Monocyte chemoattractant protein-1: plasma concentrations and A(−2518)G promoter polymorphism of its gene in systemic lupus erythematosus

Department of Pharmacology and Center for Pharmacogenetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
The Journal of Rheumatology (Impact Factor: 3.17). 04/2007; 34(4):740-6.
Source: PubMed

ABSTRACT To determine (1) whether the A(-2518)G polymorphism of CCL-2, the gene encoding monocyte chemoattractant protein-1 (MCP-1), is associated with disease, MCP-1 concentration, nephritis, or coronary artery calcification (CAC) in systemic lupus erythematosus (SLE); and (2) whether MCP-1 and homocysteine (Hcy) concentrations are correlated.
Statistical tests were applied to determine the relationships between CCL-2 A(-2518)G genotypes, plasma MCP-1 concentrations, and clinical variables in Caucasian and African American patients with SLE and controls.
The CCL-2 (-2518)G allele was not significantly associated with SLE in the whole study sample (p = 0.07). Among Caucasians, but not African Americans, G allele carriers had significantly increased risk of SLE (OR 4.2, 95% CI 1.8-9.6, p < 0.0001). Genotype was not associated with nephritis, CAC, or MCP-1 concentrations when all patients or all controls were considered; however, among recently diagnosed patients, G allele carriers had significantly higher MCP-1 concentrations than AA homozygotes (p = 0.02). SLE patients had higher MCP-1 concentrations than controls (p < 0.0001), African American patients had higher concentrations than Caucasian patients (p = 0.006), and patients with nephritis had higher concentrations than those without nephritis (p = 0.02). Although not associated with CAC, MCP-1 concentrations were significantly positively correlated with Hcy. CONCLUSION. CCL-2 A(-2518)G genotype is a significant risk factor for SLE among Caucasians but not African Americans, suggesting that genetically mandated differences in MCP-1 expression contribute to SLE etiology in the former. The positive correlation between MCP-1 and Hcy concentrations is consistent with the hypothesis that active inflammation and hyperhomocysteinemia are etiologically linked.

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    • "The MCP-1 –2518 G allele, compared to the –2518 A allele, is linked with increased production of both MCP-1 transcript and protein [20] [21]. Involvement of the MCP-1 –2518 A>G promoter polymorphism in SLE development and its contribution to some clinical manifestations of SLE remains controversial [22] [23] [24] [25] [26] [27] [28]. We analysed the distribution of functional MCP-1 –2518 A>G polymorphic variants in SLE patients (n = 199) and controls (n = 250). "
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    ABSTRACT: There is conflicting evidence on the contribution of the MCP-1 −2518 A>G (rs 1024611) polymorphism to SLE incidence and clinical manifestations. We examined the prevalence of the MCP-1 −2518 A>G polymorphism in SLE patients (n = 199) and controls (n = 250) in Poland. We did not observe a significant difference in the distribution of MCP-1 −2518 A>G polymorphic variants in patients with SLE and healthy individuals. However, we found an association between the GG versus AG and AA genotypes as well as the AG and GG versus AA genotypes with renal manifestations of SLE OR = 3.614 (1.123–11.631, P = 0.0345) and OR = 2.297 (1.301–4.057, P = 0.0046), respectively. We also observed that the MCP-1 AG and GG -genotypes contribute to the occurrence of thrombocytopenia in SLE patients OR = 2.618 (1.280–5.352, P = 0.0089). Our observations indicate that either MCP-1 −2518 G variant can be associated with some clinical findings in patients with SLE.
    BioMed Research International 04/2010; 2010:130265. DOI:10.1155/2010/130265 · 2.71 Impact Factor
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    • "Several conditions associated with a high-Hcy/low-folate phenotype may have shared aspects of their underlying etiologies, such as changes in inflammatory mediators. In a study of the relationship between MCP-1 and Hcy in women with SLE and matched controls, MCP-1 concentrations were higher in patients, and were positively correlated with Hcy [14]. In a subsequent pilot study [15], non-significant trends towards associations between MCP-1 concentrations and both folate/Hcy phenotype and MTHFR 677CNT genotype were observed in pre-menopausal Caucasian women. "
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    ABSTRACT: Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that recruits monocytes into the subendothelial cell layer in atherosclerotic lesions. Elevated homocysteine (hyperhomocysteinemia), which is usually associated with low-folate status, is a known risk factor for many pathologies with inflammatory etiologies. The present study was undertaken to examine whether there are associations between MCP-1 concentrations and folate/Hcy phenotype or methylenetetrahydrofolate reductase (MTHFR) 677C>T genotype in healthy young adults. In females, MCP-1 concentrations were positively correlated with Hcy and negatively correlated with both serum and red blood cell folate; female smokers and MTHFR 677T carriers had particularly elevated MCP-1 concentrations. Similar relationships were not seen in males. These findings may have implications for understanding the female predominance observed for a range of autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis.
    Clinical Immunology 08/2009; 133(1):132-7. DOI:10.1016/j.clim.2009.06.008 · 3.99 Impact Factor
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    • "However, in an experimental model of chronic mild folate depletion in endothelial cells, MCP-1 mRNA and protein synthesis were up-regulated (Brown and others, 2006). Hence, the observed association of MCP-1 levels with MTHFR 677C>T and RBC THF, provides further support for the hypothesis that perturbations in folate/homocysteine metabolism contribute to the induction of MCP-1 expression (Brown and others, 2007). "
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    ABSTRACT: Women with the AA genotype at the (-2518)A>G promoter polymorphism of CCL-2, which encodes the potent pro-inflammatory chemokine monocyte chemoattractant protein 1 (MCP-1), may be at increased risk for having offspring affected by spina bifida. As the A allele at this locus has been associated with decreased transcription of MCP-1 mRNA relative to the G allele, the observed genetic association suggests that the risk of spina bifida may be increased in the offspring of women with low MCP-1 levels. The present study was undertaken to identify potential determinants of MCP-1 levels in women of reproductive age. A small cohort of Caucasian and African-American women of reproductive age was recruited to participate in an exploratory investigation of the determinants of several disease-related, biochemical phenotypes, including MCP-1. Subjects completed a brief questionnaire and provided a fasting blood sample for biochemical and genetic studies. Potential biochemical, genetic, and lifestyle factors were assessed for their association with MCP-1 levels using linear regression analyses. In this cohort, MCP-1 levels were significantly higher in Caucasians as compared to African-Americans. Further, among women of both races, there was evidence that MCP-1 levels were associated with smoking status, MTHFR 677C>T genotype, and red blood cell tetrahydrofolate levels. The results of these analyses indicate that, if maternal CCL-2 genotype is related to the risk of spina bifida, this relationship is likely to be more complex than initially hypothesized, perhaps depending upon folate intake, MTHFR 677C>T genotype, the distribution of folate derivatives, and immune/inflammatory activity.
    Birth Defects Research Part A Clinical and Molecular Teratology 10/2008; 82(10):736-41. DOI:10.1002/bdra.20507 · 2.21 Impact Factor
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