Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort

Abstract

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disorder with a complex pathogenesis in which genetic, hormonal and environmental factors have a role. Rare mutations in the TREX1 gene, the major mammalian 3 0 -5 0 exonuclease, have been reported in sporadic SLE cases. Some of these mutations have also been identified in a rare pediatric neurological condition featuring an inflammatory encephalopathy known as Aicardi-Goutiè res syndrome (AGS). We sought to investigate the frequency of these mutations in a large multi-ancestral cohort of SLE cases and controls. A total of 40 single-nucleotide polymorphisms (SNPs), including both common and rare variants, across the TREX1 gene, were evaluated in B8370 patients with SLE and B7490 control subjects. Stringent quality control procedures were applied, and principal components and admixture proportions were calculated to identify outliers for removal from analysis. Population-based case-control association analyses were performed. P-values, false-discovery rate q values, and odds ratios (OR) with 95% confidence intervals (CI) were calculated. The estimated frequency of TREX1 mutations in our lupus cohort was 0.5%. Five heterozygous mutations were detected at the Y305C polymorphism in European lupus cases but none were observed in European controls. Five African cases incurred heterozygous mutations at the E266G polymorphism and, again, none were observed in the African controls. A rare homozygous R114H mutation was identified in one Asian SLE patient, whereas all genotypes at this mutation in previous reports for SLE were heterozygous. Analysis of common TREX1 SNPs (minor allele frequency (MAF)410%) revealed a relatively common risk haplotype in European SLE patients with neurological manifestations, especially seizures, with a frequency of 58% in lupus cases compared with 45% in normal controls (P ¼ 0.0008, OR ¼ 1.73, 95% CI ¼ 1.25-2.39). Finally, the presence or absence of specific autoantibodies in certain populations produced significant genetic associations. For example, a strong association with anti-nRNP was observed in the European cohort at a coding synonymous variant rs56203834 (P ¼ 2.99EÀ13, OR ¼ 5.2, 95% CI ¼ 3.18-8.56). Our data confirm and expand previous reports and provide additional support for the involvement of TREX1 in lupus pathogenesis.

Typing TREX1 gene in patients with systemic lupus erythematosus

“…We also confirmed the presence of two synonymous mutations, which were reported by our cohort with a similar rate among patients and controls and showed a frequency similar to that of a large multiancestral cohort (9). Synonymous SNPs do not cause an amino acid change, and the role of these mutations in the pathogenesis of diseases is still debated.…”

“…In fact, TREX1-deficient mice develop an inflammatory myocarditis and die of circulatory failure (4). In humans, mutations of the TREX1 gene have been identified in patients with Aicardi-Goutierès syndrome (AGS) (5,6) and also in several autoimmune diseases, namely familial chilblain lupus (7), systemic lupus erythematosus (SLE) (8,9), Sjögren's syndrome and systemic sclerosis (10). AGS is a rare encephalopathy arising during the first year of life after an uneventful pregnancy (11).…”

Cutting Edge: Antimalarial Drugs Inhibit IFN-β Production through Blockade of Cyclic GMP-AMP Synthase–DNA Interaction

“…However, family studies of individuals without autoantibodies (5), direct evidence of IFN-b involvement (6,7), and incomplete neutralization of ISGs in clinical trials using biologics targeting IFN-a suggest that other IFN-Is are involved in SLE (8). Approximately 25% of patients with AGS and 1-2% of SLE patients have mutations in the 3-59 DNA exonuclease TREX1 (9,10). TREX1 deficiency in mice leads to the accumulation of intracellular DNA and cell-intrinsic production of IFN-b (11).…”

Dominant Mutations of the TREX1 Exonuclease Gene in Lupus and Aicardi-Goutières Syndrome

“…Mutations in the human TREX1 gene have been linked to a spectrum of autoimmune diseases including the severe neurological brain disease Aicardi-Goutières syndrome (AGS) 2 (11), to a monogenic form of cutaneous lupus erythematosus named "familial chilblain lupus" (FCL) (12)(13)(14), to systemic lupus erythematosus (15,16), and to retinal vasculopathy and cerebral leukodystrophy (17). Approximately 40 TREX1 disease-causing missense and frameshift mutations have been identified, mapping to positions located throughout the gene (18,19).…”