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1.  Prevalence, Severity and Predictors of Fatigue in Primary Sjogren’s Syndrome 
Arthritis and rheumatism  2008;59(12):1780-1787.
OBJECTIVES
To investigate the relationship of fatigue severity to other clinical features in primary Sjogren’s syndrome (PSS) and to identify factors contributing to the physical and mental aspects of fatigue.
METHODS
We identified 94 subjects who met the American-European consensus criteria for the classification of PSS. Fatigue was assessed with a VAS, the Fatigue Severity Scale (FSS) and the Profile of Fatigue (ProF.) Associations with fatigue was compared using multivariate regression.
RESULTS
Abnormal fatigue defined as a FSS score of greater than or equal to 4 was present in 67% of the patients. Pain, helplessness and depression were the strongest predictors of both FSS and the somatic fatigue domain of the ProF (Prof-S), both with and without adjustment for physiologic and serologic characteristics. Depression was associated with higher levels of fatigue; however, the majority of patients with abnormal fatigue were not depressed. Anti-Ro/SSA positive patients were no more likely to report fatigue than seronegative patients. The regression models explained 62% of the variance in FSS and 78% of the variance in Prof-S. Mental fatigue was correlated with depression and helplessness, but the model predicted only 54% of the variance in mental fatigue (Prof-M.).
CONCLUSIONS
Psychosocial variables are determinants of fatigue, but only partly account for it. While fatigue is associated with depression, depression is not the primary cause of fatigue in PSS. Investigation of the pathophysiologic correlates of physical and mental aspects of fatigue is needed to guide the development of more effective interventions.
doi:10.1002/art.24311
PMCID: PMC3106978  PMID: 19035421
2.  Peripheral blood gene expression profiling in Sjögren’s syndrome 
Genes and Immunity  2009;10(4):285-296.
Sjögren’s syndrome (SS) is a common chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands. Affected cases commonly present with oral and ocular dryness, thought to be the result of inflammatory cell-mediated gland dysfunction. To identify important molecular pathways involved in SS, we used high-density microarrays to define global gene expression profiles in peripheral blood. We first analyzed 21 SS cases and 23 controls and identified a prominent pattern of overexpressed genes that are inducible by interferons (IFNs). These results were confirmed by evaluation of a second independent dataset of 17 SS cases and 22 controls. Additional inflammatory and immune-related pathways with altered expression patterns in SS cases included B and T cell receptor, IGF-1, GM-CSF, PPARα/RXRα, and PI3/AKT signaling. Exploration of these data for relationships to clinical features of disease revealed that expression levels for most IFN-inducible genes were positively correlated with titers of anti-Ro/SSA (P<0.001) and anti-La/SSB (P<0.001) autoantibodies. Diagnostic and therapeutic approaches targeting IFN signaling pathway may prove most effective in the subset of SS cases who produce anti-Ro/SSA and anti-La/SSB autoantibodies. Our results strongly support innate and adaptive immune processes in the pathogenesis of SS and provide numerous candidate disease markers for further study.
doi:10.1038/gene.2009.20
PMCID: PMC3273959  PMID: 19404300
3.  NOVEL GENETIC VARIANTS CONTRIBUTING TO LEFT VENTRICULAR HYPERTROPHY: THE HYPERGEN STUDY 
Journal of hypertension  2009;27(8):1585-1593.
Objectives
To identify genes contributing to variation in echocardiographic left ventricular (LV) mass and related traits using linkage and linkage disequilibrium analysis in sibships ascertained on hypertension.
Methods
The HyperGEN Study of LV hypertrophy characterized LV mass, relative wall thickness (RWT), and aortic root diameter (ARD) with echocardiograms collected using a standardized protocol at four HyperGEN field centers. A high-throughput scanning fluorescence detector system genotyped 387 polymorphisms distributed throughout the genome. Linkage analyses were conducted once genotyping results became available for 885 siblings from 382 sibships.
Results
Although single LOD score peaks ≥ 1.2 were found on chromosomes 1, 4, 5, 6, 7, 8, 9, 10, 12, 14, 17, and 21, we observed a broad band of peaks in both ethnic groups (white and black) on chromosome 4 and selected candidate genes (NPY1R, NPY2R, NPY5R, SFPR2, CPE, IL15, EDNRA) from this region. Using cases and controls from extremes of the LV mass index, RWT, and ARD distributions, we assessed associations with these phenotypes and haplotype-tagging single nucleotide polymorphisms (SNPs) in the candidates. Among blacks, SNPs in IL15, NPY2R, and NPY5R showed strong evidence for association (p < 0.005); all candidates except EDNRA showed suggestive association (p < 0.05). In whites, NPY2R, NPY5R, and SFRP2 SNPs offered suggestive evidence of association with one or more traits (p < 0.05).
Conclusions
Genetic variation in NPY1R, NPY2R, NPY5R, CPE, IL15, and SFRP2, detected using linkage analysis in hypertensive siblings, was associated with LV phenotypes in blacks and/or whites.
doi:10.1097/HJH.0b013e32832be612
PMCID: PMC2868312  PMID: 19593212
left ventricular hypertrophy; genetics; echocardiography
4.  Meta-analysis and Imputation Identifies a 109 kb Risk Haplotype Spanning TNFAIP3 Associated with Lupus Nephritis and Hematologic Manifestations 
Genes and immunity  2009;10(5):470-477.
TNFAIP3 encodes the ubiquitin modifying enzyme, A20, a key regulator of inflammatory signaling pathways. We previously reported association between TNFAIP3 variants and systemic lupus erythematosus (SLE). In order to further localize the risk variant(s), we performed a meta-analysis using genetic data available from two Caucasian case/control datasets (1453 total cases, 3381 total controls) and 713 SLE trio families. The best result was found at rs5029939 (P = 1.67 × 10−14, OR = 2.09, 95% CI 1.68–2.60). We then imputed SNPs from the CEU Phase II HapMap using genotypes from 431 SLE cases and 2155 controls. Imputation identified eleven SNPs in addition to three observed SNPs, which together, defined a 109 kb SLE risk segment surrounding TNFAIP3. When evaluating whether the rs5029939 risk allele was associated with SLE clinical manifestations, we observed that heterozygous carriers of the TNFAIP3 risk allele at rs5029939 have a two-fold increased risk of developing renal or hematologic manifestations compared to homozygous non-risk subjects. In summary, our study strengthens the genetic evidence that variants in the region of TNFAIP3 influence risk for SLE, particularly in patients with renal and hematologic manifestations, and narrows the risk effect to a 109 kb DNA segment that spans the TNFAIP3 gene.
doi:10.1038/gene.2009.31
PMCID: PMC2714405  PMID: 19387456
systemic lupus erythematosus; TNFAIP3; imputation; meta-analysis
5.  Genetic Variants Near TNFAIP3 on 6q23 are Associated with Systemic Lupus Erythematosus (SLE) 
Nature genetics  2008;40(9):1059-1061.
SLE is an autoimmune disease influenced by genetic and environmental components. We performed a genome-wide association scan (GWAS) and observed novel association evidence with a variant inTNFAIP3(rs5029939, P = 2.89×10−12, OR = 2.29). We also found evidence of two independent signals of association to SLE risk, including one described in Rheumatoid Arthritis. These results establish that genetic variation inTNFAIP3contributes to differential risk for SLE and RA.
doi:10.1038/ng.200
PMCID: PMC2772171  PMID: 19165918

Results 1-5 (5)