Terrance P. O'Hanlon

Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus.

Monozygotic (MZ) twins are partially concordant for most complex diseases, including autoimmune disorders. Whereas phenotypic concordance can be used to study heritability, discordance suggests the role of non-genetic factors. In autoimmune diseases, environmentally driven epigenetic changes are thought to contribute to their etiology. Here we report the first high-throughput and candidate sequence analyses of DNA methylation to investigate discordance for autoimmune disease in twins. We used a cohort of MZ twins discordant for three diseases whose clinical signs often overlap: systemic lupus erythematosus (SLE), rheumatoid arthritis, and dermatomyositis. Only MZ twins discordant for SLE featured widespread changes in the DNA methylation status of a significant number of genes. Gene ontology analysis revealed enrichment in categories associated with immune function. Individual analysis confirmed the existence of DNA methylation and expression changes in genes relevant to SLE pathogenesis. These changes occurred in parallel with a global decrease in the 5-methylcytosine content that was concomitantly accompanied with changes in DNA methylation and expression levels of ribosomal RNA genes, although no changes in repetitive sequences were found. Our findings not only identify potentially relevant DNA methylation markers for the clinical characterization of SLE patients but also support the notion that epigenetic changes may be critical in the clinical manifestations of autoimmune disease.

Myositis: Immunologic Contributions to Understanding Cause, Pathogenesis, and Therapy

Dr. Paul H. Plotz (National Institutes of Health [NIH], Bethesda, Maryland): Myositis, or idiopathic inflammatory myopathy, is one of the rarest inflammatory illnesses in the family of autoimmune diseases. With an incidence of only about 10 new cases per 1 million persons per year in the United States, a busy rheumatologist, neurologist, or dermatologist (the three consultants most likely to make a diagnosis) is unlikely to meet more than one or two new patients with the disorder per year [1, 2]. The rarity of the condition has held back both scholarly and therapeutic study. The notable reports of large series of cases, especially a large experience in Los Angeles reviewed by Bohan and colleagues [3], have provided a framework for all subsequent studies. For the past decade, our group in the Arthritis and Rheumatism Branch of NIH has tried to understand the connection between disease-specific autoantibodies and the diseases in which they are found. We have met and examined approximately 400 patients with myositis or a disease that mimics myositis, and we have done both laboratory and therapeutic studies on many of them. In this report, we concentrate on the clinical and immunologic observations we and others have made in attempting to understand the cause and pathogenesis of an autoimmune disease by understanding the relation of the autoantibodies to the disease. Clinical Features and the Differential Diagnosis of Myositis The study of myositis must begin with a correct diagnosis. Myositis, or, as it is perhaps more usefully called, idiopathic inflammatory myopathy, is a disease of muscle inflammation. Muscle weakness and sometimes pain, often but not always symmetrical and proximal, are limited to the trunk, neck, and limbs. These symptoms are accompanied by signs of muscle damage: the liberation of muscle enzymes, including creatine kinase, aldolase, and other intracellular enzymes (such as aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase); characteristic changes on electromyography; and the presence of degenerating and regenerating myocytes with inflammatory cells, especially lymphocytes, in and around muscle cells and sometimes also around vessels. We have also observed a characteristic series of patterns on magnetic resonance images of inflamed muscles (Figure 1). Figure 1. Magnetic resonance image in a patient with myositis. The differential diagnosis of the weak patient includes a broad spectrum of diseases and toxicities. The borders separating myositis from its close relatives among the rheumatologic diseases are not sharply defined. For example, systemic lupus erythematosus shares both clinical and serologic manifestations with myositis. The late-onset, indolent myositisinclusion body myositisis difficult to distinguish from a bewildering variety of rare cases that in the literature are usually called dystrophies [4]. Some cases treated as myositis are examples of rare or as-yet unrecognized metabolic disorders. The term metabolic myopathy is used for diseases that feature a recognizable genetic deficiency of an enzyme that is vital to the energy production of a muscle cell; the term dystrophy is used for diseases in which no such deficiency is present but in which muscle-cell degeneration has occurred that is presumably caused by genetic defects of one or more structural proteins. This latter assumption is based on the discovery of dystrophin mutations in Duchenne dystrophy. However, because inflammation may be seen in some cases of dystrophy, and because many cases of both metabolic muscle diseases and dystrophies represent either new mutations or the first manifestations of a recessive disease in a family, the real boundaries of all of these illnesses remain unknown. Therefore, it is important to consider them in every case of suspected myositis. For each new case, a review of the major classes of similar diseases catches many of the masqueraders (Table 1). Clinicians should remember that aminotransferase abnormalities do not always indicate liver disease; that fatigue and weakness may be present in the muscles as well as in the head; that drugs and toxins can cause muscle disease; and that a family history of a similar illness, neurologic signs, asymmetry, cranial nerve involvement, and an onset of symptoms related to exercise or eating militate against a diagnosis of myositis. Table 1. Differential Diagnosis of Myositis We studied myositis because some patients with myositis have autoantibodies directed against the ubiquitous intracellular protein, histidyl-transfer RNA (tRNA) synthetase, the enzyme that joins histidine to its cognate tRNA [5]. These antibodies are not seen in any other disease. This strikingly specific association was made even more tantalizing by the subsequent discovery that a small group of patients developed autoantibodies directed against the synthetases responsible for ligating alanine, glycine, isoleucine, or threonine to their respective cognate tRNAs. Furthermore, other myositis-specific autoantibodies have been described in the past decade [6]. In a startling findingthe result of observations by several groups, including Drs. Lori Love, Fred Miller, and colleagues at NIHthe myositis-specific autoantibodies delineated groups of patients who have a remarkably similar clinical illness and share many other features. The common syndromes are summarized in Table 2. Patients with antisynthetase autoantibodies can have either polymyositis or dermatomyositis; those with anti-signal recognition particle (anti-SRP) autoantibodies always have polymyositis; and those with anti-Mi-2 autoantibodies always have dermatomyositis. In the traditional categories, patients with cancer-associated myositis or inclusion body myositis only rarely have myositis-specific autoantibodies, although there are a few exceptions. Table 2. Syndromes Associated with Myositis-Specific Autoantibodies Childhood Myositis: Newly Recognized Diversity Dr. Lisa G. Rider (Food and Drug Administration, Bethesda, Maryland): The idiopathic inflammatory myopathies of childhood are a diverse group of acquired diseases of unknown cause that are all characterized by chronic inflammation in skeletal muscle. Although juvenile dermatomyositis is the most common of these disorders in children, each clinicopathologic entity described in adults has also been reported in children [7], including polymyositis [8], myositis associated with another connective tissue disease (overlap myositis) [9], cancer-associated myositis [10], focal myositis [11], orbital myositis [12], inclusion body myositis [13], eosinophilic myositis [14], and granulomatous myositis [7]. Although the frequency of these clinical conditions in children and adults probably differs, the clinical features, histopathologic findings, and clinical courses appear to be similar in both populations. The most common idiopathic inflammatory myopathy in children is juvenile dermatomyositis, which in children has a peak incidence between ages 5 and 14 years. Juvenile dermatomyositis is similar to adult dermatomyositis and is characterized by the classic Gottron and heliotrope rashes, proximal and symmetrical muscle weakness, and perivascular muscle inflammation. Juvenile and adult dermatomyositis also share immunopathogenetic features, including damage to the endothelial cells of the primary muscle capillaries, perivascular infiltration of B lymphocytes that is associated with deposition of immunoglobulins and the terminal C5b-9 membrane attack complex on the intramuscular microvasculature, and infiltration of T lymphocytes [15]. Juvenile dermatomyositis may differ from the adult disease in the following ways: 1) The clinical presentation in children is more frequently insidious and may be dominated by constitutional symptoms of fatigue, malaise, fever, anorexia, and weight loss [16]; 2) children more often have a multisystem vasculitis that may involve the skin, gastrointestinal mucosa, muscle, heart, and retina [16]; 3) calcinosis develops more frequently in children, particularly in children with longstanding, untreated disease, those with generalized cutaneous vasculitis, or those with a chronic and severe disease course [17]; and 4) once remission is achieved, children appear to return to normal strength and function more frequently than adults with dermatomyositis [18]. The association of malignancy with the development of myositis has been well described in adults but only rarely reported in children. No cases of malignancy have been reported in retrospective studies of large cohorts of children with myositis [19]. However, tumors (most commonly leukemia and lymphoma) have been described in 10 patients with juvenile dermatomyositis and 3 children with polymyositis [7, 10]. In many of these children, the myositis showed atypical features, such as the absence of Gottron papules or the presence of unusual rashes, unilateral muscle weakness, or distal rather than proximal muscle weakness. Some children developed adenopathy, splenomegaly, or an abdominal mass that was seen on examination; the latter prompted a diagnosis of cancer. The myositis followed a paraneoplastic course in that muscle strength, skin rash, and muscle enzyme levels improved with treatment of the underlying cancer. The myositis-specific autoantibodies also develop in children. To date, autoantibodies to threonyl-tRNA synthetase [20], alanyl-tRNA synthetase [21], and histidyl-tRNA synthetase (HRS) (22; unpublished observations) have been found in six children. Anti-signal recognition particle autoantibodies [20] have been detected in one child with polymyositis, and anti-Mi-2 autoantibodies have been found in 10 children with juvenile dermatomyositis [20, 23, 24]. We have found that the clinical features of children with myositis-specific autoantibodies for whom complete clinical data are available are similar to those of adults with the same autoantibodies [20]. Some a

Age-Related Somatic Structural Changes in the Nuclear Genome of Human Blood Cells

Structural variations are among the most frequent interindividual genetic differences in the human genome. The frequency and distribution of de novo somatic structural variants in normal cells is, however, poorly explored. Using age-stratified cohorts of 318 monozygotic (MZ) twins and 296 single-born subjects, we describe age-related accumulation of copy-number variation in the nuclear genomes in vivo and frequency changes for both megabase- and kilobase-range variants. Megabase-range aberrations were found in 3.4% (9 of 264) of subjects ≥60 years old; these subjects included 78 MZ twin pairs and 108 single-born individuals. No such findings were observed in 81 MZ pairs or 180 single-born subjects who were ≤55 years old. Recurrent region- and gene-specific mutations, mostly deletions, were observed. Longitudinal analyses of 43 subjects whose data were collected 7-19 years apart suggest considerable variation in the rate of accumulation of clones carrying structural changes. Furthermore, the longitudinal analysis of individuals with structural aberrations suggests that there is a natural self-removal of aberrant cell clones from peripheral blood. In three healthy subjects, we detected somatic aberrations characteristic of patients with myelodysplastic syndrome. The recurrent rearrangements uncovered here are candidates for common age-related defects in human blood cells. We anticipate that extension of these results will allow determination of the genetic age of different somatic-cell lineages and estimation of possible individual differences between genetic and chronological age. Our work might also help to explain the cause of an age-related reduction in the number of cell clones in the blood; such a reduction is one of the hallmarks of immunosenescence.

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.

Abstract: 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. Abbreviations: AH = ancestral haplotype, DM = dermatomyositis, EA = European Americans, HVR3 = third hypervariable region, IBM = inclusion body myositis, IIM = idiopathic inflammatory myopathies, MAA = myositis-associated autoantibodies, MHC = major histocompatibility complex, MSA = myositis-specific autoantibodies, PM = polymyositis, RF = random forests, RSP = restrictive supertype patterns, SRP = signal recognition particle.

Predictors of acquired lipodystrophy in juvenile-onset dermatomyositis and a gradient of severity

We describe the clinical features of 28 patients with juvenile dermatomyositis (JDM) and 1 patient with adult-onset dermatomyositis (DM), all of whom developed lipodystrophy (LD) that could be categorized into 1 of 3 phenotypes, generalized, partial, or focal, based on the pattern of fat loss distribution. LD onset was often delayed, beginning a median of 4.6 years after diagnosis of DM. Calcinosis, muscle atrophy, joint contractures, and facial rash were DM disease features found to be associated with LD. Panniculitis was associated with focal lipoatrophy while the anti-p155 autoantibody, a newly described myositis-associated autoantibody, was more associated with generalized LD. Specific LD features such as acanthosis nigricans, hirsutism, fat redistribution, and steatosis/nonalcoholic steatohepatitis were frequent in patients with LD, in a gradient of frequency and severity among the 3 sub-phenotypes. Metabolic studies frequently revealed insulin resistance and hypertriglyceridemia in patients with generalized and partial LD. Regional fat loss from the thighs, with relative sparing of fat loss from the medial thighs, was more frequent in generalized than in partial LD and absent from DM patients without LD. Cytokine polymorphisms, the C3 nephritic factor, insulin receptor antibodies, and lamin mutations did not appear to play a pathogenic role in the development of LD in our patients. LD is an under-recognized sequela of JDM, and certain DM patients with a severe, prolonged clinical course and a high frequency of calcinosis appear to be at greater risk for the development of this complication. High-risk JDM patients should be screened for metabolic abnormalities, which are common in generalized and partial LD and result in much of the LD-associated morbidity. Further study is warranted to investigate the pathogenesis of acquired LD in patients with DM. Abbreviations: CI = confidence interval, CT = computerized tomography, dlk = delta-like, DM= dermatomyositis, DXA = dual-energy X-ray absorptiometry, HDL = high-density lipoprotein, HIV = human immunodeficiency virus, HOMA-IR = homeostasis model assessment of insulin resistance, IL = interleukin, IR = insulin resistance, JDM = juvenile dermatomyositis, LA = lipoatrophy, LD = lipodystrophy, LDL = low-density lipoprotein, LMNA= lamin A, MRI = magnetic resonance imaging, NASH = nonalcoholic steatohepatitis, NIH = National Institutes of Health, OGTT = oral glucose tolerance test, OR = odds ratio, PCR = polymerase chain reaction, TNF = tumor necrosis factor, TTP = tristetraprolin.

Immunogenetic Risk and Protective Factors for the Idiopathic Inflammatory Myopathies: Distinct Hla-a, -b, -cw, -drb1 and -dqa1 Allelic Profiles and Motifs Define Clinicopathologic Groups in Caucasians

Abstract: The idiopathic inflammatory myopathies (IIM) are systemic connective tissue diseases in which autoimmune pathology is suspected to promote chronic muscle inflammation and weakness. We have performed low to high resolution genotyping to characterize the allelic profiles of HLA-A, -B, -Cw, -DRB1, and -DQA1 loci in a large population of North American Caucasian patients with IIM representing the major clinicopathologic groups (n = 571). We confirmed that alleles of the 8.1 ancestral haplotype were important risk markers for the development of IIM, and a random forests classification analysis suggested that within this haplotype, HLA-B*0801, DRB1*0301 and/ or closely linked genes are the principal HLA risk factors. In addition, we identified several novel HLA factors associated distinctly with 1 or more clinicopathologic groups of IIM. The DQA1*0201 allele and associated peptide-binding motif (47KLPLFHRL54) were exclusive protective factors for the CD8+ T cell-mediated IIM forms of polymyositis (PM) and inclusion body myositis (IBM) (pc < 0.005). In contrast, HLA-A*68 alleles were significant risk factors for dermatomyositis (DM) (pc = 0.0021), a distinct clinical group thought to involve a humorally mediated immunopathology. While the DQA1*0301 allele was detected as a possible risk factor for IIM, PM, and DM patients (p < 0.05), DQA1*03 alleles were protective factors for IBM (pc = 0.0002). Myositis associated with malignancies was the most distinctive group of IIM wherein HLA Class I alleles were the only identifiable susceptibility factors and a shared HLA-Cw peptide-binding motif (90AGSHTLQWM98) conferred significant risk (pc = 0.019). Together, these data suggest that HLA susceptibility markers distinguish different myositis phenotypes with divergent pathogenetic mechanisms. These variations in associated HLA polymorphisms may reflect responses to unique environmental triggers resulting in the tissue pathospecificity and distinct clinicopathologic syndromes of the IIM. Abbreviations: AH = ancestral haplotype, CAM = cancer-associated myositis, CTM = connective tissue disease overlap myositis, DM = dermatomyositis, IBM = inclusion body myositis, IIM = idiopathic inflammatory myopathies, MHC = major histocompatibility complex, PM = polymyositis, RF = random forests, RSP = restrictive supertype patterns.

Genome-wide association study of dermatomyositis reveals genetic overlap with other autoimmune disorders

OBJECTIVE To identify new genetic associations with juvenile and adult dermatomyositis (DM). METHODS We performed a genome-wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1,178) and controls (n = 4,724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single-nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM. RESULTS Compared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS-level significance (P < 5 × 10(-8)) at 80 genotyped SNPs. An analysis of 141 non-MHC SNPs previously associated with autoimmune diseases showed that 3 SNPs linked with 3 genes were associated with DM, with a false discovery rate (FDR) of <0.05. These genes were phospholipase C-like 1 (PLCL1; rs6738825, FDR = 0.00089), B lymphoid tyrosine kinase (BLK; rs2736340, FDR = 0.0031), and chemokine (C-C motif) ligand 21 (CCL21; rs951005, FDR = 0.0076). None of these genes was previously reported to be associated with DM. CONCLUSION Our findings confirm the MHC as the major genetic region associated with DM and indicate that DM shares non-MHC genetic features with other autoimmune diseases, suggesting the presence of additional novel risk loci. This first identification of autoimmune disease genetic predispositions shared with DM may lead to enhanced understanding of pathogenesis and novel diagnostic and therapeutic approaches.

Cytokine gene polymorphisms as risk and severity factors for juvenile dermatomyositis

OBJECTIVE To study tumor necrosis factor alpha (TNFalpha) and interleukin-1 (IL-1) cytokine polymorphisms as possible risk and protective factors, define their relative importance, and examine these as severity factors in patients with juvenile dermatomyositis (DM). METHODS TNFalpha and IL-1 cytokine polymorphism and HLA typing were performed in 221 Caucasian patients with juvenile DM, and the results were compared with those in 203 ethnically matched healthy volunteers. RESULTS The genotypes TNFalpha -308AG (odds ratio [OR] 3.6), TNFalpha -238GG (OR 3.5), and IL-1alpha +4845TT (OR 2.2) were risk factors, and TNFalpha -308GG (OR 0.26) as well as TNFalpha -238AG (OR 0.22) were protective, for the development of juvenile DM. Carriage of a single copy of the TNFalpha -308A (OR 3.8) or IL-1beta +3953T (OR 1.7) allele was a risk factor, and the TNFalpha -238A (OR 0.29) and IL-1alpha +4845G (OR 0.46) alleles were protective, for juvenile DM. Random Forests classification analysis showed HLA-DRB1*03 and TNFalpha -308A to have the highest relative importance as risk factors for juvenile DM compared with the other alleles (Gini scores 100% and 90.7%, respectively). TNFalpha -308AA (OR 7.3) was a risk factor, and carriage of the TNFalpha -308G (OR 0.14) and IL-1alpha -889T (OR 0.41) alleles was protective, for the development of calcinosis. TNFalpha -308AA (OR 7.0) was a possible risk factor, and carriage of the TNFalpha -308G allele (OR 0.14) was protective, for the development of ulcerations. None of the studied TNFalpha, IL-1alpha, and IL-1beta polymorphisms were associated with the disease course, disease severity at the time of diagnosis, or the patients sex. CONCLUSION TNFalpha and IL-1 genetic polymorphisms contribute to the development of juvenile DM and may also be indicators of disease severity.

Dense genotyping of immune-related loci in idiopathic inflammatory myopathies confirms HLA alleles as the strongest genetic risk factor and suggests different genetic background for major clinical subgroups

Objectives The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases characterised by muscle weakness and extramuscular manifestations such as skin rashes and interstitial lung disease. We genotyped 2566 IIM cases of Caucasian descent using the Immunochip; a custom array covering 186 established autoimmune susceptibility loci. The cohort was predominantly comprised of patients with dermatomyositis (DM, n=879), juvenile DM (JDM, n=481), polymyositis (PM, n=931) and inclusion body myositis (n=252) collected from 14 countries through the Myositis Genetics Consortium. Results The human leucocyte antigen (HLA) and PTPN22 regions reached genome-wide significance (p<5×10−8). Nine regions were associated at a significance level of p<2.25×10−5, including UBE2L3, CD28 and TRAF6, with evidence of independent effects within STAT4. Analysis of clinical subgroups revealed distinct differences between PM, and DM and JDM. PTPN22 was associated at genome-wide significance with PM, but not DM and JDM, suggesting this effect is driven by PM. Additional suggestive associations including IL18R1 and RGS1 in PM and GSDMB in DM were identified. HLA imputation confirmed that alleles HLA-DRB1*03:01 and HLA-B*08:01 of the 8.1 ancestral haplotype (8.1AH) are most strongly associated with IIM, and provides evidence that amino acids within the HLA, such as HLA-DQB1 position 57 in DM, may explain part of the risk in this locus. Associations with alleles outside the 8.1AH reveal differences between PM, DM and JDM. Conclusions This work represents the largest IIM genetic study to date, reveals new insights into the genetic architecture of these rare diseases and suggests different predominating pathophysiology in different clinical subgroups.

Immunoglobulin gene polymorphisms are susceptibility factors in clinical and autoantibody subgroups of the idiopathic inflammatory myopathies.

OBJECTIVE To investigate possible associations of GM and KM markers with adult and juvenile forms of the idiopathic inflammatory myopathies (IIMs) in Caucasian and African American patients. METHODS We performed serologic analyses of polymorphic determinants associated with immunoglobulin gamma heavy chains (GM) and kappa light chains (KM) in large populations of Caucasian patients (n= 514 [297 adults and 217 children]) and African American patients (n=123 [73 adults and 50 children]) with IIM representing the major clinical and autoantibody groups. RESULTS For Caucasian patients with dermatomyositis (DM), the Gm 3 23 5,13 phenotype was a risk factor in both adults (odds ratio [OR] 2.2, corrected P [Pcorr]=0.020) and children (OR 2.2, Pcorr=0.0013). Of interest, the GM 13 allotype was a risk factor for juvenile DM in both Caucasian subjects (OR 3.9, Pcorr<0.0001) and African American subjects (OR 4.8, Pcorr=0.033). However, the Gm 1,3,17 5,13,21 phenotype was a risk factor for juvenile DM in Caucasian subjects but not African American subjects. Among the IIM autoantibody groups, Gm 3 23 5,13 was a risk factor in Caucasian adults with anti-Jo-1 autoantibodies (OR 3.4, Pcorr=0.0031), while the GM 3 allotype was protective in adults with anti-threonyl-transfer RNA synthetase or anti-U RNP autoantibodies (OR 0.1, Pcorr=0.047 and OR 0.2, Pcorr=0.034, respectively). In contrast, GM 6 was a risk factor in African American adults with anti-signal recognition particle autoantibodies (OR 7.5, Pcorr=0.041). CONCLUSION These data suggest that polymorphic alleles of GM and KM loci are differentially associated with IIM subgroups defined by age, ethnicity, clinical features, and autoantibody status, and expand the list of immune response genes that are possibly important in the pathogenesis of myositis.