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: 3.19). 04/2007; 34(4):740-6.
Source: PubMed


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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    • "Hyperhomocysteinemia may be related to an increased level of some inflammatory markers,37 which may contribute to the progression of active disease.38,39 Brown found that monocyte chemoattractant protein-1 concentrations in plasma were strongly positively correlated with homocysteine concentrations in patients with SLE, indicating that active inflammation in SLE and hyperhomocysteinemia may be etiologically linked.40 Higher intake of vitamin B6 may prevent hyperhomocysteinemia, which may lead to the suppression of active inflammation, ie, active disease. "
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    ABSTRACT: Intakes of selected vitamins and dietary fiber may influence the clinical course of systemic lupus erythematosus (SLE). Using a cohort study method, we investigated the associations of dietary intake of vitamin B6 and B12, folate, and dietary fiber with the risk of active disease and atherosclerotic vascular events in SLE. The study included female SLE patients in the Miyagi Lupus Cohort, which was founded in 1995. Dietary nutrients at baseline were estimated by a semiquantitative food frequency questionnaire. The association of each nutrient intake with the risk of active disease was investigated in 216 patients who had inactive disease at baseline. The association with atherosclerotic vascular events was assessed in 196 women who had inactive disease and no history of atherosclerotic diseases at baseline. Forty-three cases of active disease were identified during 9966 person-months of follow-up (1995-1999). During 19 575 person-months of follow-up (1995-2005), 20 atherosclerotic vascular events were documented. The Cox proportional hazards model revealed an inverse association between vitamin B6 intake and the risk of active disease (hazard ratio for the highest as compared with the lowest tertile, 0.41; 95% confidence interval, 0.18-0.97; P for trend = 0.04). An inverse association was also found for dietary fiber intake (P for trend = 0.01). However, no significant association was observed between intakes of these nutrients and the risk of atherosclerotic vascular events. Higher intake of vitamin B6 and dietary fiber may prevent the occurrence of active disease in SLE.
    Journal of Epidemiology 04/2011; 21(4):246-54. DOI:10.2188/jea.JE20100157 · 3.02 Impact Factor
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    • "Carriers of the MCP1 -2581G allele were at an increased risk of clinical TB in study groups from Mexico and Korea [4], Peru [6] and Zambia [7] compared to individuals carrying the alternative -2581A allele. For MCP1 -2581G, several studies have demonstrated increased gene expression in vitro and elevated MCP-1 plasma levels in vivo [4,6,8-10]. In contrast to these observations, Japanese MCP1 -2581AA genotype carriers exhibited higher MCP-1 plasma levels than did carriers of the -2581AG or GG genotypes [11]. "
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    ABSTRACT: The monocyte chemoattractant protein 1 (MCP-1) is involved in the recruitment of lymphocytes and monocytes and their migration to sites of injury and cellular immune reactions. In a Ghanaian tuberculosis (TB) case-control study group, associations of the MCP1 -362C and the MCP1 -2581G alleles with resistance to TB were recently described. The latter association was in contrast to genetic effects previously described in study groups originating from Mexico, Korea, Peru and Zambia. This inconsistency prompted us to further investigate the MCP1 gene in order to determine causal variants or haplotypes genetically and functionally. A 14 base-pair deletion in the first MCP1 intron, int1del554-567, was strongly associated with protection against pulmonary TB (OR=0.84, CI 0.77-0.92, Pcorrected=0.00098). Compared to the wildtype combination, a haplotype comprising the -2581G and -362C promoter variants and the intronic deletion conferred an even stronger protection than did the -362C variant alone (OR=0.78, CI 0.69-0.87, Pnominal=0.00002; adjusted Pglobal=0.0028). In a luciferase reporter gene assay, a significant reduction of luciferase gene expression was observed in the two constructs carrying the MCP1 mutations -2581 A or G plus the combination -362C and int1del554-567 compared to the wildtype haplotype (P=0.02 and P=0.006). The associated variants, in particular the haplotypes composed of these latter variants, result in decreased MCP-1 expression and a decreased risk of pulmonary TB. In addition to the results of the previous study of the Ghanaian TB case-control sample, we have now identified the haplotype combination -2581G/-362C/int1del554-567 that mediates considerably stronger protection than does the MCP1 -362C allele alone (OR=0.78, CI 0.69-0.87 vs OR=0.83, CI 0.76-0.91). Our findings in both the genetic analysis and the reporter gene study further indicate a largely negligible role of the variant at position -2581 in the Ghanaian population studied.
    BMC Genetics 04/2011; 12:34. DOI:10.1186/1471-2156-12-34 · 2.40 Impact Factor
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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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