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2.  Age- and gender-specific modulation of serum osteopontin and interferon-α by osteopontin genotype in systemic lupus erythematosus 
Genes and immunity  2009;10(5):487-494.
Osteopontin (OPN) is a multifunctional cytokine involved in long bone remodeling and immune system signaling. Additionally, OPN is critical for interferon-α (IFN-α) production in murine plasmacytoid dendritic cells. We have previously shown that IFN-α is a heritable risk factor for systemic lupus erythematosus (SLE). Genetic variants of OPN have been associated with SLE susceptibility, and one study suggests that this association is particular to men. In this study, the 3′ UTR SLE-risk variant of OPN (rs9138C) was associated with higher serum OPN and IFN-α in men (P = 0.0062 and P = 0.0087, respectively). In women, the association between rs9138 C and higher serum OPN and IFN-α was restricted to younger subjects, and risk allele carriers showed a strong age-related genetic effect of rs9138 genotype on both serum OPN and IFN-α (P<0.0001). In African-American subjects, the 5′ region single nucleotide polymorphisms, rs11730582 and rs28357094, were associated with anti-RNP antibodies (odds ratio (OR) = 2.9, P = 0.0038 and OR = 3.9, P = 0.021, respectively). Thus, we demonstrate two distinct genetic influences of OPN on serum protein traits in SLE patients, which correspond to previously reported SLE-risk variants. This study provides a biologic relevance for OPN variants at the protein level, and suggests an influence of this gene on the IFN-α pathway in SLE.
PMCID: PMC2762275  PMID: 19339987
systemic lupus erythematosus; interferon-α; osteopontin; age; gender; autoantibodies
3.  Lack of Association of the TP53 Arg72Pro SNP and the MDM2 SNP309 with systemic lupus erythematosus in Caucasian, African American, and Asian children and adults 
Lupus  2009;18(1):61-66.
The p53 tumour suppressor is the central regulator of apoptosis. Previously, the functional TP53 Arg72Pro polymorphism was found to be associated with systemic lupus erythematosus (SLE) in Koreans but not Spaniards. MDM2 is the major negative regulator of p53. An intronic polymorphism in MDM2, the SNP309, attenuates p53 activity and is associated with accelerated tumour development in premenopausal women. Polymorphic variation in MDM2 has never been studied in SLE. The aim of this study is to further assess the contribution of p53-pathway genetic variation to SLE by testing the association of the TP53 Arg72Pro polymorphism and the MDM2 SNP309 with SLE in a well-characterised and ethnically diverse cohort of patients with both childhood- and adult-onset SLE (n = 314). No association was found between the TP53 Arg72Pro polymorphism and SLE in patients of European descent, Asian descent or in African Americans, nor was an association found between the MDM2 SNP309 and SLE in patients of European descent or in African Americans. In addition, there was no correlation between either variant and early-onset disease or nephritis, an index of severe disease. It is concluded that neither the TP53 Arg72Pro polymorphism nor the MDM2 SNP309 contributes significantly to either susceptibility or disease severity in SLE.
PMCID: PMC2801155  PMID: 19074170
genetic polymorphism; nephritis; pediatrics; systemic lupus erythematosus
4.  High serum IFN-α activity is a heritable risk factor for systemic lupus erythematosus 
Genes and immunity  2007;8(6):492-502.
Interferon α (IFN-α) levels are elevated in many patients with systemic lupus erythematosus (SLE); however it is not known whether high serum IFN-α activity is a cause or a result of the disease. We studied 266 SLE patients and 405 of their healthy relatives, and frequently found high serum IFN-α activity in both patients and healthy relatives as compared to healthy unrelated individuals. High IFN-α activity was clustered in specific families in both SLE patients and their healthy first-degree relatives, suggesting a heritable trait. Heritability was also supported by quantitative familial correlation of IFN-α activity, concordance in affected sib pairs and frequent transmission of the high IFN-α activity trait from parents to offspring. Autoantibodies to RNA-binding proteins and double-stranded DNA were associated with high IFN-α activity in SLE patients; however these autoantibodies were very uncommon in healthy family members and did not explain the observed familial correlations. The frequency of high IFN-α activity was similar across all studied ethnic backgrounds. These data suggest that high serum IFN-α activity is a complex heritable trait, which plays a primary role in SLE pathogenesis.
PMCID: PMC2702174  PMID: 17581626
interferon α; systemic lupus erythematosus; genetics; epidemiology; autoantibodies

Results 1-6 (6)