Results from a Genome-wide Search for Predisposing Genes in Sarcoidosis

Abstract

Sarcoidosis is a systemic disease of granulomatous inflammation and unknown etiology. An inherited predisposition is involved, and many candidate susceptibility genes have been tested in association studies. We have applied the more general strategy of genome-wide microsatellite linkage analysis to identify chromosomal regions that contribute to the risk of sarcoidosis. On the basis of 225 microsatellite markers tested in 63 families with affected siblings (138 patients) and multipoint nonparametric linkage (NPL) analysis, we found the most prominent peak (six adjacent markers including D6S1666; NPL score = 2.99; p = 0.001) at the major histocompatibility complex (MHC). Six minor peaks (p < 0.05) were found on chromosomes 1 (D1S1665 ), 3 (D3S1766 ), 7 (D7S821 and D7S3070), 9 (D9S934), and the X chromosome (DXS6789). A subset of nine families with more than two affected siblings (30 patients) contributed little to the peak at the MHC (D6S1666; NPL score = 0.79; p = 0.21). Our results point to locus heterogeneity of susceptibility to sarcoidosis, with a major effect of the MHC.

Genome-wide search for sarcoidosis susceptibility genes in African Americans

“…Their most significant finding was with D6S1666 (P ¼ 0.001), which resides in the MHC class II gene region. Table 3 compares our results for the MHC region with those previously reported by Schurmann et al 14 In our sample, we typed D6S1666 and three additional markers in a 3 cM region that spanned the MHC. We thought this dense marker coverage of the MHC was warranted given the strong linkage to sarcoidosis found in German Caucasians and the multitude of reported HLA associations with sarcoidosis including an association we previously reported between HLA-DQB1 and sarcoidosis susceptibility in a separate African-American sample.…”

“…Schurmann et al 23 first reported that familial sarcoidosis is linked to the MHC region using seven microsatellite markers in a sample of 55 German families with 78 affected sibling pairs. For the genome-wide scan in the larger sample of 63 families reported by Schurmann et al, 14 the most prominent peak was found on the short arm of chromosome 6 (6p21-6p22) for six adjacent makers spanning a region of 16 cM including the MHC. Their most significant finding was with D6S1666 (P ¼ 0.001), which resides in the MHC class II gene region.…”

“…In comparing the results of our genome scan with that of Schurmann et al, 14 it should be noted that our sample includes ASP, DSP and a few unaffected sib pairs (USP), whereas the sample analyzed by Schurmann et al was entirely ASP. When we restricted our analysis to only ASP, many of our linkage peaks were significantly diminished.…”

“…A minor peak was detected with D1S551 on 1p22.3 (P ¼ 0.044). Schurmann et al, 14 detected a minor peak for D1S1665 (P ¼ 0.03) on 1p22 about 11 cM away from D1S551. We found suggestive evidence for linkage with D9S1825 on 9q34.1 (P ¼ 0.013).…”

“…10,12,13 While sarcoidosis in the US has an annual disease incidence ranging from 11 per 100 000 in Caucasians to 36 per 100 000 in African Americans, 9 firstdegree relatives of African-American sarcoidosis cases have about a three-fold increased disease risk. 10 Schurmann et al 14 reported a genome-wide search for predisposing genes in sarcoidosis. On the basis of 225 microsatellite markers tested in 63 German families (Caucasians) with affected sib pairs, linkage at the major histocompatibility complex (MHC) on chromosome 6p was found with additional suggested linkage to markers on chromosome 1, 3, 9 and X.…”