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Published ahead of print on July 25, 2003, doi:10.1164/rccm.200303-456OC

Am. J. Respir. Crit. Care Med., Volume 168, Number 10, November 2003, 1162-1166

A more recent version of this article appeared on November 15, 2003
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Submitted on March 31, 2003
Accepted on July 18, 2003

C-C CHEMOKINE RECEPTOR 2 AND SARCOIDOSIS: ASSOCIATION WITH LOFGREN'S SYNDROME

PAOLO SPAGNOLO1, ELISABETTA A RENZONI2, ATHOL U WELLS2, HIROE SATO2, JAN C GRUTTERS3, PIERSANTE SESTINI4, ATIYEH ABDALLAH2, ENZO GRAMICCIONI5, HENK J.T. RUVEN6, ROLAND M du BOIS2, and KENNETH I WELSH2*

1 DEPARTMENT OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE, CLINICAL GENOMICS GROUP, ROYAL BROMPTON HOSPITAL; NATIONAL HEART AND LUNG INSTITUTE; IMPERIAL COLLEGE OF SCIENCE, TECHNOLOGY AND MEDICINE, LONDON, UNITED KINGDOM; INSTITUTE OF RESPIRATORY DISEASES, UNIVERSITY OF BARI, BARI, ITALY, 2 DEPARTMENT OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE, CLINICAL GENOMICS GROUP, ROYAL BROMPTON HOSPITAL; NATIONAL HEART AND LUNG INSTITUTE; IMPERIAL COLLEGE OF SCIENCE, TECHNOLOGY AND MEDICINE, LONDON, UNITED KINGDOM, 3 DEPARTMENT OF PULMONOLOGY, SINT ANTONIUS HOSPITAL, HEART LUNG CENTER, UTRECHT, NIEUWEGEIN, THE NETHERLANDS, 4 INSTITUTE OF RESPIRATORY DISEASE, UNIVERSITY OF SIENA, SIENA, ITALY, 5 INSTITUTE OF RESPIRATORY DISEASES, UNIVERSITY OF BARI, BARI, ITALY, 6 DEPARTMENT OF CLINICAL CHEMISTRY, SINT ANTONIUS HOSPITAL, UTRECHT, NIEUWEGEIN, THE NETHERLANDS

* To whom correspondence should be addressed. 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 hypothesised 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-Lofgren-sarcoidosis, 47 Lofgren's syndrome, 167 controls). From the investigated CCR2 polymorphisms nine haplotypes were deduced (haplotypes 1-9). In patients with Lofgren's syndrome, a strongly significant increase in the frequency of CCR2-haplotype 2, which includes 4 unique alleles (A at nucleotide position -6752, A at 3000, T at 3547, and T at 4385), was observed compared to controls (74% vs. 38% respectively, p<0.0001), whereas no difference was found between non-Lofgren sarcoidosis and controls (both 38%). The association between CCR2-haplotype 2 carriage frequency and Lofgren's syndrome (Odds Ratio: 4.4, p<0.0001) remained significant after adjustment for HLA haplotype DRB1*0301-DQB1*0201 (Odds Ratio: 11.5, p<0.0001) and female gender (OR 3.2, p=0.003), two known risk factors for Lofgren's syndrome. In conclusion, this report describes a strong association between CCR2 haplotype 2 and Lofgren's syndrome. Further studies are needed to understand the molecular mechanisms underlying this association.
Key words: polymorphisms, cytokines, sarcoidosis




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