Marcie Major

Heterogeneity of familial risk in sarcoidosis.

Familial clustering of sarcoidosis and the higher prevalence and clinical severity of sarcoidosis in African Americans suggests etiologic heterogeneity. To test for heterogeneity in familial risk of sarcoidosis, we studied 3,395 siblings and parents of 558 index cases (361 African American, 197 Caucasian) diagnosed at Henry Ford Hospital between 1951 and 1994. Using the age‐ and sex‐specific cumulative incidence of sarcoidosis in our sample, we found a statistically significant heterogeneity in familial risk of disease (P < .001). To determine if this was due to a greater risk of sarcoidosis in African Americans, we recalculated disease probabilities using age‐, sex‐, and race‐specific disease cumulative incidence and found the same amount of heterogeneity in familial risk (P < .001). Index cases (n = 69) from high‐risk families were more likely to be African American (odds ratio [OR] = 3.24; 95% confidence interval (CI) = 1.71−6.14) and to have an offspring or second‐degree relative affected (OR = 6.21; 95% CI = 2.86−13.45).

GENETICS OF SARCOIDOSIS

Sarcoidosis likely results from an interplay of environmental and genetic factors. Despite a recent large multicenter study, A Case-Control Etiologic Study of Sarcoidosis (ACCESS), no single causative environmental agent has been identified. Family clustering and differences in racial incidence of sarcoidosis support an inherited susceptibility to sarcoidosis. Siblings of patients with sarcoidosis have about a fivefold increased risk of developing sarcoidosis. Certain human leukocyte antigen (HLA) alleles have been consistently associated with sarcoidosis susceptibility. Furthermore, HLA-DRB1*0301/DQB1*0201 has been associated with good prognosis in Löfgrens syndrome. Many candidate genes studied based on their potential function in immunopathogenesis have been evaluated in case-control studies, but few have been consistently associated with sarcoidosis across populations. Two genome scans have been reported in sarcoidosis. One in African Americans reporting linkage to chromosome 5 and the other in German families reporting linkage to chromosome 6. Follow-up studies on chromosome 6 identified the BTNL2 gene, a B7 family costimulatory molecule to be associated with sarcoidosis. Advances in genotyping and statistical analysis are helping to elucidate the genetics of sarcoidosis.

TGF-β1 Variants in Chronic Beryllium Disease and Sarcoidosis

Evidence suggests a genetic predisposition to chronic beryllium disease (CBD) and sarcoidosis, which are clinically and pathologically similar granulomatous lung diseases. TGF-β1, a cytokine involved in mediating the fibrotic/Th1 response, has several genetic variants which might predispose individuals to these lung diseases. We examined whether certain TGF-β1 variants and haplotypes are found at higher rates in CBD and sarcoidosis cases compared with controls and are associated with disease severity indicators for both diseases. Using DNA from sarcoidosis cases/controls from A Case Control Etiologic Study of Sarcoidosis Group (ACCESS) and CBD cases/controls, TGF-β1 variants were analyzed by sequence-specific primer PCR. No significant differences were found between cases and controls for either disease in the TGF-β1 variants or haplotypes. The −509C and codon 10T were significantly associated with disease severity indicators in both CBD and sarcoidosis. Haplotypes that included the −509C and codon 10T were also associated with more severe disease, whereas one or more copies of the haplotype containing the −509T and codon 10C was protective against severe disease for both sarcoidosis and CBD. These studies suggest that the −509C and codon 10T, implicated in lower levels of TGF-β1 protein production, are shared susceptibility factors associated with more severe granulomatous disease in sarcoidosis and CBD. This association may be due to lack of down-regulation by TGF-β1, although future studies will be needed to correlate TGF-β1 protein levels with known TGF-β1 genotypes and assess whether there is a shared mechanisms for TGF-β1 in these two granulomatous diseases.

The influence of T cell receptor and cytokine genes on sarcoidosis susceptibility in African Americans

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.

The Distribution of Long Range Admixture Linkage Disequilibrium in an African-American Population

Objectives: To better understand the effect of admixture on long range linkage disequilibrium (LD), we characterized extended LD in gene-rich regions of an African-American population. Methods: Approximately 290 cM of chromosomes 1, 3, 6, 11–17, 20 and 22 were scanned using 109 polymorphic microsatellite markers spaced an average of 3 cM apart. Disequilibrium between loci (D′) was based on maximum-likelihood estimates of haplotype frequencies computed for 200 unrelated African Americans. Results: Mean D′ values were highest on chromosomes 6p23–p21.3 (D′ = 0.33) and 15p22.2–p25.3 (D′ = 0.34), and lowest on chromosome 12p11.2–q14 (D′ = 0.21). Overall, the variance in LD among chromosomes accounted for approximately two-thirds of the total LD variance. Of the 434 locus pairs spaced between 0.3 and 38.7 cM apart, there was no detectable correlation between LD and recombination distance and a weak negative correlation between LD and physical distance (rs = –0.12; p = 0.031). For the 192 intrachromosomal locus pairs where allele frequency data were available from the Centre d’Etude du Polymorphisme humain (CEPH), we found a statistically significant positive correlation between LD and the allelic frequency differences (δ) between the African-American study population and Caucasian reference CEPH population (rs = 0.53; p < 0.0001). The correlation between LD and both recombination and physical distance was markedly increased for locus pairs with high δ levels. Conclusions: Our results suggest that recent Caucasian admixture maintains a high level of long range LD in African Americans on a genomic scale, and selected markers with large African American/Caucasian δ levels may be useful in association studies.