ARTHRITIS & RHEUMATISM Vol. 43, No. 3, March 2000, pp 515–521 © 2000, American College of Rheumatology THE ASSOCIATION OF VARIANT MANNOSE-BINDING LECTIN GENOTYPES WITH RADIOGRAPHIC OUTCOME IN RHEUMATOID ARTHRITIS NIELS A. GRAUDAL, HANS O. MADSEN, ULRIK TARP, ARNE SVEJGAARD, ANNE GRETHE JURIK, HANS K. GRAUDAL, and PETER GARRED Objective. To investigate the possible association of mannose-binding lectin (MBL) genotypes with the outcome of rheumatoid arthritis (RA). Methods. MBL genotypes and plasma concentra- tions were retrospectively determined in 140 RA pa- tients who were selected from a major cohort followed up prospectively for up to 32 years. Results. MBL-insufficient patients (those with 2 defective structural MBL alleles or with 1 defective allele combined with a low-expression variant of the normal allele) had unfavorable outcomes. The relative risk of a severe radiographic outcome event (30% of maximum radiographic destruction, or an RE30) was 3.1 (95% confidence interval 1.8–5.1) in the MBL- insufficient group versus the MBL-competent group (P < 0.0001). An RE30 occurred in 50% of MBL- competent patients within 17 years, while such an event occurred 9 years earlier in MBL-insufficient patients (i.e., within 8 years) (P < 0.0001). During the first 15 years, there was a significant trend toward lower hemo- globin levels (P < 0.04), higher erythrocyte sedimenta- tion rates (P < 0.02), and a higher number of swollen joints (P < 0.05) in the MBL-insufficient group. Conclusion. MBL genotypes giving rise to MBL insufficiency are highly significant risk factors for fast progression of radiographic joint destruction. Mannose-binding lectin (MBL) is involved in the first line of host defense as an “ante antibody” prior to the establishment of adaptive immune protection (1). MBL is associated with serine proteases which activate the lectin complement pathway independently of C1q and C1r 2 C1s 2 (2,3). MBL also has an intrinsic ability to opsonize and mediate phagocytosis by receptors that are shared with other collagen-like mammalian lectins (4). Human MBL is derived from a single gene on chromo- some 10 (MBL-2). Located on the same chromosome is an MBL pseudogene (MBL-1) (5). The normal struc- tural MBL allele is named A, while the common desig- nation for the 3 variant structural alleles B (codon 54), C (codon 57), and D (codon 52) is 0. These variant alleles occur with a high combined allele frequency of 20% in the Caucasian population. In general, individuals with a normal genotype (A/A) have MBL concentrations in serum that are 6–8 times higher than those in individuals heterozygous for 1 of the variant alleles (A/0: A/B, A/C, or A/D), while individuals with a defective genotype (2 variant alleles: B/B, C/C, D/D, B/C, B/D, or C/D) have almost undetectable MBL serum levels (6). Moreover, MBL expression is influenced by polymorphic sites in the upstream part of the MBL gene (6,7). In particular, a base substitution in codon 221 (G 3 C) (promoter allele type X) has a strong down-regulating effect on serum concentration, in contrast with promoter allele type Y (6,7). The presence of MBL variant alleles has been associated with infections (8–12), systemic lupus ery- thematosus (SLE) (13–15), and autoimmune disease in chronic granulomatous disease (16). The predisposition of patients with MBL insufficiency to infections may be stronger in those with existing autoimmune disease, as recently shown for SLE (17). In a study of rheumatoid arthritis (RA), we previously found that low serum levels of MBL predisposed patients to having poorer out- Supported by the Danish Rheumatism Association, the Dan- ish Insurance Association, the Danish Medical Research Council, the J.Aa. Sørensen and Wife Memorial Foundation, and the Novo Nordisk Research Foundation. Niels A. Graudal, MD, Ulrik Tarp, MD, DMSc, Anne Grethe Jurik, MD, DMSc: Aarhus University Hospital, Aarhus, Denmark; Hans O. Madsen, MSc, Arne Svejgaard, MD, DMSc, Peter Garred, MD, DMSc: National University Hospital, Copenhagen, Denmark. Dr. Hans K. Graudal is deceased. Address reprint requests to Niels A. Graudal, MD, Tissue Typing Laboratory - 7631, Department of Clinical Immunology, Rigshospitalet, Tagensvej 20, DK-2200 Copenhagen, Denmark. Submitted for publication August 5, 1999; accepted in revised form November 20, 1999. 515