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1.  Autoimmune thyroid disease is associated with a diagnosis of secondary Sjögren's syndrome in familial systemic lupus 
Annals of the Rheumatic Diseases  2006;66(3):410-413.
Background
Autoimmune thyroid disease is common in systemic lupus erythematosus (SLE). About 20% of patients with SLE have secondary Sjögren's syndrome.
Methods
Families with more than one patient with SLE were identified. All patients met the revised classification criteria, although SLE‐unaffected relatives were confirmed not to satisfy these criteria. Diagnosis of autoimmune thyroid disease and Sjögren's syndrome was made on the basis of a review of medical records, interview and questionnaire administered to patients with SLE, and by a questionnaire administered to SLE‐unaffected subjects.
Results
Of a total of 1138 patients with SLE, 169 had a diagnosis of Sjögren's syndrome. Of these 50 (29.6%) patients also had autoimmune thyroid disease. Of the 939 patients with SLE with no diagnosis of Sjögren's syndrome, 119 (12.7%) had autoimmune thyroid disease (χ2 = 20.1, p = 0.000009). There was no association of a diagnosis of hypertension with secondary Sjögren's syndrome (42% vss 47%). Among 2291 SLE‐unaffected relatives, 44 had diagnosed primary Sjögren's syndrome and 16 (36.3%) of these also had autoimmune thyroid disease. 265 of 2247 (11.8%) subjects had autoimmune thyroid disease but no Sjögren's syndrome (χ2 = 24.2, p<0.001).
Conclusions
Autoimmune thyroid disease is found in excess among patients with SLE with a diagnosis of secondary Sjögren's syndrome, as well as among their SLE‐unaffected relatives with a diagnosis of primary Sjögren's syndrome.
doi:10.1136/ard.2006.055103
PMCID: PMC1856020  PMID: 16984944
2.  Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci 
Nature genetics  2008;40(2):204-210.
Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with complex etiology but strong clustering in families (λS = ~30). We performed a genome-wide association scan using 317,501 SNPs in 720 women of European ancestry with SLE and in 2,337 controls, and we genotyped consistently associated SNPs in two additional independent sample sets totaling 1,846 affected women and 1,825 controls. Aside from the expected strong association between SLE and the HLA region on chromosome 6p21 and the previously confirmed non-HLA locus IRF5 on chromosome 7q32, we found evidence of association with replication (1.1 × 10−7 < Poverall < 1.6 × 10−23; odds ratio 0.82–1.62)in four regions: 16p11.2 (ITGAM), 11p15.5 (KIAA1542), 3p14.3 (PXK) and 1q25.1 (rs10798269). We also found evidence for association (P < 1 × 10−5) at FCGR2A, PTPN22 and STAT4, regions previously associated with SLE and other autoimmune diseases, as well as at ≥9 other loci (P < 2 × 10−7). Our results show that numerous genes, some with known immune-related functions, predispose to SLE.
doi:10.1038/ng.81
PMCID: PMC3712260  PMID: 18204446
3.  The Lupus Family Registry and Repository 
Rheumatology (Oxford, England)  2010;50(1):47-59.
The Lupus Family Registry and Repository (LFRR) was established with the goal of assembling and distributing materials and data from families with one or more living members diagnosed with SLE, in order to address SLE genetics. In the present article, we describe the problems and solutions of the registry design and biometric data gathering; the protocols implemented to guarantee data quality and protection of participant privacy and consent; and the establishment of a local and international network of collaborators. At the same time, we illustrate how the LFRR has enabled progress in lupus genetics research, answering old scientific questions while laying out new challenges in the elucidation of the biologic mechanisms that underlie disease pathogenesis. Trained staff ascertain SLE cases, unaffected family members and population-based controls, proceeding in compliance with the relevant laws and standards; participant consent and privacy are central to the LFRR’s effort. Data, DNA, serum, plasma, peripheral blood and transformed B-cell lines are collected and stored, and subject to strict quality control and safety measures. Coded data and materials derived from the registry are available for approved scientific users. The LFRR has contributed to the discovery of most of the 37 genetic associations now known to contribute to lupus through 104 publications. The LFRR contains 2618 lupus cases from 1954 pedigrees that are being studied by 76 approved users and their collaborators. The registry includes difficult to obtain populations, such as multiplex pedigrees, minority patients and affected males, and constitutes the largest collection of lupus pedigrees in the world. The LFRR is a useful resource for the discovery and characterization of genetic associations in SLE.
doi:10.1093/rheumatology/keq302
PMCID: PMC3307518  PMID: 20864496
Systemic lupus erythematosus; Registry; Repository; Autoimmune diseases; Genetics; Heritability; Genome-wide association studies; Linkage analysis; Minorities; Women
4.  High density genotyping of STAT4 gene reveals multiple haplotypic associations with Systemic Lupus Erythematosus in different racial groups 
Arthritis and rheumatism  2009;60(4):1085-1095.
Objective
Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disorder with complex etiology and a strong genetic component. Recently, gene products involved in the interferon pathway have been under intense investigation in SLE pathogenesis. STAT1 and STAT4 are transcription factors that play key roles in the interferon and Th1 signaling pathways, making them attractive candidates for SLE susceptibility.
Methods
Fifty-six single-nucleotide polymorphisms (SNPs) across STAT1 and STAT4 genes on chromosome 2 were genotyped using Illumina platform as a part of extensive association study in a large collection of 9923 lupus cases and controls from different racial groups. DNA from patients and controls was obtained from peripheral blood. Principal component analyses and population based case-control association analyses were performed and the p values, FDR q values and Odds ratios with 95% confidence intervals (95% CIs) were calculated.
Results
We observed strong genetic associations with SLE and multiple SNPs located within the STAT4 gene in different ethnicities (Fisher combined p= 7.02×10−25). In addition to strong confirmation of the association in the 3rd intronic region of this gene reported previously, we identified additional haplotypic association across STAT4 gene and in particular a common risk haplotype that is found in multiple racial groups. In contrast, only a relatively weak suggestive association was observed with STAT1, probably due to the proximity to STAT4.
Conclusion
Our findings indicate that the STAT4 gene is likely to be a crucial component in SLE pathogenesis among multiple racial groups. The functional effects of this association, when revealed, might improve our understanding of the disease and provide new therapeutic targets.
doi:10.1002/art.24387
PMCID: PMC2776081  PMID: 19333953
5.  Klinefelter’s Syndrome, 47,XXY, in Male Systemic Lupus Erythematosus Supports a Gene Dose Effect from the X Chromosome 
Arthritis and rheumatism  2008;58(8):2511-2517.
Background
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that predominantly affects women. Despite Klinefelter's syndrome (47,XXY) and SLE coexisting in isolated cases, no association has been established with SLE or any other autoimmune disease. Methods: Sex chromosome genotyping was performed in 981 SLE patients (213 were men). A first group of 843 SLE patients from 378 multiplex families and a second group of 138 men with non-familial SLE were evaluated. Fluorescent in situ hybridization (FISH) and karyotyping in transformed B cell lines enumerated chromosomes for selected cases.
Results
Of 213 men with SLE, five had Klinefelter's syndrome (or 1 in 43). Four of them were heterozygous at X markers. FISH and karyotyping confirmed Klinefelter’s syndrome in the fifth. An overall rate of 235 47,XXY per 10,000 male SLE patients (95%CI: 77 to 539) was found, a dramatic increase over the known prevalence of Klinefelter's syndrome in an unselected population (17 per 10,000 live male births). Asking men with SLE about fertility was highly sensitive (100%) for Klinefelter’s syndrome. All 768 SLE women were heterozygous at X.
Conclusions
47,XXY Klinefelter's syndrome, often subclinical, is increased in men with SLE by ~14-fold, compared to its prevalence in men without SLE. Diagnostic vigilance for 47,XXY males in SLE is warranted. These data are the first to associate Klinefelter's syndrome with an autoimmune disease found predominantly in women. The risk of SLE in Klinefelter's syndrome is predicted to be similar to the risk in normal 46,XX women and ~14-fold higher than in 46,XY men, consistent with SLE susceptibility being partly explained by a X chromosome gene dose effect.
doi:10.1002/art.23701
PMCID: PMC2824898  PMID: 18668569
6.  The effects of previous Hysterectomy on Lupus 
Lupus  2009;18(11):1000-1005.
Summary
Hysterectomy is one of the most common surgical procedures performed in United States, and currently, one in three women in United States has had a hysterectomy by the age of 60 years. Systemic lupus erythematosus (SLE) is a common autoimmune disease and especially targets women of childbearing age at least 10 times higher than men, which reflects the major role of female sex hormones. In this retrospective study, we evaluate the potential effects of previous hysterectomy in our lupus cohort.Data collected fromstudy subject questionnaires were obtained fromthe Lupus Family Registry and Repository (LFRR) at the OklahomaMedical Research Foundation. Hysterectomy data were available from 3389 subjects. SLE patients with a positive history of hysterectomy have been selected and compared with matched lupus patients with a negative history of hysterectomy and healthy controls. Association analyses were performed, and the P values and adjusted odds ratios (ORs) were calculated. SLE patients with a negative history of hysterectomy more likely had kidney nephritis or positive anti-dsDNA than age-matched SLE patients with a history of hysterectomy before disease onset. This effect was independent of ethnicity with an OR of 6.66 (95% CI = 3.09–14.38, P = 1.00 × 10−8) in European patients and 2.74 (95% CI = 1.43–5.25, P = 0.001) in African-Americans. SLE patients with a positive history of hysterectomy before disease onset also had a later age of disease onset (P = 0.0001) after adjustment for age and race. Our findings support the notion that the influence of female sex hormones in SLE and various clinical findings are tremendous and that surgical menopause such as this could significantly affect the outcome of disease and clinical manifestations
doi:10.1177/0961203309104315
PMCID: PMC2769169  PMID: 19762402

Results 1-6 (6)