals to estimate age-adjusted direct standardized rates for 22 AIDs for 2010 through 2016 by gender, race, and US census division. These were compared to previously published estimates.ResultsFemale-to-male ratios were comparable with published studies. Almost all observed Multiracial AID rates were significantly higher than Caucasian rates, as well as 9 of 22 AID rates observed among Native Americans and 8 of 22 AID rates estimated among African-American patients. Regional variation was noted: highest African-American systemic lupus erythematosus rates were observed in the West North Central and South Atlantic divisions, highest African-American multiple sclerosis rates in the South Atlantic and Pacific divisions, and highest Native American rheumatoid arthritis rates in the West North Central, Mountain, and Pacific divisions.ConclusionsSubstantial AID heterogeneity exists by race and by geographic area. An important research area is further exploring factors related to heterogeneity such as potential interactions between genetic susceptibility and environmental factors.     

1987 Philip Levine award lecture. MHC haplotypes in biology and medicine

(1) The MHC genes or genes within or near the MHC region are involved in the immune response. The polymorphism of the MHC loci can be used as markers for immune response because the recognition of antigens involves their interaction with the MHC antigens. Specific portions of an antigen bind to the polymorphic region of class II molecules. Identification of an MHC class II molecule with a peptide results in a lack of an immune response as a result of self-tolerance. Similarities, but not identity of these molecules, result in immune responses restricted by the variable region of the MHC (class II molecule). This also explains a high repertoire of alloreactive T-cells. (2) By virtue of their restriction of the immune response to foreign antigens that cross-react with self-antigen, the MHC genes or genes within or near the MHC region show an association with the autoimmune diseases. (3) Several alleles encoded by different MHC loci are found nonrandomly associated at the population level. The resulting haplotypes could predict identity of segments of chromosome 6 among unrelated persons. (4) Matching of nonrandomly associated alleles (extended haplotypes) can serve potentially for selection of donors for allotransplantation, especially of bone marrow. (5) Several diseases associated with alleles of the class II MHc loci, and at least in the case of the lack of response to hepatitis B vaccine, have been shown to be more significantly associated with extended haplotypes. In such cases, the extended haplotypes may contain a susceptibility MHC allele of a known MHC locus or may contain a susceptibility gene of a yet undiscovered locus.