title: Female-specific association of C-C chemokine receptor 5 gene polymorphisms with Löfgren's syndrome.
abstract: C-C chemokine receptors have been suggested to play an important role in sarcoidosis pathogenesis. Previous investigation of the C-C chemokine receptor 5 (CCR5) gene revealed the association of the HHC haplotype with "persistent lung involvement" in two European sarcoidosis populations. Based on this finding, we investigated a possible association of the HHC haplotype and its marker alleles in an extended German sarcoidosis sample that comprised 995 German sarcoidosis families including individuals with the chronic and acute form of the disease, further refined to patients with and without Löfgren's syndrome. We genotyped this sample and 538 healthy control subjects for 8 single nucleotide polymorphisms (SNPs) that define the HHC haplotype in the CCR5 genomic region. Analysis of 3 sarcoidosis phenotypes (chronic, acute and Löfgren's syndrome) revealed that the HHC haplotype was not associated with chronic sarcoidosis although a substantial overlap can be assumed between the chronic form examined in our study and "persistent parenchymal lung involvement", the phenotype for which an association was previously established. However, 2 marker alleles in the putative CCR5 promoter, which are part of the HHC haplotype, are associated with Löfgren's syndrome. Strikingly, the association is restricted to females. This finding is consistent with recently described sex-specific manifestations of Löfgren's syndrome and with previous functional studies suggesting an estrogen-dependent CCR5 expression. The female-specific association of SNPs in the putative CCR5 promoter region with Löfgren's syndrome raises the possibility that the dysregulated, sex-specific modification of CCR5 expression could contribute to the increased risk of women to develop the disease.
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schittenhelmstrasse 12, 24105, Kiel, Germany.
authors.forename: Annegret
authors.initials: A
authors.lastname: Fischer
authors.forename: Ruta
authors.initials: R
authors.lastname: Valentonyte
authors.forename: Almut
authors.initials: A
authors.lastname: Nebel
authors.forename: Michael
authors.initials: M
authors.lastname: Nothnagel
authors.forename: Joachim
authors.initials: J
authors.lastname: Müller-Quernheim
authors.forename: Manfred
authors.initials: M
authors.lastname: Schürmann
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D005819:Genetic Markers; D005858:Germany; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D019713:Receptors, CCR5 / Q000235:genetics*; D012507:Sarcoidosis / Q000235:genetics; D012727:Sex Characteristics; D013577:Syndrome; D044465:White People / Q000235:genetics
chemical_list: D005819:Genetic Markers; D019713:Receptors, CCR5