The contribution of non-MHC genes to susceptibility to autoimmune diseases.

Genetic studies of experimental models of autoimmune diseases, including systemic lupus-like syndromes and organ-specific autoimmunity, provide major information on genetic control of autoimmune diseases. In addition to genes known to be linked to the major histocompatibility complex (MHC), these studies point to multiple genes located outside the MHC that influence the onset and the progression of autoimmune diseases. Identification of these genes and of their interrelationships is now a major task that will be facilitated by recent progress in molecular biology and gene mapping. Among candidate genes, antigen-receptor genes (i.e., immunoglobulin- and T-cell receptor genes) most likely contribute an important part of the autoimmune susceptibility in several of these animal models. Available linkage data suggest a similar involvement of these antigen-receptor genes in several human autoimmune diseases. In addition to a better understanding of pathogenic mechanisms associated with autoimmunity, the knowledge of these disease-predisposing genes is expected to permit a better classification of often complex syndromes as well as the design of new treatments.     

The effects of HLA class II genes on the susceptibility to autoimmune thyroid diseases

Immunogenetic factors such as HLA, C4, T cell receptor and immunoglobulin allotypes were investigated in 115 Japanese patients with Graves' disease. The patients showed strong positive association with HLA-A2 (R.R. = 3.45, chi 2 = 14.93, Pc less than 0.002), Bw46 (R.R. = 6.47, chi 2 = 16.25, Pc less than 0.002), Cw11 (R.R. = 4.47, chi 2 = 9.19, Pc less than 0.04) and DRw8 (R.R. = 2.22, chi 2 = 5.62, P less than 0.03, Pc: n.s.) which form one of the typical HLA haplotypes in Japanese population due to the strong linkage disequilibria. On the other hand, the patients showed negative association with HLA-B7 (R.R. = 0.15, chi 2 = 7.15), Bw52 (R.R. = 0.24, chi 2 = 7.86), DR1 (R.R. = 0.07, chi 2 = 9.71) and DQw1 (R.R. = 0.45, chi 2 = 5.62), which form HLA-B7-DR1-DQw1 and Bw52-DR2-DQw1 haplotypes. Because HLA-A2 -Bw46-Cw11-DR9 haplotype was reported to be associated with Chinese Graves' patients, and because Bw46 showed the strongest association with the Japanese patients, it was suggested that HLA class 1 antigen, Bw46, might be the primary immunogenetic factor involved in the pathogenesis of Graves' disease. Since HLA-DQw6 was reported to be associated negatively with Hashimoto's thyroiditis as same as the current observation in Graves' disease, it was suggested that HLA-DQw6 may determine the resistance to autoimmune thyroiditis. The effect of HLA-DQw6 gene, therefore, on the experimental autoimmune murine thyroiditis (EAMT) was examined, using DQw6-transgenic mouse. F1 with C3H mouse, and backcross progeny between the F1 and C3H mouse which is a susceptible strain to EAMT. The measurement of anti-thyroglobulin antibody indicated that C3H mouse, (C3H x DQ-B6) F1 and backcross progeny between the F1 and C3H were high responders to the thyroglobulin, but that B6 mouse and DQ-B6 mouse were low responders. The histological examination of the thyroid gland of these mice failed to demonstrate the significant difference in susceptibility to EAMT among these mice. These results suggested that the immune response to the thyroglobulin was controlled by H-2k haplotype and that the effect of HLA-DQw6 gene on the immune response to thyroglobulin and on the autoimmune thyroiditis was marginal.     

Expression of genes involved in susceptibility to multifactorial autoimmune diseases: estimating genotype effects

Several single nucleotide polymorphisms (SNPs) have been associated with susceptibility to autoimmune diseases, but the mechanisms responsible for the associations are poorly understood. To test the hypothesis that the variation of the basal levels of the gene products is significantly influenced by genetic polymorphism, we investigated whether SNPs in genes CD40, CD28, CTLA4, CD80, CD86, BAFF and IL6 are affecting mRNA or protein expression. The surface expression of the proteins on unstimulated monocytes, B cells, NK cells, CD4+ T cells and CD8+ T cells, as well as the mRNA levels in peripheral blood mononuclear cells (PBMC) was compared among healthy volunteers with different genotypes. Despite the low basal expression level and large interindividual variation, average BAFF expression was significantly higher in carriers of genotype C/C of the BAFF‐871C>T SNP (rs9514828) when compared with carriers of the C/T and T/T genotypes. Genotype C/C carriers presented higher levels of the protein on CD8+ T cells, monocytes and NK cells and of mRNA in PBMC. Moreover, carriers of T allele of CTLA4‐318C>T (rs5742909) showed a significantly increased expression of CTLA‐4 on CD8+ T cells. No significant variation among genotypes was found in the protein or mRNA levels of other investigated genes.     

Unraveling the genetics of complex diseases: Susceptibility genes for rheumatoid arthritis and psoriasis

Talk of numerous genetic risk factors for rheumatoid arthritis (RA) and psoriasis has been percolating for years, but with the exception of the human leukocyte antigen (HLA) region, none have been definitively identified. Recently the results of multiple, well powered, genetic case–control studies have begun to appear providing convincing statistical evidence for at least ten non-HLA related risk genes or loci (C5/TRAF1, CD40, CTLA4, KIF5A/PIP4K2C, MMEL1/TNFRSF14, PADI4, PRKCQ, PTPN22, STAT4, and TNFAIP3/OLIG3) for RA and six (IL12B, IL13, IL23R, STAT2/IL23A, TNFAIP3, and TNIP1) for psoriasis. These initial, novel findings are beginning to shed light on the molecular pathways pertinent to the individual diseases and highlight the pleiotropic effects of several risk factors as well as the allelic heterogeneity underlying susceptibility to these and other autoimmune diseases.     

Obesity and susceptibility to autoimmune diseases

For decades, obesity has been considered to be the result of the complex interaction between genes and the environment and its pathogenesis is still unresolved. The discovery of hormones and neural mediators responsible for the control of food intake and metabolism at the hypothalamic level has provided fundamental insights into the complicated pathways that control food intake. However, the molecular basis for the association between obesity and low-degree chronic inflammation is still unknown. More recently, the discovery of leptin, one of the most abundant adipocyte-derived hormones, has suggested that nutritional status, through leptin secretion, can control immune self-tolerance modulating Treg suppressive function and responsiveness. Furthermore, recent experimental evidence has shown the presence of an abundant adipose tissue-resident Treg population responsible for the control of metabolic parameters and glucose homeostasis. Better knowledge of the intricate network of interactions among leptin-related energy regulation, Treg activities and obesity could lead to valuable strategies for therapeutic intervention in obesity and obesity-associated insulin resistance.     

Non-MHC-linked genes in autoimmune diseases

The gene responsible for the lpr mutation in MRL mice that are prone to systemic lupus erythematosus has been shown to encode the apoptosis-inducing Fas antigen, thus pointing to control of apoptosis as a major regulatory mechanism in autoimmunity. In the non-obese diabetic mouse model for insulin-dependent diabetes, four non-MHC-linked loci have been localized in the murine genome that were found to be associated with successive stages of the disease. These findings should soon have a major impact on our understanding of human autoimmune diseases.     

Non-MHC-linked genes in autoimmune diseases

Single-locus mutations in mice associated with autoimmune manifestations or influencing them, including Ipr, motheaten and xid have been characterized at the molecular level. Mutations have been described in the genes encoding FcγRI, interleukin-2 and natural resistance associated macrophage protein, which are all candidate genes for susceptibility loci associated with autoimmune diabetes in non-obese diabetic mice. Twelve regions of DNA that are associated with disease susceptibility have now been identified in this polygenic model of autoimmunity. In human autoimmune diseases, the region of DNA surrounding the insulin gene that is associated with susceptibility to insulin dependent diabetes mellitus has been narrowed down to 4.1 kilobases.     

Recent findings on genetics of systemic autoimmune diseases

Association studies of over 1 million SNPs capturing most of the human genome common variation became possible thanks to the information provided by the HapMap International project and the development of high-throughput genotyping technologies at accessible prices. Genome-wide scans analyzing thousands of individuals have now identified most if not all of the major genes involved in susceptibility for several systemic autoimmune diseases. In particular, results for rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc) are reviewed here. While most genes are shared between diseases, few seem to be unique reflecting that we still are long before knowing all genes, their interactions with other genes and the environment and their impact on biological functions.     

Integrating genomic and clinical medicine: searching for susceptibility genes in complex lung diseases

The integration of molecular, genomic, and clinical medicine in the post-genome era provides the promise of novel information on genetic variation and pathophysiologic cascades. The current challenge is to translate these discoveries rapidly into viable biomarkers that identify susceptible populations and into the development of precisely targeted therapies. In this article, we describe the application of comparative genomics, microarray platforms, genetic epidemiology, statistical genetics, and bioinformatic approaches within examples of complex pulmonary pathobiology. Our search for candidate genes, which are gene variations that drive susceptibility to and severity of enigmatic acute and chronic lung disorders, provides a logical framework to understand better the evolution of genomic medicine. The dissection of the genetic basis of complex diseases and the development of highly individualized therapies remain lofty but achievable goals.     

The complex role of vitamin D in autoimmune diseases

Vitamin D, besides having well-known control functions of calcium and phosphorus metabolism, bone formation and mineralization, also has a role in the maintenance of immune-homeostasis. The immune-regulatory role of vitamin D affects both the innate and adaptive immune system contributing to the immune-tolerance of self-structures. Impaired vitamin D supply/regulation, amongst other factors, leads to the development of autoimmune processes in animal models of various autoimmune diseases. The administration of vitamin D in these animals leads to improvement of immune-mediated symptoms. Moreover, in human autoimmune diseases, such as multiple sclerosis, or rheumatoid arthritis the pathogenic role of vitamin D has been described. The review aims at describing the complex immune-regulatory role of vitamin D from the cellular level through autoimmune animal models and depicting the known contribution of vitamin D in the pathogenesis of human autoimmune diseases.     

Simple and complex genetics of colorectal cancer susceptibility

There are several hereditary conditions associated with an increased risk of colorectal cancer (CRC). These include well-characterized autosomal dominant syndromes, such as familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). A novel autosomal recessive form of FAP, caused by mutations in the base excision repair gene MYH, has recently been recognized. This discovery has provided further evidence for the importance of DNA repair mechanisms in CRC development, already documented by the involvement of the mismatch repair in HNPCC. Additional CRC-predisposing conditions, such as hyperplastic polyposis and hereditary mixed polyposis syndrome, are being outlined. Heterogeneity of genetic mechanisms has important consequences for counseling and surveillance in hereditary CRC. Nevertheless, classical mendelian conditions represent only a minor share of the total CRC population burden. Alleles of the same genes that are involved in hereditary syndromes might also act as low penetrance variants, as shown for APC 1307K in the Ashkenazi. However, the level of complexity of multifactorial CRC is such that current tools appear inadequate to pinpoint all the involved components. A combination of different strategies, including careful clinical observation, analysis of homogeneous patient populations, and critical evaluation of data derived from experimental models, along with methodological improvements in nucleic acid analysis, will probably be necessary to unravel the basis of nonmendelian CRC. Once this is achieved, it will be possible to realize the ultimate goal of targeted CRC prevention, with the adoption of measures tailored according to individual risk levels. .     

全基因组关联研究的策略及面临的挑战

在人类基因组测序费用还没有足够低廉的情况下,全基因组关联研究( genome-wide association study,GWAS)仍然是复杂疾病易感基因研究的有效策略之一.在此文中,对GWAS的研究设计、遗传分析方法、多重假设检验调整方法等基本原理和面临的挑战等问题进行了系统的阐述.     

The genetics of human autoimmune disease

Autoimmune diseases are known to have a multifactorial pathogenesis, with both environmental and inherited components. Wide technical progresses together with the completion of the sequencing of human genome have recently allowed the identification of new genetic risk variants in many autoimmune disorders. While part of these studies confirmed previous knowledge, most of the data has disclosed novel and unsuspected roles in the development of autoimmunity for molecules involved in various pathogenic pathways. After the current first wave of data from high-density genome-wide studies, we now need to further characterize these genetic factors and find additional ones, possibly among rare variants. In addition, a role for sex chromosomes in the development of autoimmune diseases has also been suggested. This review will focus on the recent discoveries related to genetics of autoimmunity.