Khan Atlas, Karakoc Gul, Liu Ge, Zanussi Jacy, Olsen Nancy J, Shi Mingjian, Cox Nancy J, Mosley Jonathan, Stein Charles Michael, Kiryluk Krysztof, Wei Wei-Qi, Mentch Frank, Hebbring Scott, Linneman James, Kawai Vivian
Columbia University Vagelos College of Physicians and Surgeons, New York city, New York, USA.
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Lupus Sci Med. 2025 Jun 12;12(1):e001476. doi: 10.1136/lupus-2024-001476.
We defined the genetic factors associated with a positive ANA test (ANA+) in the absence of autoimmune disease and tested the association with SLE.
Using a case-control design, we performed a genome-wide association study (GWAS) in individuals of European ancestry without an autoimmune disease who had ANA tested as part of clinical care from DNA biobanks linked to de-identified electronic medical records: BioVU and Electronic Medical Records and Genomics. GWAS results were meta-analysed and single nucleotide polymorphism (SNP) heritability was calculated. A polygenic risk score (PRS) for ANA+ and for SLE was constructed and compared in patients with SLE, ANA+ and ANA negative (ANA-) individuals without autoimmune disease and general controls who never had ANA testing performed.
A total of 7287 individuals of European ancestry were included in the meta-analyses (2169 ANA+ and 5118 ANA-); an SNP upstream of the in the HLA locus (rs1967688) was associated with ANA+ (p=4.84×10). SNP heritability for ANA+ was low (h = 0.04), and the PRS for ANA+ was not significantly different in ANA+ and ANA- individuals. In contrast, the PRS for SLE was significantly higher in SLE compared with ANA+ individuals (p<2.2×10) but did not differ among ANA+, ANA- and general control groups (p=0.17).
ANA+ occurring in the absence of autoimmune disease has a genetic association with the region, but overall heritability is low. In addition, few SLE-associated SNPs were associated with ANA+, and the PRS for SLE was not associated with ANA+, indicating limited genetic overlap.
我们确定了在无自身免疫性疾病情况下与抗核抗体检测阳性（ANA+）相关的遗传因素，并测试了其与系统性红斑狼疮（SLE）的关联。
采用病例对照设计，我们对欧洲血统且无自身免疫性疾病的个体进行了全基因组关联研究（GWAS），这些个体的ANA检测作为与去识别化电子病历相关的DNA生物样本库临床护理的一部分：BioVU和电子病历与基因组学。对GWAS结果进行荟萃分析并计算单核苷酸多态性（SNP）遗传力。构建了ANA+和SLE的多基因风险评分（PRS），并在SLE患者、ANA+和无自身免疫性疾病的ANA阴性（ANA-）个体以及从未进行过ANA检测的一般对照中进行比较。
荟萃分析共纳入7287名欧洲血统个体（2169名ANA+和5118名ANA-）；HLA基因座中 上游的一个SNP（rs1967688）与ANA+相关（p = 4.84×10）。ANA+的SNP遗传力较低（h = 0.04），ANA+个体和ANA-个体的ANA+ PRS无显著差异。相比之下，SLE患者的SLE PRS显著高于ANA+个体（p<2.2×10），但在ANA+、ANA-和一般对照组之间无差异（p = 0.17）。
在无自身免疫性疾病情况下出现的ANA+与该 区域存在遗传关联，但总体遗传力较低。此外，很少有与SLE相关的SNP与ANA+相关，SLE的PRS与ANA+无关，表明遗传重叠有限。
