Sex-specific autosomal susceptibility loci in systemic sclerosis: a genome-wide association study.

Although genome-wide association studies (GWAS) have advanced the understanding of systemic sclerosis genetics, sex-aware approaches remain scarce.

尽管全基因组关联研究（GWAS）已经推进了对系统性硬化症遗传学的理解，但考虑到性别的方法仍然稀缺。

We aimed to address this gap by examining autosomal sex-specific genetic factors in systemic sclerosis.

我们旨在通过检查系统性硬化症中的性别特异性常染色体遗传因素来解决这一差距。

Methods

Based on a chromosomal definition of sex, we conducted a sex-stratified autosomal meta-analysisof GWAS in systemic sclerosis.

基于染色体性别定义，我们对系统性硬化症进行了性别分层的常染色体全基因组关联研究的荟萃分析。

We retrieved patient-level and control data from a previous GWAS for systemic sclerosis and newly recruited participants from an international multicentre collaboration (data cutoff June 1, 2024).

我们从之前的一项系统性硬化症全基因组关联研究（GWAS）中检索了患者级别的数据，并从国际多中心合作中招募了新的参与者（数据截止日期为2024年6月1日）。

Adult patients (aged ≥18 years) were required to meet the 2013 American College of Rheumatology-European League Against Rheumatism classification criteria or the criteria for early systemic sclerosis proposed by LeRoy and Medsger, 2001.

成年患者（年龄≥18岁）必须满足2013年美国风湿病学会-欧洲抗风湿病联盟的分类标准，或满足LeRoy和Medsger在2001年提出的早期系统性硬化症标准。

Patients with systemic sclerosis were compared with healthy controls through sex-stratified analyses.

通过性别分层分析，将患有系统性硬化症的患者与健康对照组进行了比较。

Sex-specific loci were functionally annotated and a sex-differential expression analysis was performed to validate the findings.

对性别特异性的位点进行了功能注释，并进行了性别差异表达分析以验证发现。

Additionally, we performed a drug repurposing analysis to explore the clinical implications of our findings.

此外，我们进行了药物再利用分析，以探讨我们发现的临床意义。

People with lived experience of systemic sclerosis were not involved in the study design or conduct.

系统性硬化症患者没有参与研究设计或执行。

Results

After quality control filtering, we included 10 653 patients with systemic sclerosis (1556 male and 9097 female) and 18 043 controls (6990 male and 11 053 female).

经过质量控制筛选后，我们纳入了10,653名系统性硬化症患者（男性1556名，女性9097名）和18,043名对照（男性6990名，女性11,053名）。

We identified eight sex-specific loci associated with systemic sclerosis: one novel male-specific locus (BCL11A odds ratio [OR] 1·32 [95% CI 1·20-1·45], p=8·39 × 10-9), two novel female-specific loci (IRF4 OR 0·78 [0·71-0·85], p=2·36 × 10-8RPL3-PDGFB OR 1·19 [1·12-1·26], p=3·18 × 10-8), and five previously known loci now characterised as female-specific.

我们确定了八个与系统性硬化症相关的性别特异性位点：一个新发现的男性特异性位点（BCL11A比值比[OR] 1.32 [95%置信区间 1.20-1.45], p=8.39 × 10^-9），两个新发现的女性特异性位点（IRF4 OR 0.78 [0.71-0.85], p=2.36 × 10^-8; RPL3-PDGFB OR 1.19 [1.12-1.26], p=3.18 × 10^-8），以及五个之前已知的位点，现在被确定为女性特异性。

Functional analyses implicated 39 candidate genes, of which five (IL12RB2, ARHGAP31, UBL7, CSK, and MPI) showed sex-differential expression in patients with systemic sclerosis.

功能性分析揭示了39个候选基因，其中五个（IL12RB2、ARHGAP31、UBL7、CSK和MPI）在系统性硬化症患者中表现出性别差异表达。

Two approved drugs, fostamatinib and dasatinib, were identified as potential repurposing candidates for systemic sclerosis sex-aware treatment.

确定了两种已批准的药物，fostamatinib和dasatinib，作为系统性硬化症性别意识治疗的潜在再利用候选药物。

interpretation

We report the first evidence of sex-specific genetic architecture in systemic sclerosis.

我们报告了系统性硬化症中性别特异性遗传结构的首个证据。

These findings offer insight into the molecular basis of sex differences in the disease, highlighting both IL12RB2 gene and interferon signalling.

这些发现为疾病中性别差异的分子基础提供了见解，突出了IL12RB2基因和干扰素信号通路。

These results also support the development of sex-aware precision medicine approaches.

这些结果也支持开发性别意识精准医学方法。

funding

Instituto de Salud Carlos III, EU's Seventh Framework Program, and European Federation of Pharmaceutical Industries and Associations companies.

西班牙卡洛斯三世健康研究所、欧盟第七框架计划以及欧洲制药工业和协会联合会公司。