Paolo Spagnolo

Purpose. The predisposition to sarcoidosis, a systemic granulomatous disorder of unknown etiology, is genetically determined, and genetics appears also to drive the disease down distinct phenotypic pathways. This study was undertaken to test the hypothesis that sarcoidosis-related uveitis represents a genetically distinct disease subset, by investigating single nucleotide polymorphisms (SNPs) in the HSP-70/1 and HSP-70/Hom genes. HSP70 molecules play a key role in the immune response by functioning both as chaperones and as inducers of proinflammatory cytokine secretion. methods. By sequence-specific primers–polymerase chain reaction (SSP-PCR) five SNPs were evaluated in 270 white patients with sarcoidosis, including 88 with sarcoid-related uveitis, and in 347 matched control subjects. One hundred twenty-five patients with idiopathic anterior uveitis (IAU) and 56 with idiopathic intermediate uveitis (IIU) were also included in the study as disease control subjects. results. The HSP-70/Hom rs2075800 G allele frequency was higher in the sarcoid-uveitis group than in both the sarcoid-non-uveitis and control groups (83% vs. 71%, OR = 2.00, P _c = 0.01; and 83% vs. 66%, OR = 2.45, P _c = 0.00005, respectively). Similar results were observed when considering the carriage frequency of the associated haplotype (HSP-70 haplotype 2) across the three study groups (47% vs. 29%, OR = 2.17, P _c = 0.03; and 47% vs. 21%, OR = 3.26, P _c = 0.0003, respectively). In addition, the carriage frequency of the HSP-70 haplotype 2 discriminated among sarcoid-related uveitis, IAU, and IIU (47% vs. 19%, OR = 3.26, P _c = 0.001; and 47% vs. 23%, OR = 2.81, P _c = 0.04, respectively). conclusions. A strong association was found between HSP-70/Hom rs2075800 G and uveitis in patients with sarcoidosis. Further studies are needed to understand the molecular mechanisms underlying this association.

Sarcoidosis is a heterogeneous disorder, both phenotypically and genetically. Two independent studies have recently shown that a functional polymorphism within butyrophilin‐like 2 (BTNL2) gene predisposes to sarcoidosis independently of the human leukocyte antigen (HLA)‐DRB1 alleles. However, in both studies, data analysis was not stratified by Löfgren’s syndrome, a clinically and genetically distinct sarcoidosis subset. BTNL2, potentially encoding an immune coreceptor, is adjacent and in linkage disequilibrium (LD) with HLA‐DRB1. We investigated six BTNL2 variants, including the functional rs2076530 (G > A), as well as HLA‐DRB1 alleles, by sequence‐specific primers–polymerase chain reaction, in 288 patients and 446 controls from two European countries. In the patient group as a whole, the HLA‐DRB1*14 [odds ratio (OR) = 3.1, P_c = 0.0003], DRB1*12 (OR = 2.5, P_c = 0.003), and BTNL2 rs2076530 A allele (OR = 1.49, P_c = 0.002) were all associated with disease susceptibility. However, after exclusion of patients presenting with Löfgren’s syndrome and after adjusting for HLA‐DRB1 alleles, the association between BTNL2 rs2076530 A and disease disappeared (P = 0.23). By contrast, both HLA‐DRB1*14 and DRB1*12 remained strongly significant (OR = 3.60, P < 0.0001 and OR = 3.03, P = 0.003, respectively). BTNL2 haplotype 4, tagged by the rs2076530 G allele, also remained associated with non‐Löfgren sarcoidosis after adjusting for HLA‐DRB1 alleles (OR 0.37, P = 0.016). In summary, HLA‐DRB1*14, DRB1*12, and BTNL2 haplotype 4 – but not rs2076530 A – are associated with non‐Löfgren sarcoidosis. However, the tight LD across the HLA complex makes it difficult to identify the precise location of the susceptibility locus/i. Larger sample sets from different ethnic groups, finer mapping, and more robust LD analyses across the HLA region are needed.

Rationale: Genetic factors are likely to influence the clinical course and pattern of sarcoidosis, a granulomatous disease of unknown origin. Objectives: We tested this hypothesis for C-C chemokine receptor 5 (CCR5), a molecule involved in recruitment and activation of mononuclear cells. Methods: In addition to the known CCR5 Delta 32 insertion/deletion, we evaluated a further eight single-nucleotide polymorphisms in 106 British patients and 142 British unaffected subjects, and second-setted the results in 112 Dutch patients and 169 healthy Dutch control subjects. Measurements and Main results: In the British population, the frequency of one of the identified haplotypes (HHC) was strongly associated with the presence of parenchymal disease (radiographic stage ⩾ II versus stages 0 and I) at presentation (odds ratio [OR], 5.2; 95% confidence interval [CI], 1.96–13.7; corrected p = 0.02), at 2 (OR, 6.6; 95% CI, 2.5–17.6; corrected p = 0.006), and at 4 years follow-up (OR, 6.8; 95% CI, 2.5–18.0; corrected p = 0.0045). In the Dutch population, the same association was seen at 2 (OR, 6.7; 95% CI, 2.8–16.4; corrected p = 0.002), and 4 years follow-up (OR, 9.0; 95% CI, 3.5–23.1; corrected p = 0.0009). Conclusions: No association between the CCR5 haplotype HHC and susceptibility to sarcoidosis was observed, indicating that this relevant gene only operates after disease induction. In summary, we report a strong association between CCR5 haplotype HHC and persistent lung involvement in sarcoidosis.