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C-C Chemokine Receptor 2 and Sarcoidosis

Association with Löfgren's Syndrome

Clinical Genomics Group, Department of Occupational and Environmental Medicine, Imperial College of Science, Technology and Medicine, National Heart and Lung Institute, London, United Kingdom; Institute of Respiratory Disease, University of Siena; Institute of Respiratory Diseases, University of Bari, Italy; Heart Lung Center Utrecht, Department of Pulmonology, and Department of Clinical Chemistry, Sint Antonius Hospital, Nieuwegein, the Netherlands

Correspondence and requests for reprints should be addressed to Kenneth I. Welsh, Ph.D., Clinical Genomics Group, Imperial College, 1B Manresa Road, London SW3 6LR, UK. E-mail: k.welsh{at}ic.ac.uk

Sarcoidosis is thought to result from the interaction between an unknown environmental antigenic trigger and the host's genetic susceptibility. We hypothesized that sarcoidosis, or one of the disease subsets, could be associated with single nucleotide polymorphisms of C-C chemokine receptor 2 (CCR2) gene. Eight single-nucleotide polymorphisms in CCR2 were studied in a total of 304 Dutch individuals (90 non-Löfgren sarcoidosis, 47 Löfgren's syndrome, 167 control subjects). From the investigated CCR2 polymorphisms, nine haplotypes were deduced (haplotypes 1–9). In patients with Löfgren's syndrome, a strongly significant increase in the frequency of CCR2-haplotype 2, which includes four unique alleles (A at nucleotide position –6752, A at 3,000, T at 3,547, and T at 4,385), was observed compared with control subjects (74% vs. 38% respectively, p < 0.0001), whereas no difference was found between non-Löfgren sarcoidosis and control subjects (both 38%). The association between CCR2-haplotype 2 carriage frequency and Löfgren's syndrome (odds ratio, 4.4; p < 0.0001) remained significant after adjustment for human leukocyte antigen haplotype DRB1*0301-DQB1*0201 (odds ratio, 11.5; p < 0.0001) and female sex (odds ratio, 3.2; p = 0.003), two known risk factors for Löfgren's syndrome. In conclusion, this report describes a strong association between CCR2-haplotype 2 and Löfgren's syndrome. Further studies are needed to understand the molecular mechanisms underlying this association.

Key Words: polymorphisms • cytokines • sarcoidosis

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