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Abstract
The pathogenesis of sarcoidosis, a multisystem granulomatous disorder, is mediated
through immunoregulatory pathways. While sarcoidosis clusters in families, inherited
risk factors remain undefined. In search of possible sarcoidosis susceptibility genes,
we examined anonymous polymorphic genetic markers tightly linked to six different
candidate gene regions on chromosomes 2q13, 5q31, 6p23-25, 7p14-15, 14q11 and 22q11.
These candidate regions contain T cell receptor, interleukin (IL) and interferon regulatory
factor (IRF) genes. Our study population consisted of 105 African-American sarcoidosis
cases and 95 unrelated healthy controls. The allelic frequency distribution of two
out of the six markers, IL-1 alpha marker (p = 0.010) on 2q13 and the F13A marker
(p = 0.0006) on 6p23-25, was statistically significantly different in cases compared
with controls. The two alleles most strongly associated with sarcoidosis were IL-1
alpha*137 (Odds Ratio (OR) = 2.60; 95% confidence interval (CI) = 1.36-4.98) and F13A*188
(OR = 2.42; 95% CI = 1.37-4.30). Individuals that had both of these alleles were at
a six-fold increased risk for sarcoidosis (OR = 6.19; 95% CI = 2.54-15.10). Restricting
the analysis to cases with at least one first or second-degree relative affected with
sarcoidosis increased the OR to 15.38. IL-1 levels are elevated in sarcoidosis and
the F13A marker is tightly linked to a gene that codes for a newly identified interferon
regulatory factor protein (IRF-4), which is thought to play a role in T cell effector
functions. Our results suggest genetic susceptibility to sarcoidosis may be conferred
by more than one immune-related gene that act synergistically on disease risk.