PubMed Health⌕ Search

Biomedical subjects

John D Reveille

Publications and source records attributed to John D Reveille.

At least 19 recordsLinked to original sources
PubMed2026

A highly prevalent lupus risk haplotype increases IRF7-dependent induction of IFN-α, enhancing antiviral defense and exacerbating autoimmunity.

Genome-wide association studies have identified genetic polymorphisms at 11p15 associated with systemic lupus erythematosus (lupus). Statistical fine mapping prioritizes a highly prevalent coding haplotype within IRF7. Analysis of ancient DNA confirms that this haplotype has persisted at high frequencies in the global population for millennia. The IRF7 risk haplotype is sufficient to increase nuclear localization of IRF7 and transcriptional activity downstream of pattern recognition receptor pathways. This risk haplotype increases IRF7 DNA-binding strength and alters IRF7 DNA sequence specificity, resulting in genotype-dependent increases in interferon-α production in numerous biological systems, including monocytes and airway epithelial cells. CRISPR engineering of the corresponding risk variant in mouse Irf7 results in both enhanced innate control of virus infection and increased autoantibody titers in a model of autoimmunity. Altogether, we establish a persistent and prominent IRF7 haplotype that amplifies IRF7 activity in a manner that has immunological risks and benefits.

ancient DNA↗
PubMed2026

A highly prevalent lupus risk haplotype increases IRF7-dependent induction of IFN-α, enhancing antiviral defense and exacerbating autoimmunity.

UNLABELLED: Genome-wide association studies have identified genetic polymorphisms at 11p15 associated with Systemic Lupus Erythematosus (lupus). Statistical fine mapping prioritizes a highly prevalent coding haplotype within the IRF7 gene. Analysis of ancient DNA confirms that this haplotype has persisted at high frequencies in the global population for millennia. The IRF7 risk haplotype is sufficient to increase nuclear localization of IRF7 and transcriptional activity downstream of pattern recognition receptor pathways. This risk haplotype increases IRF7 DNA binding strength and alters IRF7 DNA sequence specificity, resulting in genotype-dependent increases in IFN-α production in numerous biological systems, including monocytes and airway epithelial cells. CRISPR engineering of a homologous risk variant in mouse Irf7 results in both enhanced innate control of virus infection and increased autoantibody titers in a model of autoimmunity. Altogether, we establish a persistent and prominent genetic IRF7 haplotype that amplifies IRF7 activity in a manner that has immunological risks and benefits. HIGHLIGHTS: Genetic analysis using modern and evolutionary datasets identifies a persistent and highly prevalent lupus-associated coding haplotype in IRF7 at 11p15 The IRF7 lupus risk haplotype increases IFN-α production by monocytes and airway epithelial cells The IRF7 lupus risk haplotype increases IRF7 DNA binding strength and alters DNA sequence specificity A homologous lupus risk variant in mouse Irf7 enhances control of vesicular stomatitis virus and exacerbates autoantibody production.

Journal Article↗
PubMed2007

Association of a TNAP haplotype with ankylosing spondylitis.

OBJECTIVE: To use a candidate gene approach to the identification of genetic markers that are significantly associated with ankylosing spondylitis (AS). METHODS: We genotyped 201 multiplex AS families with 1 exonic and 5 intronic single-nucleotide polymorphisms (SNPs) in TNAP, the gene that encodes tissue-nonspecific alkaline phosphatase, and performed family-based association analyses. RESULTS: In our cohort of 201 multiplex AS families, the TNAP haplotype rs3767155 (G)/rs3738099 (G)/rs1780329 (T) was significantly associated with AS (P = 0.032 by additive model). Haplotype-Based Association Testing (HBAT) analyses of AS families in which both men and women were affected showed that the same TNAP haplotype was significantly associated with AS (P = 0.002 by additive model). Using setafftrait code 1 0 0 in the HBAT program, testing specifically for affected men in AS families containing affected individuals of both sexes, this TNAP haplotype was also significantly associated with AS (P = 0.001 by additive model). The HBAT -p option (haplotype permutation test) was used to compute the "exact" P value via a Monte Carlo method for each haplotype (haplotype permutation test) and for the minimum observed P value among the haplotypes (whole marker permutation using the minimal P test), and both P values were statistically significant (2-sided P value for haplotype rs3767155 [G]/rs3738099 [G]/rs1780329 [T] = 0.00059, the smallest observed P value among all the individual haplotype scores = 0.003). Interestingly, this haplotype was not associated with AS in affected women from the same families. CONCLUSION: Our results indicate that the TNAP haplotype rs3767155 (G)/rs3738099 (G)/rs1780329 (T) is a novel genetic marker in men that is significantly associated with AS in multiplex families containing affected individuals of both sexes.

Adolescent↗
PubMed2006

Are there gender differences in severity of ankylosing spondylitis? Results from the PSOAS cohort.

OBJECTIVE: To examine the clinical and radiographic features in men and women in the Prospective Study of Outcomes in Ankylosing Spondylitis cohort, a large well-defined cross-sectional study of patients with AS, in order to understand the influence of gender in determining the severity of ankylosing spondylitis. METHODS: Extensive clinical assessments and spine radiographs were performed in 302 men and 100 women with AS of > or = 20 years duration. Radiographs were scored using the Bath Ankylosing Spondylitis Radiographic Index Spine (BASRI-spine) score (range 2-12). Functional impairment was measured by the Bath Ankylosing Spondylitis Functional Index (BASFI) and the Health Assessment Questionnaire for the Spondyloarthropathies (HAQ-S). RESULTS: Radiographic severity was worse among men. The unadjusted median BASRI-spine score for men was 10, compared with 6.5 for women (p<0.001). Functional disability, as measured by the BASFI and HAQ-S, was not different between men and women. However, after adjusting for radiographic spinal damage, women were found to report worse functioning than men at any given level of radiographic damage. Women had a slightly earlier age of disease onset; however, disease duration was identical in both groups. Women more frequently reported family histories of AS in first-degree relatives and were more likely to be treated with intra-articular steroids, sulphasalazine and prednisone. CONCLUSIONS: Among patients with longstanding AS, men have more severe radiographic changes; findings of treatment differences suggest that women may have more peripheral arthritis. At any given level of radiographic damage, self-reported functional limitations were worse for women.

Age of Onset↗
PubMed2006

African-American and Hispanic ethnicities, renal involvement and obesity predispose to hypertension in systemic lupus erythematosus: results from LUMINA, a multiethnic cohort (LUMINAXLV).

OBJECTIVE: To examine the predictors of the occurrence of hypertension in a large multiethnic US cohort. PATIENTS AND METHODS: There were 614 patients with systemic lupus erythematoses (SLE; > or = 4 American College of Rheumatology revised criteria) with < or = 5 years of disease duration at entry into the cohort (T0) and of Hispanic (Texan or Puerto Rican), African-American or Caucasian ethnicity. T0 variables were compared between patients who did and did not develop hypertension (blood pressure > or = 140/90 mm Hg on at least two occasions and/or the use of antihypertensive drugs) after T0. Significant and clinically relevant variables were then examined by a stepwise logistic regression model. RESULTS: A total of 379 patients without hypertension at T0 were included (patients who developed hypertension prior to SLE diagnosis (n = 126) or before T0 (n = 109) were excluded). Predictors of hypertension were African-American and Texan-Hispanic ethnicities, renal involvement and a higher body mass index. CONCLUSIONS: Traditional cardiovascular risk factors, disease-related factors and ethnicity play a role in the occurrence of hypertension in patients with SLE. Controlling renal involvement and optimising body weight may prevent the occurrence of hypertension.

Adult↗
PubMed2006

Systemic lupus erythematosus in a multiethnic US cohort, XXXVII: association of lymphopenia with clinical manifestations, serologic abnormalities, disease activity, and damage accrual.

OBJECTIVE: To determine if lymphopenia is associated with clinical/immunologic manifestations, disease activity, and disease damage in systemic lupus erythematosus (SLE). METHODS: The study group comprised 591 patients with SLE participating in a multiethnic, longitudinal outcome study. Cumulative clinical/immunologic (per American College of Rheumatology criteria) and pharmacologic treatment variables were obtained at enrollment (T0) and last visit (TL). Lymphopenia (<1,500/mm3) was scored only when clinically attributable to SLE and not to medications or other causes. Lymphocyte counts were expressed in 4 categories per the Systemic Lupus Activity Measure (SLAM): normal (> or =1,500/mm3), mild (1,000-1,499/mm3), moderate (500-999/mm3), and marked (<500/mm3). Disease activity was assessed with the SLAM and the Physician's Global Assessment (PGA). Disease damage was determined with the Systemic Lupus International Collaborating Clinics Damage Index (SLICC-DI). The relationship of lymphopenia with cumulative clinical/immunologic and pharmacologic treatment variables was first examined, then the association between the SLAM, PGA, and SLICC-DI scores with different categories of lymphopenia was examined by generalized estimating equation (GEE) regression analyses. Ethnicity, age, and sex were entered into all regression models. RESULTS: At T0 and TL, lymphopenia was found to be positively associated with renal involvement, leukopenia, anti-double-stranded DNA antibodies, anti-Ro antibodies, and the use of glucocorticoids, azathioprine, and methotrexate, but was negatively associated with photosensitivity. On GEE analyses, marked lymphopenia at T0 and moderate and marked lymphopenia for all visits were independently associated with higher SLAM, PGA, and SLICC-DI scores. CONCLUSION: Lymphopenia is associated with several clinical/immunologic manifestations in SLE. Moderate and marked lymphopenia are associated with higher disease activity and damage accrual.

Adult↗
PubMed2006

Changing spectrum of the diffuse infiltrative lymphocytosis syndrome.

OBJECTIVE: To describe the changing clinical spectrum of patients with diffuse infiltrative lymphocytosis syndrome (DILS) after the introduction of highly active antiretroviral treatment (HAART), and to carry out HLA class II oligotyping in these patients. METHODS: A retrospective chart review of patients with DILS who were referred to an outpatient facility for human immunodeficiency virus (HIV)-positive individuals between 1994 and 2003 was performed. DILS was diagnosed as suggested by previous criteria. Demographic features and relevant clinical, laboratory, and radiologic data were recorded and results analyzed. RESULTS: A total of 129 patients with DILS were identified. Of them, 56 (43%) were African American, 41 (32%) were white, and 32 (25%) were Hispanic. Parotid gland swelling appeared to be the sine qua non of DILS. Twenty-seven percent of patients had opportunistic infections. The status of 103 patients was available as of December 2003: 26 (25%) had died, of which only 6 (6%) succumbed to opportunistic infections. The prevalence of DILS had significantly decreased in the post-HAART era (1998 onwards) compared with that of the pre-HAART period (P < 0.000001). The prevalence of lymphocytic interstitial pneumonitis had also dropped significantly following introduction of HAART therapy (P = 0.015). A higher frequency of certain HLA class II alleles (DRB1) was found in African Americans with DILS compared with those with HIV without DILS (P = 0.006). CONCLUSION: The epidemiology, clinical presentation, and certain extraglandular manifestations of DILS have changed, concomitant with the introduction of HAART, further suggesting that DILS is an antigen (viral)-driven response and the primary treatment for it is anti-HIV therapy.

AIDS-Related Opportunistic Infections↗
PubMed2006

Trust in physicians and elements of the medical interaction in patients with rheumatoid arthritis and systemic lupus erythematosus.

OBJECTIVE: To identify components of the patient-doctor relationship associated with trust in physicians. METHODS: We assessed 102 patients with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA) seen at publicly funded hospitals in Houston, Texas. Patients completed a self-response survey examining patient perceptions of the medical encounter and trust in their physicians. Evaluated components of physicians' behaviors included: informativeness, sensitivity to concerns, reassurance and support, patient-centeredness, and participatory decision-making style. Scales were scored 0 to 10, with higher numbers indicating more positive perceptions of communication. RESULTS: Seventy patients had RA and 32 SLE; 25% were white, 43% Latino, 31% African American, and 75% were female. Mean scores for the medical interaction and trust scales ranged from 6.2-7.1, indicating moderate degrees of positive perceptions. All components were highly and positively correlated with each other, and with trust, suggesting that these traits are all elements of a positive style of doctor-patient communication. In multivariate analysis, ethnicity, physicians' informativeness, physicians' sensitivity to concerns, patient-centeredness, disease activity, and patient trust in the US health care system were independent predictors of trust in physicians. A separate model examined the predictors of patient disclosure of information. Patient perceptions of physicians' patient-centeredness and severity of disease activity were independently predictive of patient disclosure of information. CONCLUSION: In patients with SLE and RA, trust in physicians is significantly associated with patients' ethnicity and their perceptions about specific components of physicians' communication style. Trust in physicians can be improved by using a patient-centered approach, being sensitive to patient concerns, and providing adequate clinical information. Furthermore, patients appear to be more willing to disclose concerns when physicians use a patient-centered communication style.

Adult↗
PubMed2006

Systemic lupus erythematosus in a multiethnic US cohort. XXXIII. Clinical [corrected] features, course, and outcome in patients with late-onset disease.

OBJECTIVE: To examine the clinical differences and the type and extent of organ damage in late- versus early-onset systemic lupus erythematosus (SLE). METHODS: A nested case-control study was performed in the context of LUMINA (LUpus in MInorities, NAture versus nurture), a large, longitudinal, multiethnic cohort. Patients who developed SLE at or after the age of 50 years were considered cases. Two controls (patients who developed SLE at age < or = 49 years) per case, matched for sex and disease duration, were randomly chosen. Selected baseline socioeconomic/demographic, behavioral, and psychological features, self-reported quality of life, and cumulative clinical data (clinical manifestations, laboratory data, disease activity, damage, and mortality) were compared between cases and controls. Multivariable analyses with late-onset lupus, damage accrual, and mortality as dependent variables were then performed. RESULTS: Two hundred seventeen patients were studied. Of them, 73 were cases. Cases were more likely to have neurologic involvement, arterial thrombotic events, osteoporosis, and hypertriglyceridemia, while renal involvement and anti-Sm antibodies were less frequent. Disease activity at baseline was lower among cases. Cases also exhibited more cardiovascular and ocular damage. Late-onset lupus was an independent predictor of damage accrual (t-test = 2.23, P = 0.028), any damage at last visit (odds ratio [OR] 23.32, 95% confidence interval [95% CI] 3.98-141.56) (P < 0.001), and mortality (OR 10.74, 95% CI 3.07-37.56) (P < 0.001). CONCLUSION: Patients with late-onset lupus exhibit distinct clinical features. Although disease activity tends to be lower in these patients, they tend to accrue more damage and experience higher mortality than patients with early-onset lupus. These findings probably reflect the contribution exerted by other comorbid conditions in the overall impact of lupus in these patients.

Adolescent↗
PubMed2006

Systemic lupus erythematosus in a multiethnic US cohort: XXXIV. Deficient mannose-binding lectin exon 1 polymorphisms are associated with cerebrovascular but not with other arterial thrombotic events.

OBJECTIVE: To study the association between deficient mannose-binding lectin (MBL) genotypes and arterial thrombotic events in systemic lupus erythematosus (SLE). METHODS: Patients with SLE of Hispanic, African American, and Caucasian ethnicity from LUMINA (LUpus in MInorities, NAture versus nurture), a multiethnic, longitudinal study of outcome, were studied. Arterial thrombotic events (myocardial infarction, angina, coronary artery bypass graft surgery, stroke, claudication, gangrene, or tissue loss and/or peripheral arterial thrombosis) that occurred after diagnosis were recorded. Genotyping for MBL gene polymorphisms was performed and their distribution was compared between patients who did and did not have thrombotic events. RESULTS: There were 58 events (21 cardiovascular, 27 cerebrovascular, and 10 peripheral vascular) in 48 patients. Patients who had thrombotic events were older and were more likely to be smokers, to have more severe disease, and to have accrued more damage overall. Also, a larger proportion of these patients had C-reactive protein values in the highest quintile of distribution. No significant difference in arterial thrombotic events was found in patients homozygous for MBL-deficient alleles compared with others. Similar results were seen within ethnic groups. Caucasians who developed potential thrombotic events exhibited a higher frequency of MBL-deficient alleles, but the difference was not statistically significant for all events together or for cardiovascular and cerebrovascular events combined. However, when only the cerebrovascular events were considered, the difference became statistically significant. CONCLUSION: Age, smoking, and measures of activity and damage were associated with arterial thrombotic events in patients with SLE, but MBL-deficient genotypes were not, with cerebrovascular events in Caucasians being the exception. The relationship between MBL-variant alleles and arterial thrombotic events may exist only within select ethnic groups and event types.

Adult↗
PubMed2006

Efficacy and safety of adalimumab in patients with ankylosing spondylitis: results of a multicenter, randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the safety and efficacy of adalimumab, a fully human recombinant IgG1 monoclonal antibody that specifically targets human tumor necrosis factor, in patients with active ankylosing spondylitis (AS). METHODS: This was a multicenter, randomized (2:1 ratio), double-blind, placebo-controlled study to evaluate a subcutaneous injection of adalimumab, 40 mg every other week, compared with placebo for 24 weeks. The primary efficacy end point was the percentage of patients with a 20% response according to the ASsessment in Ankylosing Spondylitis International Working Group criteria for improvement (ASAS20) at week 12. Secondary outcome measures included the ASAS20 at week 24 and multiple measures of disease activity, spinal mobility, and function, as well as ASAS partial remission. RESULTS: At week 12, 58.2% of adalimumab-treated patients (121 of 208) achieved an ASAS20 response, compared with 20.6% of placebo-treated patients (22 of 107) (P < 0.001). More patients in the adalimumab group (45.2% [94 of 208]) than in the placebo group (15.9% [17 of 107]) had at least a 50% improvement in the Bath Ankylosing Spondylitis Disease Activity Index at week 12 (P < 0.001). Significant improvements in the ASAS40 response and the response according to the ASAS5/6 criteria at weeks 12 and 24 were also demonstrated (P < 0.001). Partial remission was achieved by more adalimumab-treated patients than placebo-treated patients (22.1% versus 5.6%; P < 0.001). Adalimumab-treated patients reported more adverse events (75.0% versus 59.8% of placebo-treated patients; P < 0.05), but there was no statistically significant difference in the incidence of infections. Most adverse events were mild or moderate in severity. CONCLUSION: Adalimumab was well-tolerated during the 24-week study period and was associated with a significant and sustained reduction in the signs and symptoms of active AS.

Adalimumab↗
PubMed2006

HLA polymorphisms in African Americans with idiopathic inflammatory myopathy: allelic profiles distinguish patients with different clinical phenotypes and myositis autoantibodies.

OBJECTIVE: To investigate possible associations of HLA polymorphisms with idiopathic inflammatory myopathy (IIM) in African Americans, and to compare this with HLA associations in European American IIM patients with IIM. METHODS: Molecular genetic analyses of HLA-A, B, Cw, DRB1, and DQA1 polymorphisms were performed in a large population of African American patients with IIM (n = 262) in whom the major clinical and autoantibody subgroups were represented. These data were compared with similar information previously obtained from European American patients with IIM (n = 571). RESULTS: In contrast to European American patients with IIM, African American patients with IIM, in particular those with polymyositis, had no strong disease associations with HLA alleles of the 8.1 ancestral haplotype; however, African Americans with dermatomyositis or with anti-Jo-1 autoantibodies shared the risk factor HLA-DRB1*0301 with European Americans. We detected novel HLA risk factors in African American patients with myositis overlap (DRB1*08) and in African American patients producing anti-signal recognition particle (DQA1*0102) and anti-Mi-2 autoantibodies (DRB1*0302). DRB1*0302 and the European American-, anti-Mi-2-associated risk factor DRB1*0701 were found to share a 4-amino-acid sequence motif, which was predicted by comparative homology analyses to have identical 3-dimensional orientations within the peptide-binding groove. CONCLUSION: These data demonstrate that North American IIM patients from different ethnic groups have both shared and distinct immunogenetic susceptibility factors, depending on the clinical phenotype. These findings, obtained from the largest cohort of North American minority patients with IIM studied to date, add additional support to the hypothesis that the myositis syndromes comprise multiple, distinct disease entities, perhaps arising from divergent pathogenic mechanisms and/or different gene-environment interactions.

Adenosine Triphosphatases↗
PubMed2006

Major histocompatibility genes and ankylosing spondylitis.

The association of HLA-B27 with ankylosing spondylitis accounts for nearly 40% of the total disease risk. However, fewer than 5% of B27-positive individuals in the general population become affected. Genomewide scans suggest that other major histocompatibility complex genes further heighten this risk, although linkage disequilibrium with HLA-B27 has confounded their precise identification. Over 31 variants of HLA-B27 have been identified to date, which have evolved from the original B27 allele (B*2705) along three geographic lines. HLA-B*2705 and B*2702 are the primary subtypes in Caucasians with spondylitis, and B*2704 and B*2707 are the primary subtypes in Asians. HLA-B*2706 and B*2709 are not disease associated. There are four theories of how HLA-27 causes spondyloarthritis: (1) HLA-B27 presents a bacterially derived 'arthritogenic peptide' (not yet identified); (2) misfolding or homodimerization of HLA-B27 heavy chains results in a pro-inflammatory response; (3) HLA-B27-positive individuals have deficient intracellular killing of arthritogenic organisms; and (4) HLA-B27 itself, due to sequence homology with bacterial proteins, becomes autoantigenic.

Amino Acid Sequence↗
PubMed2006

Infection and musculoskeletal conditions: Rheumatologic complications of HIV infection.

The pandemic caused by the human immunodeficiency virus (HIV) has entered its second quarter-century, with 40 million people now affected worldwide - particularly in Africa, where the impact has been most devastating. A complex array of rheumatic disease manifestations has been described, including diseases specific to HIV infection such as HIV-associated arthritis and the diffuse infiltrative lymphocytosis syndrome; other conditions which occur prominently in HIV-positive individuals include vasculitis, reactive and psoriatic arthritis and HIV-associated polymyositis, opportunistic musculoskeletal infections, and finally disorders that were originally ameliorated by HIV infection, such as rheumatoid arthritis and lupus. Effective antiretroviral treatment ameliorates many of these disorders; however, the introduction of highly active antiretroviral treatment (HAART) has introduced a new spectrum of disorders and new challenges confronting the clinician, including osteonecrosis, rhabdomyolysis, and, with immune reconstitution, the appearance de novo of a variety of autoimmune disorders and phenomena.

Antiretroviral Therapy, Highly Active↗
PubMed2006

The genetic basis of ankylosing spondylitis.

PURPOSE OF REVIEW: Genetic factors provide over 90% of the overall susceptibility to ankylosing spondylitis, with about half of the genetic contribution attributed to HLA-B27 and other major histocompatibility complex genes. Recent studies have focused on non-major histocompatibility complex genes. This review is aimed at summarizing the status of major histocompatibility complex and non-major histocompatibility complex genes in ankylosing spondylitis susceptibility, and suggests areas for future studies. RECENT FINDINGS: A recent meta-analysis of published scans of ankylosing spondylitis susceptibility has confirmed sites on chromosomes 3q, 6p (the major histocompatibility complex), 10q, 16q and 19q in ankylosing spondylitis susceptibility. Non-major histocompatibility complex candidate gene analyses have confirmed a role for the IL-1 gene complex. The search for other non-major histocompatibility complex candidate genes, however, has been complicated by inadequate power in most previous studies. Innovations in genetic methodologies will allow thorough genome wide linkage disequilibrium mapping studies in large cohorts of patients that will result in the dissection of the genetic susceptibility to ankylosing spondylitis. SUMMARY: Nearly half of the susceptibility to ankylosing spondylitis is provided by major histocompatibility complex genes. Non-major histocompatibility complex genes, most notably the IL-1 gene complex, have been identified and novel technologies promise that a more thorough examination of the rest of the genome will soon elucidate the genetic basis of this disease.

Chromosome Mapping↗
PubMed2006

Immunogenetic risk and protective factors for the idiopathic inflammatory myopathies: distinct HLA-A, -B, -Cw, -DRB1, and -DQA1 allelic profiles distinguish European American patients with different myositis autoantibodies.

The idiopathic inflammatory myopathies (IIM) are systemic connective tissue diseases defined by chronic muscle inflammation and weakness associated with autoimmunity. We have performed low to high resolution molecular typing to assess the genetic variability of major histocompatibility complex loci (HLA-A, -B, -Cw, -DRB1, and -DQA1) in a large population of European American patients with IIM (n = 571) representing the major myositis autoantibody groups. We established that alleles of the 8.1 ancestral haplotype (8.1 AH) are important risk factors for the development of IIM in patients producing anti-synthetase/anti-Jo-1, -La, -PM/Scl, and -Ro autoantibodies. Moreover, a random forests classification analysis suggested that 8.1 AH-associated alleles B*0801 and DRB1*0301 are the principal HLA risk markers. In addition, we have identified several novel HLA susceptibility factors associated distinctively with particular myositis-specific (MSA) and myositis-associated autoantibody (MAA) groups of the IIM. IIM patients with anti-PL-7 (anti-threonyl-tRNA synthetase) autoantibodies have a unique HLA Class I risk allele, Cw*0304 (pcorr = 0.046), and lack the 8.1 AH markers associated with other anti-synthetase autoantibodies (for example, anti-Jo-1 and anti-PL-12). In addition, HLA-B*5001 and DQA1*0104 are novel potential risk factors among anti-signal recognition particle autoantibody-positive IIM patients (pcorr = 0.024 and p = 0.010, respectively). Among those patients with MAA, HLA DRB1*11 and DQA1*06 alleles were identified as risk factors for myositis patients with anti-Ku (pcorr = 0.041) and anti-La (pcorr = 0.023) autoantibodies, respectively. Amino acid sequence analysis of the HLA DRB1 third hypervariable region identified a consensus motif, 70D (hydrophilic)/71R (basic)/74A (hydrophobic), conferring protection among patients producing anti-synthetase/anti-Jo-1 and -PM/Scl autoantibodies. Together, these data demonstrate that HLA signatures, comprising both risk and protective alleles or motifs, distinguish IIM patients with different myositis autoantibodies and may have diagnostic and pathogenic implications. Variations in associated polymorphisms for these immune response genes may reflect divergent pathogenic mechanisms and/or responses to unique environmental triggers in different groups of subjects resulting in the heterogeneous syndromes of the IIM.

Alleles↗