Genetic linkage analysis of sarcoidosis phenotypes: the sarcoidosis genetic analysis (SAGA) study

Abstract

The sarcoidosis genetic analysis (SAGA) study previously identified eight chromosomal regions with suggestive evidence for linkage to sarcoidosis susceptibility in African-American sib pairs. Since the clinical course of sarcoidosis is variable and likely under genetic control, we used the affected relative pair portion of the SAGA sample (n ¼ 344 pairs) to perform multipoint linkage analyses with covariates based on pulmonary and organ involvement phenotypes. Chest radiographic resolution was the pulmonary phenotype with the highest LOD (logarithm of the backward odds, or likelihood ratio) score of 5.11 at D1S3720 on chromosome 1p36 (P ¼ 4 Â 10 À5). In general, higher LOD scores were attained for covariates that modeled clustered organ system involvement rather than individual organ systems, with the cardiac/renal group having the highest LOD score of 6.65 at chromosome 18q22 (P ¼ 2 Â 10 À5 ). The highest LOD scores for the other three organ involvement groups of liver/spleen/bone marrow, neuro/lymph and ocular/skin/joint were 3.72 at 10p11 (P ¼ 0.0004), 5.16 at 7p22 (P ¼ 4 Â 10 À5 ) and 2.93 at 10q26 (P ¼ 0.001), respectively. Most of the phenotype linkages did not overlap with the regions previously found linked to susceptibility. Our results suggest that genes influencing clinical presentation of sarcoidosis in African Americans are likely to be different from those that underlie disease susceptibility.

Fluorine-18 Fluorodeoxyglucose with Positron Emission Tomography Revealed Bone Marrow Involvement in Sarcoidosis Patients with Anaemia

“…Interestingly, our 3 cases came from North Africa whereas only 2 of our 7 controls did, which suggests that ethnicity could play a role in bone marrow involvement. This is in keeping with previous genetic reports showing that bone marrow involvement seems to be highly influenced by genetic factors [14,15] . A participation of anaemia of chronic inflammation cannot be excluded since there was mild increase in ␣ 2 -globulin levels in our 3 cases.…”

Association of HLA-DRB1 with Sarcoidosis Susceptibility and Progression in African Americans

“…Diagnostic criteria for patients with sarcoidosis and follow-up for radiographic resolution of pulmonary disease were described previously (31). Across all three studies, patients with sarcoidosis met diagnostic criteria for "definite" or "highly probable" sarcoidosis (29). "Definite" cases had histological confirmation of noncaseating granulomas and evidence of disease in either the thorax or two or more other organ systems; "highly probable" cases lacked histologic confirmation but had characteristic chest radiographs (bilateral symmetrical hilar adenopathy) and either a history of erythema nodosum or at least 2 years observation during which time no other disease was found to explain radiographic abnormalities.…”

“…The sample was assembled from the following three studies: (1) A Case-Control Etiologic Study of Sarcoidosis (ACCESS) (28), (2) a multisite affected-sibling sarcoidosis linkage study (29), and (3) a nuclear family-based sample ascertained through a single affected individual (30). The varied sampling schemes across studies resulted in a final analytic sample of related and unrelated cases and control subjects (see Table E1 in the online supplement for a more complete description of the study sample).…”

Dendritic Cells in the Pathogenesis of Sarcoidosis

“…As previously described in this review, TNF is both a product and an activator of myeloid DCs. The second study was conducted in 229 African-American families, and identified a major linkage on 5q11 with minor loci at 3p21-14, 1p22, 9q34, 2p25, 5p15-13, 5q35, 11p15, and 20q13 (125). Both the white German and the African-American groups shared allele 3p21 containing chemokine receptors CCR2 and CCR5, which bind macrophage chemotactic protein 1 (MCP-1), promoting monocyte, macrophage, and DC recruitment into the lungs (64).…”