Variation in the Lymphotoxin-α/Tumor Necrosis Factor Locus Modifies Risk of Erythema Nodosum in Sarcoidosis

Abstract

Sarcoidosis is a multi-system inflammatory disease with organ involvement that varies by race and sex. Family studies indicate that genes play a role in the etiology and extent of organ involvement in sarcoidosis. In this study, we evaluated whether 25 variants distributed in 19 genes with a known role in inflammation were associated with erythema nodosum status in 659 sarcoidosis patients and 658 controls from A Case–Control Etiologic Study of Sarcoidosis (ACCESS). We found no association with affectation status; however, a variant in the promoter of tumor necrosis factor (TNF) at position −308 was found to be associated with erythema nodosum in Caucasian sarcoidosis patients (study-wide P = 0.027). When separated by sex, a variant in intron 1 of lymphotoxin-α (LTA), a gene adjacent to TNF, was associated with erythema nodosum in female Caucasian sarcoidosis patients (study-wide P = 0.027). These DNA variants frequently occur together in Caucasians, and each variant has individually been associated with erythema nodosum in sarcoidosis patients. These results confirm that variation in the LTA/TNF gene cluster modifies a major skin manifestation of sarcoidosis and may explain the higher rate of erythema nodosum in females with sarcoidosis.

Dendritic Cells in the Pathogenesis of Sarcoidosis

“…However, there is also evidence that TNF promoter polymorphisms may be irrelevant, or may predispose patients to variant forms of sarcoidosis, such as Lofgren syndrome (131)(132)(133)(134). Other DC-related candidate genes include innate bacterial antigen receptors TLR2 (135) and TLR4 (136), although these genes have not yet been confirmed using unbiased genome-wide scans.…”

Genetics of Sarcoidosis

“…An association between TNF-α 308A (rs1800629) allele and LS and between TNF-α -857T allele and non-LS sarcoidosis was also found in a British and Dutch cohort [78] and German cohorts [79][80][81]. An association was found between the TNF-α -308 (rs1800629) and LTA252G(rs909253) SNPs and erythema nodosum in US white women [73] but no association between polymorphisms in the TNF-α gene and sarcoidosis in African Americans was detected. [82] There was also an increased frequency of the -857T allele in British and Dutch sarcoidosis patients compared to controls.…”

“…TNF-α and LTA genes are located within the MHC class III region on chromosome 6p21.3 [73][74][75]. TNF-α plays a pivotal role in sarcoidosis [76].…”

Genetic Aspects of Panniculitis in a Russian Population: A Pilot Study

“…Изучение гена ИЛ1РА при УЭ не выявило достоверных различий в частоте генотипов и аллелей между больными и контролем [5]. Исследование полиморфизмов генов лимфотоксина α и фактора некроза опухоли α (ФНОα) показало связь гена ФНОα с УЭ среди кавказоидных больных с саркоидозом [6].…”