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Meta-Analysis
. 2025 Mar;77(3):356-361.
doi: 10.1002/art.43032. Epub 2024 Nov 14.

Genetic Analysis of Asymptomatic Antinuclear Antibody Production

Mehmet Hocaoǧlu  1 , Desiré Casares-Marfil  1 , Amr H Sawalha  1
Affiliations
Meta-Analysis

Genetic Analysis of Asymptomatic Antinuclear Antibody Production

Mehmet Hocaoǧlu et al. Arthritis Rheumatol. 2025 Mar.

Abstract

Objective: Antinuclear antibodies (ANA) are detected in up to 14% of the population, and many individuals with ANA are asymptomatic. The literature on the genetic contribution to asymptomatic ANA positivity is limited. In this study, we aimed to perform a genome-wide association study of asymptomatic ANA positivity in multiple populations.

Methods: Asymptomatic individuals who were either ANA positive or ANA negative from the All of Us Research Program were included in this study, selecting those with an ANA test performed by immunofluorescence and no evidence of autoimmune disease. Imputation was performed, and a multipopulation meta-analysis including approximately 6 million single-nucleotide polymorphisms (SNPs) was conducted. Genome-wide SNP-based heritability was estimated using the Genome-wide Complex Trait Analysis software. A cumulative genetic risk score for lupus was constructed using previously reported genome-wide significant loci.

Results: A total of 1,955 asymptomatic ANA positive and 3,634 asymptomatic ANA negative individuals across three populations were included. The multipopulation meta-analysis revealed SNPs with a suggestive association (P <1 × 10-5) across 8 different loci, but no genome-wide significant loci were identified. A gene variant upstream of HLA-DQB1, (rs17211748, P = 1.4 × 10-6, odds ratio 0.82, 95% confidence interval 0.76-0.89), showed the most significant association. The heritability of asymptomatic ANA positivity was estimated to be 24.9%. Individuals who were asymptomatic and ANA positive did not exhibit increased cumulative genetic risk for lupus compared with individuals who were ANA negative.

Conclusion: ANA production is not associated with significant genetic risk and is primarily determined by environmental factors.

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Figures

Figure 1
Figure 1
A Manhattan plot depicting the results from the meta‐analysis across genetic similarity groups comparing individuals who were asymptomatic and ANA positive with individuals who were asymptomatic and ANA negative. The Y and X axes refer to the −log10 P values and chromosome positions, respectively. The red horizontal line represents the genome‐wide association threshold (P < 5 × 10−8), and the blue line represents the suggestive association threshold (P < 1×10−5). Blue and orange dots represent individual SNPs. ANA, antinuclear antibody.
Figure 2
Figure 2
Comparison of cumulative genetic risk scores for SLE in individuals who were asymptomatic and ANA positive, individuals who were asymptomatic and ANA negative, and patients with SLE of (A) European genetic similarity, (B) African genetic similarity, and (C) Admixed American genetic similarity. Dashed lines represent the means of cumulative genetic risk score of each group. ANA, antinuclear antibody; SLE, systemic lupus erythematosus.
See this image and copyright information in PMC

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References

    1. Bossuyt X, De Langhe E, Borghi MO, et al. Understanding and interpreting antinuclear antibody tests in systemic rheumatic diseases. Nat Rev Rheumatol 2020;16(12):715–726. - PubMed
    1. Satoh M, Chan EK, Ho LA, et al. Prevalence and sociodemographic correlates of antinuclear antibodies in the United States. Arthritis Rheum 2012;64(7):2319–2327. - PMC - PubMed
    1. Miller FW. The increasing prevalence of autoimmunity and autoimmune diseases: an urgent call to action for improved understanding, diagnosis, treatment, and prevention. Curr Opin Immunol 2023;80:102266. - PMC - PubMed
    1. Parks CG, Miller FW, Satoh M, et al. Reproductive and hormonal risk factors for antinuclear antibodies (ANA) in a representative sample of U.S. women. Cancer Epidemiol Biomarkers Prev 2014;23(11):2492–2502. - PMC - PubMed
    1. Terao C, Ohmura K, Yamada R, et al; Nagahama Study Group . Association between antinuclear antibodies and the HLA class II locus and heterogeneous characteristics of staining patterns: the Nagahama study. Arthritis Rheumatol 2014;66(12):3395–3403. - PubMed

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