ARTHRITIS & RHEUMATISM Vol. 43, No. 7, July 2000, pp 1633–1640 © 2000, American College of Rheumatology DISTRIBUTION OF NOVEL POLYMORPHISMS OF THE INTERLEUKIN-8 AND CXC RECEPTOR 1 AND 2 GENES IN SYSTEMIC SCLEROSIS AND CRYPTOGENIC FIBROSING ALVEOLITIS ELISABETTA RENZONI, PENNY LYMPANY, PIERSANTE SESTINI, PANAGIOTIS PANTELIDIS, ATHOL WELLS, CAROL BLACK, KEN WELSH, CHRIS BUNN, CHRIS KNIGHT, PATRICK FOLEY, and R. M. DU BOIS Objective. To search for single-nucleotide poly- morphisms in the interleukin-8 (IL-8) and IL-8 receptor CXCR-1 and CXCR-2 genes, and to compare their distribution among patients with systemic sclerosis (SSc) with fibrosing alveolitis (FASSc) or without fibro- sing alveolitis (NFASSc), or patients with cryptogenic fibrosing alveolitis (CFA), and normal healthy subjects. Methods. Fifty control subjects were screened for potential polymorphisms by using polymerase chain reaction in association with sequence-specific primers incorporating mismatches at the 3 end. The novel polymorphisms were subsequently examined in British Caucasian subjects, including 194 healthy controls, 71 patients with CFA, and 128 patients with SSc who were further subdivided into 78 FASSc patients and 50 NFASSc patients. Results. Three novel biallelic polymorphisms were identified in the IL-8 gene (all in noncoding areas of the gene), 1 was found in the CXCR-1 gene (resulting in a conservative amino acid change), and 3 were observed in the CXCR-2 gene, of which the first resulted in a silent codon change and the others were in the 3 untranslated area of exon 3. Compared with controls, a significant increase in the frequency of the CXCR-2 785 CC homozygote and of the CXCR-2 1208 TT homozygote was found in the SSc patients (37% versus 22% [P  0.01] and 33% versus 17% [P  0.003], respectively). A subgroup analysis revealed this associ- ation to be significant both in the FASSc patients and in the NFASSc patients. Conclusion. This report describes an association between SSc and 2 polymorphisms occurring close to each other in the CXCR-2 gene. This finding and its functional significance need to be confirmed and ana- lyzed in future studies. Interleukin-8 (IL-8) is a member of the CXC chemokine family, which acts as a potent chemoattrac- tant for neutrophils (1) and is encoded by a gene situated in the CXC chemokine locus on chromosome 4q12–q21. The IL-8 gene consists of 4 exons and 3 introns (2). Cellular activities of IL-8 are mediated by 2 related receptors, CXCR-1 (previously called IL8RA) and CXCR-2 (or IL8RB), which are encoded by 2 single-copy genes and located on chromosome 2q34–q35 (3). The CXCR-1 gene consists of 3 exons, interrupted by 2 introns, whereas the CXCR-2 gene consists of 11 exons that are differentially spliced, giving rise to distinct messenger RNA (mRNA) variants (4,5). For both genes, the open reading frame is encoded entirely by a single exon. The 2 receptors have in common 78% of the protein amino acid sequence and bind IL-8 with similar affinity. However, whereas CXCR-1 binds only IL-8, CXCR-2 binds, with high affinity, other related CXC chemokines, such as the growth-related oncogene (GRO) family of proteins (GRO, GRO, and GRO) and neutrophil-activating peptide 2. The pathogenesis of cryptogenic fibrosing alve- Supported in part by a research fellowship to Dr. Renzoni from the European Respiratory Society. Elisabetta Renzoni, MD, Penny Lympany, PhD, Panagiotis Pantelidis, PhD, Athol Wells, MD, Patrick Foley, BSc, R. M. du Bois, MD: Imperial College of Science, Technology and Medicine, National Heart and Lung Institute, London, UK; Piersante Sestini, MD: University of Siena, Ospedale “Le Scotte,” Siena, Italy; Carol Black, MD, Chris Bunn, PhD, Chris Knight, BSc: Royal Free Hospital and School of Medicine, London, UK; Ken Welsh, PhD: The Churchill Hospital, Oxford, UK. Address reprint requests to R. M. du Bois, MD, Interstitial Lung Disease Unit, Department of Occupational and Environmental Medicine, Imperial College of Science, Technology and Medicine, National Heart and Lung Institute, Emmanuel Kaye Building, 1B Manresa Road, London SW3 6LR, UK. Submitted for publication January 24, 2000; accepted in revised form March 1, 2000. 1633