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Identification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups.

ABSTRACT: Systemic lupus erythematosus (SLE), a worldwide autoimmune disease with high heritability, shows differences in prevalence, severity and age of onset among different ancestral groups. Previous genetic studies have focused more on European populations, which appear to be the least affected. Consequently, the genetic variations that underlie the commonalities, differences and treatment options in SLE among ancestral groups have not been well elucidated. To address this, we undertake a genome-wide association study, increasing the sample size of Chinese populations to the level of existing European studies. Thirty-eight novel SLE-associated loci and incomplete sharing of genetic architecture are identified. In addition to the human leukocyte antigen (HLA) region, nine disease loci show clear ancestral differences and implicate antibody production as a potential mechanism for differences in disease manifestation. Polygenic risk scores perform significantly better when trained on ancestry-matched data sets. These analyses help to reveal the genetic basis for disparities in SLE among ancestral groups.

SUBMITTER: Wang YF

PROVIDER: S-EPMC7858632 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Identification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups.

Wang Yong-Fei YF Zhang Yan Y Lin Zhiming Z Zhang Huoru H Wang Ting-You TY Cao Yujie Y Morris David L DL Sheng Yujun Y Yin Xianyong X Zhong Shi-Long SL Gu Xiaoqiong X Lei Yao Y He Jing J Wu Qi Q Shen Jiangshan Jane JJ Yang Jing J Lam Tai-Hing TH Lin Jia-Huang JH Mai Zhi-Ming ZM Guo Mengbiao M Tang Yuanjia Y Chen Yanhui Y Song Qin Q Ban Bo B Mok Chi Chiu CC Cui Yong Y Lu Liangjing L Shen Nan N Sham Pak C PC Lau Chak Sing CS Smith David K DK Vyse Timothy J TJ Zhang Xuejun X Lau Yu Lung YL Yang Wanling W

Nature communications 20210203 1

Systemic lupus erythematosus (SLE), a worldwide autoimmune disease with high heritability, shows differences in prevalence, severity and age of onset among different ancestral groups. Previous genetic studies have focused more on European populations, which appear to be the least affected. Consequently, the genetic variations that underlie the commonalities, differences and treatment options in SLE among ancestral groups have not been well elucidated. To address this, we undertake a genome-wide ...[more]

PMID: 33536424

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Project description:Systemic lupus erythematosus (SLE) is a chronic, rare autoimmune disease. In recent years, multiple monogenic diseases with early onset autoimmunity and lymphoproliferation have been identified, such as autoimmune lymphoproliferative syndrome, rat sarcoma (RAS)-associated autoimmune leukoproliferative disease, signal transducer and activator of transcription 3 gain-of-function syndrome and interleukin-2 receptor α deficiency. Therefore, we performed whole-exome sequencing in children with SLE with lymphoproliferation to identify genes associated with these conditions.We enrolled 7 patients with SLE with lymphoproliferation from different families. Demographic data, clinical manifestations, laboratory and histopathologic findings, treatment, and outcome were documented. Whole-exome sequencing was performed in 7 patients and their families. Suspected variants were confirmed by Sanger sequencing. Protein levels were detected in patients with gene mutations by western blot.Four patients were male, and 3 were female. No consanguinity was reported within the 7 families. The average age at onset was 5.0 years (range: 1.2-10.0 years). The most common features were renal (7/7 patients) and hematologic (6/7 patients) involvement and recurrent fever (6/7 patients), while only 2 patients presented with skin involvement. Antinuclear antibodies at a titer of ≥1:320 were positive in all patients. All patients fulfilled four 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) criteria for the classification of SLE. We identified a somatic activating NRAS variant (c.38 A>G, p.G13C) in peripheral venous blood from 4 patients, at levels ranging from 8.8% to 42.8% in variant tissues that were absent from their parents. B cell lymphoma (BCL)-2-interacting mediator of cell death levels in peripheral blood mononuclear cells from 4 patients were markedly reduced, whereas those in the control were normal. Another 2 mutations, c.559C>T (p.Q187X) in the TNFAIP3 gene and c.3061G>A (p.E1021K) in the PIK3CD gene were detected in 2 patients.The SLE is a novel phenotype of somatic mutations in the NRAS gene and germline mutations in the PI3CKD gene. These genes, NRAS, TNFAIP3, and PIK3CD, should be considered candidates for children with SLE with lymphoproliferation. If patients with SLE and lymphoproliferation present with renal and hematologic involvement and recurrent fever, they need gene testing, especially male patients.

Dataset Information

Identification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups.

Publications

Identification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups.

Similar Datasets

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