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Open Access Research article

Mannan Binding Lectin (MBL) genotypes coding for high MBL serum levels are associated with rheumatoid factor negative rheumatoid arthritis in never smokers

Saedis Saevarsdottir123*, Bo Ding2, Kristjan Steinsson4, Gerdur Grondal4, Helgi Valdimarsson3, Lars Alfredsson2, Lars Klareskog1 and Leonid Padyukov1

Author Affiliations

1 Rheumatology Unit, Department of Medicine, Karolinska University Hospital Solna, D2:01, 17176 Stockholm, Sweden

2 Institute of Environmental Medicine, Karolinska Institutet, Nobels väg 13, 17177 Stockholm, Sweden

3 Department of Immunology, Landspitali University Hospital, Hringbraut (Building 14 at Eiriksgata), 101 Reykjavik, Iceland

4 Center for Rheumatology Research, Landspitali University Hospital, Hringbraut (Building 14 at Eiriksgata), 101 Reykjavik, Iceland

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Arthritis Research & Therapy 2011, 13:R65  doi:10.1186/ar3321

Published: 15 April 2011

Abstract

Introduction

Previous studies have provided inconsistent results on whether variants in the MBL2 gene, coding for the complement-activating mannan-binding lectin (MBL) protein, associate with rheumatoid arthritis (RA). We re-evaluated this in context of the main environmental and genetic risk factors (smoking, HLA-DRB1 'shared epitope' (SE), PTPN22*620W), which predispose to rheumatoid factor (RF) and/or anti-citrullinated-protein antibody (ACPA)-positive RA.

Methods

In this population-based EIRA study, rheumatoid factor (RF), ACPA, smoking, SE and PTPN22*620W status was determined in incident RA cases and matched controls. MBL-high (n = 1330) and MBL-low (n = 1257) genotypes predicting MBL levels were constructed from four promoter and exon-1 polymorphisms in the MBL2 gene. Odds ratios with 95% confidence interval (OR, 95% CI) were calculated by logistic regression. In extended families (n = 316), previously reported data were re-analyzed, considering RF and smoking.

Results

MBL-high genotypes tended to be associated with RF-negative (OR = 1.20, 95% CI 0.96-1.51) but not RF-positive (OR = 1.00, 95% CI 0.83-1.20) RA. Results divided by ACPA status did not differ. When stratified for smoking, MBL-high genotype was strongly associated with RF-negative RA in never smokers (OR = 1.82, 95% CI 1.24-2.69) but not in ever smokers (OR = 0.96, 95% CI 0.73-1.30). In never smokers, the association was observed in both the RF-negative/ACPA-negative (OR = 1.67, 95% CI 1.10-2.55) and RF-negative/ACPA-positive subgroups (OR = 3.07, 95% CI 1.37-6.89), and remained on an SE/PTPN22*620W negative background. In the extended families, the reported association between high MBL and RA was in fact confined to never smokers.

Conclusions

High MBL may predispose to RF-negative RA but only in individuals who have never smoked. This illustrates the importance of phenotypic subgrouping in genetic studies.