Susceptibility To Autoimmune Diseases Research Articles

Investigation on association between five common polymorphisms in vascular endothelial growth factor and prototypes of autoimmune diseases

BackgroundVascular endothelial growth factor (VEGF) is a crucial regulator in angiogenesis. Previous research has indicated that modified VEGF–VEGFR signaling pathway has an impact on the development of inflammatory diseases. It has been proved that single nucleotide polymorphisms (SNPs) for critical genes might be associated with the susceptibility of autoimmune diseases. In this study, we targeted five common VEGF SNPs, i.e. −1154G>A, +405G>C, −2578C>A, +936C>T and −460T>C. Their associations with eleven prototypes autoimmune disease were assessed by our meta-analysis. MethodsPubMed/Medline and CNKI were searched for related articles. Studies fulfilled the inclusion criteria were enrolled in this analysis. Meta-analysis was performed using odds ratio and 95% confidence intervals as effect measures. Results73 studies from 30 relevant articles were retrieved in accordance with the data selection methods. A total of 11,354 cases and 8694 controls from the 30 included studies were enrolled in this meta-analysis. In the overall analysis, no statistically significant association was confirmed concerning five common VEGF polymorphisms and the susceptibility of autoimmune diseases. Interestingly, in the stratified analysis by ethnicity, the C allele of +405G>C polymorphism in Caucasian people was found to be correlated to increase autoimmune diseases risk, while an inverse trend of association was observed in Asian people. Also, decreased susceptibility to Graves’ disease was detected in Caucasian people with G allele in +405G>C polymorphism. Besides, a trend of decreased risk of psoriatic arthritis was confirmed among population with T allele of +936C>T polymorphism. ConclusionIn summary, as suggested by our analysis, +405G>C polymorphism in VEGF might exert an influence on autoimmune diseases, with opposite effect observed in Asians and Caucasians. No association between the other four common SNPs (−2578C>A, −1154G>A and −460T>C) and autoimmune diseases susceptibility was confirmed.

The Prevalence of Antinuclear Antibodies in the General Population of China: A Cross-Sectional Study

BackgroundThe incidence of autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and primary biliary cirrhosis has increased significantly in China. Information about the susceptibility or potential of autoimmune diseases in the general population is lacking. ObjectiveTo explore the prevalence of antinuclear antibody (ANA) and its specificities in the general population in China. MethodsTwenty thousand nine hundred seventy sera samples were taken from the physical examination center in Baoding, China. Indirect immunofluorescence and line immunoassays were used to detect ANA and its specificities, respectively. ResultsSamples from females had a higher prevalence of ANA than samples from males (χ2 = 278.55; P < 0.01). For both sexes, the prevalence of ANA positively correlated with age and there were significant differences among different age groups at 10-year intervals, except the 80 years group (P < 0.05). One thousand two hundred forty-three ANA-positive samples were further analyzed with line immunoassays. There was a significant difference among age groups and between sex groups in terms of the specific autoantibodies (P < 0.01). The autoantibodies with the top-3 positive frequencies were anti-Ro-52, anti-M2, and anti-SSA. ConclusionsThere was a high prevalence of ANA positivity in the general Chinese population that seemed to be influenced by sex and age and correlated with specific autoantibodies.

Exacerbation of autoimmune neuro-inflammation in mice cured from blood-stage Plasmodium berghei infection.

The thymus plays an important role shaping the T cell repertoire in the periphery, partly, through the elimination of inflammatory auto-reactive cells. It has been shown that, during Plasmodium berghei infection, the thymus is rendered atrophic by the premature egress of CD4+CD8+ double-positive (DP) T cells to the periphery. To investigate whether autoimmune diseases are affected after Plasmodium berghei NK65 infection, we immunized C57BL/6 mice, which was previously infected with P.berghei NK65 and treated with chloroquine (CQ), with MOG35–55 peptide and the clinical course of Experimental Autoimmune Encephalomyelitis (EAE) was evaluated. Our results showed that NK65+CQ+EAE mice developed a more severe disease than control EAE mice. The same pattern of disease severity was observed in MOG35–55-immunized mice after adoptive transfer of P.berghei-elicited splenic DP-T cells. The higher frequency of IL-17+- and IFN-γ+-producing DP lymphocytes in the Central Nervous System of these mice suggests that immature lymphocytes contribute to disease worsening. To our knowledge, this is the first study to integrate the possible relationship between malaria and multiple sclerosis through the contribution of the thymus. Notwithstanding, further studies must be conducted to assert the relevance of malaria-induced thymic atrophy in the susceptibility and clinical course of other inflammatory autoimmune diseases.

Protein tyrosine phosphatase PTPN22 +1858C/T polymorphism is associated with active vitiligo.

Vitiligo is characterized by a skin depigmentation disorder resulting from an autoimmune response targeting melanocytes. Within the genetic factors involved in the development of the vitiligo immune response, various genes in the major histocompatibility complex (MHC) and non-MHC loci have been considered to be risk factors. The PTPN22 gene encodes for a lymphoid protein tyrosine phosphatase, a regulator of the activation and development of T-cells. The +1858C/T polymorphism has been associated to autoimmune disease susceptibility in different populations and could be implicated in the onset of vitiligo. To assess the possible association between the presence of PTPN22 +1858C/T and vitiligo, 187 patients with vitiligo and 223 control subjects were analyzed in the study. Genomic DNA was isolated using the salting-out method and samples were subjected to polymerase chain reaction-restriction fragment length polymorphism in order to detect the PTPN22 +1858C/T polymorphism. Causal associations were determined by χ2 test and their respective odds ratio (OR) was assessed in a 2×2 contingency table. The results showed an association between active vitiligo and the allele T load [P=0.0418; OR, 2.5706; 95% confidence interval (CI), 1.0040–6.5816], and active vitiligo-CT genotype (P=0.0389, OR, 2.6548; 95% CI, 1.0191–6.9156). In conclusion, the present data indicates a possible association between the PTPN22 +1858C/T genotype and a significant susceptibility of developing an active form of vitiligo.

The tyrosine kinase Lyn limits the cytokine responsiveness of plasma cells to restrict their accumulation in mice.

Maintenance of an appropriate number of plasma cells, long-lived antibody-producing cells that are derived from B cells, is essential for maintaining immunological memory while limiting disease. Plasma cell survival relies on extrinsic factors, the limited availability of which determines the size of the plasma cell population. Mice deficient in the nonreceptor tyrosine kinase Lyn are prone to an autoimmune disease that is characterized by inflammation and an excess of plasma cells (plasmacytosis). We demonstrated that the plasmacytosis was intrinsic to B cells and independent of inflammation. We also showed that Lyn attenuated signaling by signal transducer and activator of transcription 3 (STAT3) and STAT5 in response to the cytokines interleukin-6 (IL-6) and IL-3, respectively, in two previously uncharacterized plasma cell signaling pathways. Thus, in the absence of Lyn, the survival of plasma cells was improved, which enabled the plasma cells to become established in excess numbers in niches in vivo. These data identify Lyn as a key regulator of survival signaling in plasma cells, limiting plasma cell accumulation and autoimmune disease susceptibility.

Association of susceptible genetic markers and autoantibodies in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder of unknown aetiology resulting in inflammation of the synovium, cartilage and bone. The disease has a heterogeneous character, consisting of clinical subsets of anti-citrullinated protein antibody (ACPA)-positive and APCA-negative disease. Although, the pathogenesis of RA is incompletely understood, genetic factors play a vital role in susceptibility to RA as the heritability of RA is between 50 and 60%, with the human leukocyte antigen (HLA) locus accounting for at least 30% of overall genetic risk. Non-HLA genes, i.e. tumour necrosis factor-α (TNF-α) within the MHC (major histocompatibility complex) have also been investigated for association with RA. Although, some contradictory results have originated from several studies on TNF-α gene, the data published so far indicate the possible existence of TNF-α gene promoter variants that act as markers for disease severity and response to treatment in RA. The correlation of HLA and non-HLA genes within MHC region is apparently interpreted. A considerable number of confirmed associations with RA and other autoimmune disease susceptibility loci including peptidylarginine deiminase type 4 (PADI4), protein tyrosine phosphatase non-receptor type 22 (PTPN22), signal transducer and activator of transcription (STAT4), cluster of differentiation 244 (CD244) and cytotoxic T lymphocyte-associated antigen 4 (CTLA4), located outside the MHC have been reported recently. In this review, we aim to give an update on recent progress in RA genetics, the importance of the combination of HLA-DRB1 alleles, non-HLA gene polymorphism, its detection and autoantibodies as susceptibility markers for early RA disease.

Association of IL-21 polymorphisms (rs907715, rs2221903) with susceptibility to multiple autoimmune diseases: A meta-analysis

Objectives: Previous published data indicated that interleukin-21 (IL-21) gene polymorphisms were shown to associate with multiple autoimmune diseases (ADs), but the results remain inconclusive. The aim of this study was to perform a meta-analysis to assess the overall association between IL-21 gene polymorphisms (rs907715, rs2221903) and multiple ADs. Methods: All eligible case–control studies were searched in the PubMed and Embase database. A meta-analysis was conducted on the association between the IL-21 gene variants and ADs using: (1) allelic contrast, (2) homozygote contrast, (3) the recessive model, and (4) the dominant model. Results: A total of 12 relevant studies including 10 535 cases and 19 356 controls were enrolled in this meta-analysis. A significant association between IL-21 rs907715 gene polymorphism and AD was found under the allelic (OR: 1.102, 95% CI: 1.057–1.149, p = 0.000), homozygous (OR: 1.220, 95% CI: 1.089–1.368, p = 0.001), dominant (OR: 1.160, 95% CI: 1.027–1.309, p = 0.017), and recessive genetic model (OR: 1.119, 95% CI: 1.055–1.187, p = 0.000) among Caucasian populations. However, there was no significant association between IL-21 rs2221903 polymorphism and AD in different genetic models. Conclusions: Data from the present study suggest that the IL-21 rs907715 polymorphism might be associated with multiple ADs susceptibility in Caucasians. Especially, the allele G of intronic rs907715 in IL-21 confers increased risk of ADs.

Autoimmune diseases association study with the KIAA1109–IL2–IL21 region in a Tunisian population

Autoimmune diseases (ADs) share several genetic factors resulting in similarity of disease mechanisms. For instance polymorphisms from the KIAA1109-interleukin 2 (IL2)-IL21 block in the 4q27 chromosome, has been associated with a number of autoimmune phenotypes. Here we performed a haplotype-based analysis of this AD related region in Tunisian patients. Ten single nucleotide polymorphisms (rs6534347, rs11575812, rs2069778, rs2069763, rs2069762, rs6852535, rs12642902, rs6822844, rs2221903, rs17005931) of the block were investigated in a cohort of 93 systemic lupus erythematosus (SLE), 68 ulcerative colitis (UC), 39 Crohn's disease (CD) patients and 162 healthy control subjects of Tunisian origin. In SLE population, haplotypes AGCAGGGTC, AGAAGAGTC, AGAAGGGTC and AGCCGAGTC provided significant evidence of association with SLE risk (p=0.013, 0.028, 0.018 and 0.048, respectively). In the UC population, haplotype AGCCGGGTC provided a susceptibility effect for UC (p=0.025). In the CD population, haplotype CAGGCC showed a protective effect against the development of CD (p=0.038). Haplotype AAGGTT provided significant evidence to be associated with CD risk (p=0.007). Our results support the existence of the associations found in the KIAA1109/IL2/IL21 gene region with ADs, thus confirms that the 4q27 locus may contribute to the genetic susceptibility of ADs in the Tunisian population.

CD22 and Siglec-G regulate inhibition of B-cell signaling by sialic acid ligand binding and control B-cell tolerance

CD22 and Siglec-G are two B-cell expressed members of the Siglec (sialic acid-binding immunoglobulin (Ig)-like lectin) family and are potent inhibitors of B-cell signaling. Genetic approaches have provided evidence that this inhibition of B-cell antigen receptor (BCR) signaling by Siglecs is dependent on ligand binding to sialic acids in specific linkages. The cis-ligand-binding activity of CD22 leads to homo-oligomer formation, which are to a large extent found in membrane domains that are distinct from those containing the BCR. In contrast, Siglec-G is recruited via sialic acid binding to the BCR. This interaction of Siglec-G with mIgM leads to an inhibitory function that seems to be specific for B-1 cells. Both CD22 and Siglec-G control B-cell tolerance and loss of these proteins, its ligands or its inhibitory pathways can increase the susceptibility for autoimmune diseases. CD22 is a target protein both in B-cell leukemias and lymphomas, as well as in B-cell mediated autoimmune diseases. Both antibodies and synthetic chemically modified sialic acids are currently tested to target Siglecs on B cells.

Expansion of the IgD class switched B cell population in carriers of the autoimmune disease associated risk haplotype in BLK (HUM2P.332)

Abstract Polymorphisms in BLK are associated with numerous autoimmune diseases including rheumatoid arthritis and lupus. BLK (B lymphocyte kinase) is a tyrosine kinase involved in signaling through the B cell receptor (BCR). The disease risk haplotype is known to be associated with reduced expression of BLK transcript and the most significant association of reduced BLK transcript is with a candidate causal SNP rs922483. We have previously shown that expression of BLK is reduced in cord blood B cells from carriers of rs922483 risk alleles (HMG 2012). B cell development is perturbed in blk transgenic and knockout mice, and B cells from these mice are hyper-responsive to BCR stimulation. To determine if reduced BLK expression affects the function of primary human B cells we measured CD86 expression in cells stimulated by anti-IgM. As in mice, cord blood B cells from risk allele carriers are hyper-responsive to BCR stimulation. We also assessed if BLK risk variants convey any variation on the composition of circulating B cell populations of healthy adults. We observed that subjects with BLK risk variants have an expansion in the proportion and number of IgD class-switched B cells, and an increase in the total number of class-switched memory B cells. These results suggest that BLK risk haplotypes confer autoimmune disease susceptibility by reducing a negative regulatory effect of BLK, making B cells more likely to receive help from CD4 T cells and to undergo class switch recombination.

A meta-analysis of the association between thyroglobulin gene polymorphism and autoimmune thyroid disease

The association between thyroglobulin gene polymorphism and autoimmune thyroid disease was investigated.A total of eight case-control studies were included.E33SNP was associated with increased susceptibility of autoimmune thyroid disease in recessive model (OR =1.54,95 ％ CI 1.21 ～ 1.97,P =0.024),while E12SNP was associated with increased susceptibility of autoimmune thyroid disease in allele model (OR =1.12,95％ CI 1.05 ～1.21,P =0.033).Thyroglobulin gene polymorphism seems to be associated with autoimmune thyroid disease. Key words: Thyroglobulin; Autoimmune thyroid disease; Gene polymorphism

Autoantibodies to IgG/HLA class II complexes are associated with rheumatoid arthritis susceptibility

Specific HLA class II alleles are strongly associated with susceptibility to rheumatoid arthritis (RA); however, how HLA class II regulates susceptibility to RA has remained unclear. Recently, we found a unique function of HLA class II molecules: their ability to aberrantly transport cellular misfolded proteins to the cell surface without processing to peptides. Rheumatoid factor (RF) is an autoantibody that binds to denatured IgG or Fc fragments of IgG and is detected in 70-80% of RA patients but also in patients with other diseases. Here, we report that intact IgG heavy chain (IgGH) is transported to the cell surface by HLA class II via association with the peptide-binding groove and that IgGH/HLA class II complexes are specifically recognized by autoantibodies in RF-positive sera from RA patients. In contrast, autoantibodies in RF-positive sera from non-RA individuals did not bind to IgGH/HLA class II complexes. Of note, a strong correlation between autoantibody binding to IgG complexed with certain HLA-DR alleles and the odds ratio for that allele's association with RA was observed (r = 0.81; P = 4.6 × 10(-5)). Our findings suggest that IgGH complexed with certain HLA class II alleles is a target for autoantibodies in RA, which might explain why these HLA class II alleles confer susceptibility to RA.

IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases

B lymphocytes have critical roles as positive and negative regulators of immunity. Their inhibitory function has been associated primarily with interleukin 10 (IL-10) because B-cell-derived IL-10 can protect against autoimmune disease and increase susceptibility to pathogens. Here we identify IL-35-producing B cells as key players in the negative regulation of immunity. Mice in which only B cells did not express IL-35 lost their ability to recover from the T-cell-mediated demyelinating autoimmune disease experimental autoimmune encephalomyelitis (EAE). In contrast, these mice displayed a markedly improved resistance to infection with the intracellular bacterial pathogen Salmonella enterica serovar Typhimurium as shown by their superior containment of the bacterial growth and their prolonged survival after primary infection, and upon secondary challenge, compared to control mice. The increased immunity found in mice lacking IL-35 production by B cells was associated with a higher activation of macrophages and inflammatory T cells, as well as an increased function of B cells as antigen-presenting cells (APCs). During Salmonella infection, IL-35- and IL-10-producing B cells corresponded to two largely distinct sets of surface-IgM(+)CD138(hi)TACI(+)CXCR4(+)CD1d(int)Tim1(int) plasma cells expressing the transcription factor Blimp1 (also known as Prdm1). During EAE, CD138(+) plasma cells were also the main source of B-cell-derived IL-35 and IL-10. Collectively, our data show the importance of IL-35-producing B cells in regulation of immunity and highlight IL-35 production by B cells as a potential therapeutic target for autoimmune and infectious diseases. This study reveals the central role of activated B cells, particularly plasma cells, and their production of cytokines in the regulation of immune responses in health and disease.

Alternative Splice Forms of CTLA-4 Induced by Antisense Mediated Splice-Switching Influences Autoimmune Diabetes Susceptibility in NOD Mice

Activated and regulatory T cells express the negative co-stimulatory molecule cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) that binds B7 on antigen-presenting cells to mediate cellular responses. Single nucleotide polymorphisms in the CTLA-4 gene have been found to affect alternative splicing and are linked to autoimmune disease susceptibility or resistance. Increased expression of a soluble splice form (sCTLA-4), lacking the transmembrane domain encoded by exon 3, has been shown to accelerate autoimmune pathology. In contrast, an exon 2-deficient form lacking the B7 ligand binding domain (liCTLA-4), expressed by diabetes resistant mouse strains has been shown to be protective when expressed as a transgene in diabetes susceptible non-obese diabetic (NOD) mice. We sought to employ an antisense-targeted splice-switching approach to independently produce these CTLA-4 splice forms in NOD mouse T cells and observe their relative impact on spontaneous autoimmune diabetes susceptibility. In vitro antisense targeting of the splice acceptor site for exon 2 produced liCTLA-4 while targeting exon 3 produced the sCTLA-4 form in NOD T cells. The liCTLA-4 expressing T cells exhibited reduced activation, proliferation and increased adhesion to intercellular adhesion molecule-1 (ICAM-1) similar to treatment with agonist α-CTLA-4. Mice treated to produce liCTLA-4 at the time of elevated blood glucose levels exhibited a significant reduction in the incidence of insulitis and diabetes, whereas a marked increase in the incidence of both was observed in animals treated to produce sCTLA-4. These findings provide further support that alternative splice forms of CTLA-4 affects diabetes susceptibility in NOD mice and demonstrates the therapeutic utility of antisense mediated splice-switching for modulating immune responses.

Association of ABCB1 gene polymorphisms and haplotypes with therapeutic efficacy of glucocorticoids in Chinese patients with immune thrombocytopenia

Resistance to glucocorticoids (GCs) remains a tricky problem complicating the therapy of ITP. Recently, ATP binding cassette gene B1 gene (ABCB1) was reported to be correlated with susceptibility and therapeutic efficacy of autoimmune diseases through P-glycoprotein (Pgp). We investigated three single nucleotide polymorphisms (SNPs) of ABCB1 and their haplotypes by PCR–RFLP (restriction fragment length polymorphism) method in 471 ITP patients and 383 healthy controls, patients were further assigned into GCs-responsive and -non-responsive group according to the therapeutic effects of GCs. We observed a remarkable difference in genotypes of G2677T/A between GCs-responsive and non-responsive group, but not between patients and controls. A frequently expression of T/A allele within G2677T/A was recorded in GCs-responsive group. Furthermore, we found that some haplotypes (CGC, CTC/CAC, CTT/CAT, TGC, TGT, TTC/TAC and TTT/TAT, in the order of position 1236-2677-3435) were presented significantly differences between non-responsive and responsive group. No difference of C1236T and C3435T polymorphisms was observed between ITP and controls, and between the GCs-responsive and -non-responsive group. Our findings suggest that ABCB1 polymorphisms, as well as haplotypes derived from C1235T, G2677T/A and C3435T, are associated with inter-individual differences of GCs treatment in ITP.

Association between CTLA-4 polymorphism and systemic lupus erythematosus

Background: Cytotoxic lymphocyte antigen-4 (CTLA-4) plays an important role in regulating T cell activities. CTLA-4 gene polymorphisms are associated with genetic susceptibility to various autoimmune diseases, including systemic lupus erythematosus (SLE). The present study was conducted to analyze the role of CTLA-4 polymorphism at positions −1722TC in patients suffering from SLE. Methods: Samples were collected from 180 SLE patients and 304 healthy people. Both groups were equal in terms of age and ethnicity. Polymerase chain reaction restriction fragments length polymorphism (PCR-RFLP) was used to analyze the genotype and allele frequencies of these polymorphisms. Data were analyzed by SPSS software. Results: No statistically significant difference was observed between the studied genotypic and allelic frequencies, SLE patients and the controls. There was a significant correlation between age range 15-45 and TT genotype (P<0.0001). However, no significant correlation was found between other risk factors and different genotypes. Conclusion: The results suggested that 1722TC polymorphism in the promoter region of the CTLA-4 gene does not play any role in the genetic susceptibility to SLE.

Idd13 is involved in determining immunoregulatory DN T-cell number in NOD mice

Immunoregulatory T cells have been identified as key modulators of peripheral tolerance and participate in preventing autoimmune diseases. CD4(-)CD8(-) (double negative, DN) T cells compose one of these immunoregulatory T-cell subsets, where the injection of DN T cells confers protection from autoimmune diabetes progression. Interestingly, genetic loci defining the function and number of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) coincide with at least some autoimmune disease susceptibility loci. Herein, we investigate the impact of major insulin-dependent diabetes (Idd) loci in defining the number of DN T cells. We demonstrate that although Idd3, Idd5 and Idd9 loci do not regulate DN T-cell number, NOD mice congenic for diabetes resistance alleles at the Idd13 locus show a partial restoration in DN T-cell number. Moreover, competitive and non-competitive bone marrow chimera experiments reveal that DN T-cell number is defined by a bone marrow-intrinsic, but DN T-cell-extrinsic, factor. This suggests that non-autonomous candidate genes define DN T-cell number in secondary lymphoid organs. Together, our results show that the regulation of DN T-cell number in NOD mice is at least partially conferred by alleles at the Idd13 locus.

Association between IRF5 polymorphisms and autoimmune diseases: a meta-analysis.

In this study, we investigated the association between 5 interferon regulatory factor-5 (IRF5) single nucleotide polymorphisms (SNPs) and autoimmune diseases using the Medline citation index. Twenty-eight studies with 74 comparisons, including 16 rheumatoid arthritis (RA), 43 systemic lupus erythematous (SLE), 2 juvenile idiopathic arthritis (JIA), 6 multiple sclerosis (MS), and 5 systemic sclerosis (SSc) studies, were examined in the meta-analysis. The SNP rs2004640 was significantly associated with SLE, MS, and SSc, but not with JIA [odds ratio (OR)=1.06, 95% confidence interval (CI)=0.90-1.24, P=0.48] or RA (OR=1.03, 95%CI=0.95-1.11, P=0.44). A significant association was observed between rs2280714 and SLE, MS, and SSc, but not RA (OR=1.01, 95%CI=0.94-1.09, P=0.80). Rs10954213 was associated with the pathogenesis of SLE, RA, MS, and SSc. rs2070197 and the exon 6 insertion were significantly associated with SLE. Haplotypes containing rs2004640T and rs2280714T were significantly associated with an increased risk of SLE, but not with RA. This meta-analysis certified that IRF5 polymorphisms confer susceptibility to SLE, MS, and SSc. To further confirm the correlations between polymorphisms of IRF5 and autoimmune disease susceptibility, studies involving a larger number of patients worldwide are necessary.

Support vector machine algorithms in the search of KIR gene associations with disease

Killer-cell immunoglobulin-like receptors (KIR) are membrane proteins expressed by natural killer cells and CD8 lymphocytes. The KIR system consists of 17 genes and 614 alleles, some of which bind human leukocyte antigens (HLA). Both KIR and HLA modulate susceptibility to haematological malignancies, viral infections and autoimmune diseases. Molecular epidemiology studies employ traditional statistical methods to identify links between KIR genes and disease. Here we describe our results at applying artificial intelligence algorithms (support vector machines) to identify associations between KIR genes and disease. We demonstrate that these algorithms are capable of classifying samples into healthy and diseased groups based solely on KIR genotype with potential use in clinical decision support systems.

The splice site variant rs11078928 may be associated with a genotype-dependent alteration in expression of GSDMB transcripts

BackgroundMany genetic variants have been associated with susceptibility to complex traits by genome wide association studies (GWAS), but for most, causal genes and mechanisms of action have yet to be elucidated. Using bioinformatics, we identified index and proxy variants associated with autoimmune disease susceptibility, with the potential to affect splicing of candidate genes. PCR and sequence analysis of whole blood RNA samples from population controls was then carried out for the 8 most promising variants to determine the effect of genetic variation on splicing of target genes.ResultsWe identified 31 splice site SNPs with the potential to affect splicing, and prioritised 8 to determine the effect of genotype on candidate gene splicing. We identified that variants rs11078928 and rs2014886 were associated with altered splicing of the GSDMB and TSFM genes respectively. rs11078928, present in the asthma and autoimmune disease susceptibility locus on chromosome 17q12-21, was associated with the production of a novel Δ exon5-8 transcript of the GSDMB gene, and a separate decrease in the percentage of transcripts with inclusion of exon 6, whereas the multiple sclerosis susceptibility variant rs2014886, was associated with an alternative TFSM transcript encompassing a short cryptic exon within intron 2.ConclusionsOur findings demonstrate the utility of a bioinformatic approach in identification and prioritisation of genetic variants effecting splicing of their host genes, and suggest that rs11078928 and rs2014886 may affect the splicing of the GSDMB and TSFM genes respectively.