Multi-scale approaches for the simulation of cardiac electrophysiology: II - Tissue-level structure and function.

Computational models of the heart, from cell-level models, through one-, two- and three-dimensional tissue-level simplifications, to biophysically-detailed three-dimensional models of the ventricles, atria or whole heart, allow the simulation of excitation and propagation of this excitation, and have provided remarkable insight into the normal and pathological functioning of the heart. In this article we present equations for modelling cellular excitation (i.e. the cell action potential) from both a phenomenological and a biophysical perspective. Hodgkin-Huxley formalism is discussed, along with the current generation of biophysically-detailed cardiac cell models. Alternative Markovian formulations for modelling ionic currents are also presented. Equations describing propagation of this cellular excitation, through one-, two- and three-dimensional idealised or realistic tissues, are then presented. For all types of model, from cell to tissue, methods for discretisation and integration of the underlying equations are discussed. The article finishes with a discussion of two tissue-level experimental imaging techniques - diffusion tensor magnetic resonance imaging and optical imaging - that can be used to provide data for parameterisation and validation of cell- and tissue-level cardiac models.

Soil dissipation of sugarcane billet seed treatment fungicides and insecticide using QuEChERS and HPLC.

Chemical treatment of sugarcane seed with fungicides and insecticides prior to planting increases yields of cane and sugar for the perennial, annually harvested crop. However, the fate of the applied chemicals is unknown. Therefore, the purpose of this study was to measure the aerobic dissipation of selected billet seed treatment chemicals in a mineral sugarcane soil from Louisiana. Soil samples from the surface 15 cm were treated with either thiamethoxam, azoxystrobin, fluxapyroxad, propiconazole, or pyraclostrobin and monitored over 100 days under laboratory conditions. Insecticide and fungicide levels were determined by high performance liquid chromatography. Dissipation data were fitted to four kinetic models: simple first-order (SFO), first order multi-compartment (FOMC), double-first order in parallel (DFOP), and hockey-stick (HS). The dissipation half-life (DT50) of thiamethoxam, azoxystrobin, fluxapyroxad, propiconazole, or pyraclostrobin were 275, 100, 144, 74, and 39 d, respectively. Overall, the DT50 for the pesticides in the study indicated medium to long persistence in soil under the conditions of the experiment. This is the first report for several of these pesticides related to the aerobic dissipation in soils used to grow sugarcane.

Screening characteristics for enrichment of individuals at higher risk for transitioning to classified SLE.

OBJECTIVE: Further prospective study is needed to elucidate the etiology and natural history of systemic lupus erythematosus development. The clinical complexity of this heterogeneous disease makes study design challenging. Our objective was to ascertain useful screening factors for identifying at-risk individuals for follow-up rheumatologic assessment or inclusion in prospective studies. METHODS: We attempted to re-contact 3823 subjects with a family history of systemic lupus erythematosus, who did not meet American College of Rheumatology systemic lupus erythematosus classification at a baseline study visit; 436 agreed to follow-up participation an average of 6.3 years after baseline. In total, 56 of these individuals had transitioned to classified systemic lupus erythematosus (≥ 4 cumulative American College of Rheumatology criteria, verified by medical record review) by the time of follow up. Generalized estimating equations assessed associations between our dichotomous outcome of transitioning to systemic lupus erythematosus with baseline characteristics, including ANA positivity, Connective Tissue Disease Screening questionnaire systemic lupus erythematosus score, and number of American College of Rheumatology criteria. We analyzed predictive accuracy of characteristics on transitioning. RESULTS: ANA positivity, Connective Tissue Disease Screening questionnaire systemic lupus erythematosus score categorization of possible or probable systemic lupus erythematosus, and greater number of American College of Rheumatology criteria at baseline were each associated with transitioning to systemic lupus erythematosus classification. Being ANA positive and having confirmed immunologic criteria at baseline had the highest positive predictive value and specificity for transitioning to systemic lupus erythematosus. American College of Rheumatology Connective Tissue Disease Screening questionnaire systemic lupus erythematosus score categorization of possible or probable systemic lupus erythematosus had a better positive predictive value, negative predictive value, sensitivity, and specificity than ANA positivity. CONCLUSION: Given limited resources, identifying individuals for follow up based on the systemic lupus erythematosus portion of the Connective Tissue Disease Screening questionnaire could be an efficient way to identify family members at highest risk of disease transition.

Evidence-Based Cognitive Rehabilitation: Systematic Review of the Literature From 2009 Through 2014.

OBJECTIVES: To conduct an updated, systematic review of the clinical literature, classify studies based on the strength of research design, and derive consensual, evidence-based clinical recommendations for cognitive rehabilitation of people with traumatic brain injury (TBI) or stroke. DATA SOURCES: Online PubMed and print journal searches identified citations for 250 articles published from 2009 through 2014. STUDY SELECTION: Selected for inclusion were 186 articles after initial screening. Fifty articles were initially excluded (24 focusing on patients without neurologic diagnoses, pediatric patients, or other patients with neurologic diagnoses, 10 noncognitive interventions, 13 descriptive protocols or studies, 3 nontreatment studies). Fifteen articles were excluded after complete review (1 other neurologic diagnosis, 2 nontreatment studies, 1 qualitative study, 4 descriptive articles, 7 secondary analyses). 121 studies were fully reviewed. DATA EXTRACTION: Articles were reviewed by the Cognitive Rehabilitation Task Force (CRTF) members according to specific criteria for study design and quality, and classified as providing class I, class II, or class III evidence. Articles were assigned to 1 of 6 possible categories (based on interventions for attention, vision and neglect, language and communication skills, memory, executive function, or comprehensive-integrated interventions). DATA SYNTHESIS: Of 121 studies, 41 were rated as class I, 3 as class Ia, 14 as class II, and 63 as class III. Recommendations were derived by CRTF consensus from the relative strengths of the evidence, based on the decision rules applied in prior reviews. CONCLUSIONS: CRTF has now evaluated 491 articles (109 class I or Ia, 68 class II, and 314 class III) and makes 29 recommendations for evidence-based practice of cognitive rehabilitation (9 Practice Standards, 9 Practice Guidelines, 11 Practice Options). Evidence supports Practice Standards for (1) attention deficits after TBI or stroke; (2) visual scanning for neglect after right-hemisphere stroke; (3) compensatory strategies for mild memory deficits; (4) language deficits after left-hemisphere stroke; (5) social-communication deficits after TBI; (6) metacognitive strategy training for deficits in executive functioning; and (7) comprehensive-holistic neuropsychological rehabilitation to reduce cognitive and functional disability after TBI or stroke.

Less than 7 hours of sleep per night is associated with transitioning to systemic lupus erythematosus.

Background The role of sleep in the etiology of systemic lupus erythematosus (SLE) has not been well studied. We examined whether sleep duration was associated with subsequent transitioning to SLE in individuals at risk for SLE. Methods Four hundred and thirty-six relatives of SLE patients who did not have SLE themselves at baseline were evaluated again an average of 6.3 (± 3.9) years later. Fifty-six individuals transitioned to SLE (≥ 4 cumulative American College of Rheumatology (ACR) criteria). Sleep duration, medication use and medical history were assessed by questionnaire; ACR criteria were confirmed by medical record review. Vitamin D was measured by ELISA. Generalized estimating equations, accounting for correlation within families, assessed associations between baseline sleep and the outcome of transitioning to SLE. Results Reporting sleeping less than 7 hours per night at baseline was more common in those who subsequently transitioned than those who did not transition to SLE (55% versus 32%, p = 0.0005; OR: 2.8, 95% CI 1.6-4.9). Those who transitioned to SLE were more likely to sleep less than 7 hours per night than those who did not transition to SLE adjusting for age, sex and race (OR: 2.8, 95% CI 1.6-5.1). This association remained after individual adjustment for conditions and early symptoms that could affect sleep, including prednisone use, vitamin D deficiency and number of ACR criteria (OR: 2.0, 95% CI 1.1-4.2). Conclusion Lack of sleep may be associated with transitioning to SLE, independent of early clinical manifestations of SLE that may influence sleep duration. Further evaluation of sleeping patterns and biomarkers in at-risk individuals is warranted.

Genetic analysis of the pathogenic molecular sub-phenotype interferon-alpha identifies multiple novel loci involved in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by inflammation of multiple organ systems and dysregulated interferon responses. SLE is both genetically and phenotypically heterogeneous, greatly reducing the power of case-control studies in SLE. Elevated circulating interferon-alpha (IFN-α) is a stable, heritable trait in SLE, which has been implicated in primary disease pathogenesis. About 40-50% of patients have high IFN-α, and high levels correspond with clinical differences. To study genetic heterogeneity in SLE, we performed a case-case study comparing patients with high vs low IFN-α in over 1550 SLE cases, including genome-wide association study and replication cohorts. In meta-analysis, the top associations in European ancestry were protein kinase, cyclic GMP-dependent, type I (PRKG1) rs7897633 (P(Meta) = 2.75 × 10(-8)) and purine nucleoside phosphorylase (PNP) rs1049564 (P(Meta) = 1.24 × 10(-7)). We also found evidence for cross-ancestral background associations with the ankyrin repeat domain 44 (ANKRD44) and pleckstrin homology domain containing, family F member 2 gene (PLEKHF2) loci. These loci have not been previously identified in case-control SLE genetic studies. Bioinformatic analyses implicated these loci functionally in dendritic cells and natural killer cells, both of which are involved in IFN-α production in SLE. As case-control studies of heterogeneous diseases reach a limit of feasibility with respect to subject number and detectable effect size, the study of informative pathogenic sub-phenotypes becomes an attractive strategy for genetic discovery in complex disease.

Genetic association of CD247 (CD3ζ) with SLE in a large-scale multiethnic study.

A classic T-cell phenotype in systemic lupus erythematosus (SLE) is the downregulation and replacement of the CD3ζ chain that alters T-cell receptor signaling. However, genetic associations with SLE in the human CD247 locus that encodes CD3ζ are not well established and require replication in independent cohorts. Our aim was therefore to examine, localize and validate CD247-SLE association in a large multiethnic population. We typed 44 contiguous CD247 single-nucleotide polymorphisms (SNPs) in 8922 SLE patients and 8077 controls from four ethnically distinct populations. The strongest associations were found in the Asian population (11 SNPs in intron 1, 4.99 × 10(-4) < P < 4.15 × 10(-2)), where we further identified a five-marker haplotype (rs12141731-rs2949655-rs16859085-rs12144621-rs858554; G-G-A-G-A; P(hap) = 2.12 × 10(-5)) that exceeded the most associated single SNP rs858554 (minor allele frequency in controls = 13%; P = 4.99 × 10(-4), odds ratio = 1.32) in significance. Imputation and subsequent association analysis showed evidence of association (P < 0.05) at 27 additional SNPs within intron 1. Cross-ethnic meta-analysis, assuming an additive genetic model adjusted for population proportions, showed five SNPs with significant P-values (1.40 × 10(-3) < P< 3.97 × 10(-2)), with one (rs704848) remaining significant after Bonferroni correction (P(meta) = 2.66 × 10(-2)). Our study independently confirms and extends the association of SLE with CD247, which is shared by various autoimmune disorders and supports a common T-cell-mediated mechanism.

Genetic variation in the HLA region is associated with susceptibility to herpes zoster.

Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). VZV initially manifests as chicken pox, most commonly in childhood, can remain asymptomatically latent in nerve tissues for many years and often re-emerges as shingles. Although reactivation may be related to immune suppression, aging and female sex, most inter-individual variability in re-emergence risk has not been explained to date. We performed a genome-wide association analyses in 22,981 participants (2280 shingles cases) from the electronic Medical Records and Genomics Network. Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P>1.0 × 10(-8)). This region tags the non-coding gene HCP5 (HLA Complex P5) in the major histocompatibility complex. This gene is an endogenous retrovirus and likely influences viral activity through regulatory functions. Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV. Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine.

GWAS identifies novel SLE susceptibility genes and explains the association of the HLA region.

In a genome-wide association study (GWAS) of individuals of European ancestry afflicted with systemic lupus erythematosus (SLE) the extensive utilization of imputation, step-wise multiple regression, lasso regularization and increasing study power by utilizing false discovery rate instead of a Bonferroni multiple test correction enabled us to identify 13 novel non-human leukocyte antigen (HLA) genes and confirmed the association of four genes previously reported to be associated. Novel genes associated with SLE susceptibility included two transcription factors (EHF and MED1), two components of the NF-κB pathway (RASSF2 and RNF114), one gene involved in adhesion and endothelial migration (CNTN6) and two genes involved in antigen presentation (BIN1 and SEC61G). In addition, the strongly significant association of multiple single-nucleotide polymorphisms (SNPs) in the HLA region was assigned to HLA alleles and serotypes and deconvoluted into four primary signals. The novel SLE-associated genes point to new directions for both the diagnosis and treatment of this debilitating autoimmune disease.

MHC associations with clinical and autoantibody manifestations in European SLE.

Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease affecting multiple organ systems and characterized by autoantibody formation to nuclear components. Although genetic variation within the major histocompatibility complex (MHC) is associated with SLE, its role in the development of clinical manifestations and autoantibody production is not well defined. We conducted a meta-analysis of four independent European SLE case collections for associations between SLE sub-phenotypes and MHC single-nucleotide polymorphism genotypes, human leukocyte antigen (HLA) alleles and variant HLA amino acids. Of the 11 American College of Rheumatology criteria and 7 autoantibody sub-phenotypes examined, anti-Ro/SSA and anti-La/SSB antibody subsets exhibited the highest number and most statistically significant associations. HLA-DRB1*03:01 was significantly associated with both sub-phenotypes. We found evidence of associations independent of MHC class II variants in the anti-Ro subset alone. Conditional analyses showed that anti-Ro and anti-La subsets are independently associated with HLA-DRB1*0301, and that the HLA-DRB1*03:01 association with SLE is largely but not completely driven by the association of this allele with these sub-phenotypes. Our results provide strong evidence for a multilevel risk model for HLA-DRB1*03:01 in SLE, where the association with anti-Ro and anti-La antibody-positive SLE is much stronger than SLE without these autoantibodies.

Smoking is not associated with autoantibody production in systemic lupus erythematosus patients, unaffected first-degree relatives, nor healthy controls.

OBJECTIVE: The objective of this paper is to examine whether smoking is associated with autoantibody production in systemic lupus erythematosus (SLE) patients, unaffected first-degree relatives (FDR) of individuals with SLE--a group at increased risk of developing SLE--or unaffected, unrelated controls. METHODS: Detailed demographic, environmental, clinical, and therapeutic information was collected by questionnaire on 1242 SLE patients, 981 FDRs, and 946 controls in the Lupus Family Registry and Repository; a blood sample was obtained. All sera were tested for multiple lupus autoantibodies by immunofluorescence and luminex bead-based assays. Generalized estimating equations, adjusting for age, gender, and ethnicity and accounting for correlation within families, were used to assess smoking status with the dichotomous outcome variables of positivity for SLE status, positivity of ANA by immunofluorescence (≥1:120), positivity for ≥1 autoantibody by the luminex assay, and positivity for each of the 11 autoantibodies. RESULTS: Current smoking was associated with being positive for ≥1 autoantibody (excluding ANA) (adjusted OR = 1.53, 95% CI 1.04-2.24) in our subjects with SLE. No association was observed in unaffected FDRs or healthy controls. Former smoking was associated with anti-Ro/SS-A60 in our unaffected FDRs. There was an increased association with anti-nRNP A seropositivity, as well as a decreased association with anti-nRNP 68 positivity, in current smokers in SLE subjects. CONCLUSIONS: No clear association between smoking status and individual autoantibodies was detected in SLE patients, unaffected FDRs, nor healthy controls within this collection. The association of smoking with SLE may therefore manifest its risk through mechanisms outside of autoantibody production, at least for the specificities tested.

The Effect of Sound Localization on Auditory-Only and Audiovisual Speech Recognition in a Simulated Multitalker Environment.

Information regarding sound-source spatial location provides several speech-perception benefits, including auditory spatial cues for perceptual talker separation and localization cues to face the talker to obtain visual speech information. These benefits have typically been examined separately. A real-time processing algorithm for sound-localization degradation (LocDeg) was used to investigate how spatial-hearing benefits interact in a multitalker environment. Normal-hearing adults performed auditory-only and auditory-visual sentence recognition with target speech and maskers presented from loudspeakers at -90°, -36°, 36°, or 90° azimuths. For auditory-visual conditions, one target and three masking talker videos (always spatially separated) were rendered virtually in rectangular windows at these locations on a head-mounted display. Auditory-only conditions presented blank windows at these locations. Auditory target speech (always spatially aligned with the target video) was presented in co-located speech-shaped noise (experiment 1) or with three co-located or spatially separated auditory interfering talkers corresponding to the masker videos (experiment 2). In the co-located conditions, the LocDeg algorithm did not affect auditory-only performance but reduced target orientation accuracy, reducing auditory-visual benefit. In the multitalker environment, two spatial-hearing benefits were observed: perceptually separating competing speech based on auditory spatial differences and orienting to the target talker to obtain visual speech cues. These two benefits were additive, and both were diminished by the LocDeg algorithm. Although visual cues always improved performance when the target was accurately localized, there was no strong evidence that they provided additional assistance in perceptually separating co-located competing speech. These results highlight the importance of sound localization in everyday communication.

Role of MYH9 and APOL1 in African and non-African populations with lupus nephritis.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by autoantibody production and organ damage. Lupus nephritis (LN) is one of the most severe manifestations of SLE. Multiple studies reported associations between renal diseases and variants in the non-muscle myosin heavy chain 9 (MYH9) and the neighboring apolipoprotein L 1 (APOL1) genes. We evaluated 167 variants spanning MYH9 for association with LN in a multiethnic sample. The two previously identified risk variants in APOL1 were also tested for association with LN in European-Americans (EAs) (N = 579) and African-Americans (AAs) (N = 407). Multiple peaks of association exceeding a Bonferroni corrected P-value of P < 2.03 × 10(-3) were observed between LN and MYH9 in EAs (N = 4620), with the most pronounced association at rs2157257 (P = 4.7 × 10(-4), odds ratio (OR) = 1.205). A modest effect with MYH9 was also detected in Gullah (rs8136069, P = 0.0019, OR = 2.304). No association between LN and MYH9 was found in AAs, Asians, Amerindians or Hispanics. This study provides the first investigation of MYH9 in LN in non-Africans and of APOL1 in LN in any population, and presents novel insight into the potential role of MYH9 in LN in EAs.

A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse clinical manifestations characterized by the development of pathogenic autoantibodies manifesting in inflammation of target organs such as the kidneys, skin and joints. Genome-wide association studies have identified genetic variants in the UBE2L3 region that are associated with SLE in subjects of European and Asian ancestry. UBE2L3 encodes an ubiquitin-conjugating enzyme, UBCH7, involved in cell proliferation and immune function. In this study, we sought to further characterize the genetic association in the region of UBE2L3 and use molecular methods to determine the functional effect of the risk haplotype. We identified significant associations between variants in the region of UBE2L3 and SLE in individuals of European and Asian ancestry that exceeded a Bonferroni-corrected threshold (P<1 × 10(-4)). A single risk haplotype was observed in all associated populations. Individuals harboring the risk haplotype display a significant increase in both UBE2L3 mRNA expression (P=0.0004) and UBCH7 protein expression (P=0.0068). The results suggest that variants carried on the SLE-associated UBE2L3 risk haplotype influence autoimmunity by modulating UBCH7 expression.

Identification of novel coding mutation in C1qA gene in an African-American pedigree with lupus and C1q deficiency.

OBJECTIVES: Homozygous C1q deficiency is an extremely rare condition and strongly associated with systemic lupus erythematosus. To assess and characterize C1q deficiency in an African-American lupus pedigree, C1q genomic region was evaluated in the lupus cases and family members. METHODS: Genomic DNA from patient was obtained and C1q A, B and C gene cluster was sequenced using next generation sequencing method. The identified mutation was further confirmed by direct Sanger sequencing method in the patient and all blood relatives. C1q levels in serum were measured using sandwich ELISA method. RESULTS: In an African-American patient with lupus and C1q deficiency, we identified and confirmed a novel homozygote start codon mutation in C1qA gene that changes amino acid methionine to arginine at position 1. The Met1Arg mutation prevents protein translation (Met1Arg). Mutation analyses of the patient's family members also revealed the Met1Arg homozygote mutation in her deceased brother who also had lupus with absence of total complement activity consistent with a recessive pattern of inheritance. CONCLUSION: The identification of new mutation in C1qA gene that disrupts the start codon (ATG to AGG (Met1Arg)) has not been reported previously and it expands the knowledge and importance of the C1q gene in the pathogenesis of lupus especially in the high-risk African-American population.

Auditory stream segregation of amplitude-modulated narrowband noise in cochlear implant users and individuals with normal hearing.

Voluntary stream segregation was investigated in cochlear implant (CI) users and normal-hearing (NH) listeners using a segregation-promoting objective approach which evaluated the role of spectral and amplitude-modulation (AM) rate separations on stream segregation and its build-up. Sequences of 9 or 3 pairs of A and B narrowband noise (NBN) bursts were presented which differed in either center frequency of the noise band, the AM-rate, or both. In some sequences (delayed sequences), the last B burst was delayed by 35 ms from their otherwise-steady temporal position. In the other sequences (no-delay sequences), the last B bursts were temporally advanced from 0 to 10 ms. A single interval yes/no procedure was utilized to measure participants' sensitivity ( d ' ) in identifying delayed vs. no-delay sequences. A higher d ' value showed the higher ability to segregate the A and B subsequences. For NH listeners, performance improved with each spectral separation. However, for CI users, performance was only significantly better for the condition with the largest spectral separation. Additionally, performance was significantly poorer for the largest AM-rate separation than for the condition with no AM-rate separation for both groups. The significant effect of sequence duration in both groups indicated that listeners made more improvement with lengthening the duration of stimulus sequences, supporting the build-up effect. The results of this study suggest that CI users are less able than NH listeners to segregate NBN bursts into different auditory streams when they are moderately separated in the spectral domain. Contrary to our hypothesis, our results indicate that AM-rate separation may interfere with the segregation of streams of NBN. Additionally, our results add evidence to the literature that CI users build up stream segregation at a rate comparable to NH listeners, when the inter-stream spectral separations are adequately large.

Music and Speech Perception in Prelingually Deafened Young Listeners With Cochlear Implants: A Preliminary Study Using Sung Speech.

PURPOSE: In the context of music and speech perception, this study aimed to assess the effect of variation in one of two auditory attributes-pitch contour and timbre-on the perception of the other in prelingually deafened young cochlear implant (CI) users, and the relationship between pitch contour perception and two cognitive functions of interest. METHOD: Nine prelingually deafened CI users, aged 8.75-22.17 years, completed a melodic contour identification (MCI) task using stimuli of piano notes or sung speech with a fixed timbre (same word for each note) or a mixed timbre (different words for each note), a speech perception task identifying matrix-styled sentences naturally intonated or sung with a fixed pitch (same pitch for each word) or a mixed pitch (different pitches for each word), a forward digit span test indexing auditory short-term memory (STM), and the matrices section of the Kaufman Brief Intelligence Test-Second Edition indexing nonverbal IQ. RESULTS: MCI was significantly poorer for the mixed timbre condition. Speech perception was significantly poorer for the fixed and mixed pitch conditions than for the naturally intonated condition. Auditory STM positively correlated with MCI at 2- and 3-semitone note spacings. Relative to their normal-hearing peers from a related study using the same stimuli and tasks, the CI participants showed comparable MCI at 2- or 3-semitone note spacing, and a comparable level of significant decrement in speech perception across three pitch contour conditions. CONCLUSION: Findings suggest that prelingually deafened CI users show similar trends of normal-hearing peers for the effect of variation in pitch contour or timbre on the perception of the other, and that cognitive functions may underlie these outcomes to some extent, at least for the perception of pitch contour. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.21217937.

The rs4774 CIITA missense variant is associated with risk of systemic lupus erythematosus.

The major histocompatibility complex (MHC) class II transactivator gene (CIITA) encodes an important transcription factor required for human leukocyte antigens (HLA) class II MHC-restricted antigen presentation. MHC genes, including the HLA class II DRB1*03:01 allele, are strongly associated with systemic lupus erythematosus (SLE). Recently the rs4774 CIITA missense variant (+1632G/C) was reported to be associated with susceptibility to multiple sclerosis. In the current study, we investigated CIITA, DRB1*03:01 and risk of SLE using a multi-stage analysis. In stage 1, 9 CIITA variants were tested in 658 cases and 1363 controls (N=2021). In stage 2, rs4774 was tested in 684 cases and 2938 controls (N=3622). We also performed a meta-analysis of the pooled 1342 cases and 4301 controls (N=5643). In stage 1, rs4774(*)C was associated with SLE (odds ratio (OR)=1.24, 95% confidence interval (95% CI)=1.07-1.44, P=4.2 × 10(-3)). Similar results were observed in stage 2 (OR=1.16, 95% CI=1.02-1.33, P=8.5 × 10(-3)) and the meta-analysis of the combined data set (OR=1.20, 95% CI=1.09-1.33, P(meta)=2.5 × 10(-4)). In all three analyses, the strongest evidence for association between rs4774(*)C and SLE was present in individuals who carried at least one copy of DRB1*03:01 (P(meta)=1.9 × 10(-3)). Results support a role for CIITA in SLE, which appears to be stronger in the presence of DRB1*03:01.