Background: Sarcoidosis (SA) is a systemic granulomatous inflammatory disorder with complex etiology and strong clustering in families. Genome-wide association studies have been successful in the identification of common risk variants for the disease. To reveal susceptibility variants with low frequencies but strong effects, we performed a genome-wide linkage scan in a large sample of SA families.
Methods: We genotyped 528 members of 181 German SA families for 3,882 single nucleotide polymorphism assays from the SNPlex System Human Linkage Mapping Set 4K.
Results: Nonparametric linkage analysis revealed one region of suggestive linkage on chromosome 12p13.31 at 20 cM (logarithm of odds [LOD] = 2.53; local P value = .0003) and another linkage peak of nearly suggestive linkage on 9q33.1 at 134 cM (LOD = 2.12; local P value = .0009). The latter has been reported to show suggestive evidence for linkage in a sample of 229 African American SA families previously. Analysis of acute and chronically affected families revealed a subphenotype-specific linkage pattern and an additional, nearly suggestive linkage peak on chromosome 16p13.11 at 38 cM (LOD = 2.09; local P value = .001), which was confined to acute SA.
Conclusion: Our results propose that the respective regions might harbor yet-unidentified, possibly subphenotype-specific risk factors for the disease (eg, with immune-related functions like the tumor necrosis factor receptor 1). They should be proved to be important for SA pathogenesis and investigated in detail with an emphasis on rare variants. Subphenotype-specific risk factors might serve for prognosis of the clinical course of the disease.