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Genetic risk and longitudinal disease activity in systemic lupus erythematosus using targeted maximum likelihood estimation

Genes & Immunity volume 17, pages 358–362 (2016)Cite this article

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Abstract

Systemic lupus erythematous (SLE) is a chronic autoimmune disease associated with genetic and environmental risk factors. However, the extent to which genetic risk is causally associated with disease activity is unknown. We utilized longitudinal-targeted maximum likelihood estimation to estimate the causal association between a genetic risk score (GRS) comprising 41 established SLE variants and clinically important disease activity as measured by the validated Systemic Lupus Activity Questionnaire (SLAQ) in a multiethnic cohort of 942 individuals with SLE. We did not find evidence of a clinically important SLAQ score difference (>4.0) for individuals with a high GRS compared with those with a low GRS across nine time points after controlling for sex, ancestry, renal status, dialysis, disease duration, treatment, depression, smoking and education, as well as time-dependent confounding of missing visits. Individual single-nucleotide polymorphism (SNP) analyses revealed that 12 of the 41 variants were significantly associated with clinically relevant changes in SLAQ scores across time points eight and nine after controlling for multiple testing. Results based on sophisticated causal modeling of longitudinal data in a large patient cohort suggest that individual SLE risk variants may influence disease activity over time. Our findings also emphasize a role for other biological or environmental factors.

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Acknowledgements

We thank Sam Lendle and Josh Schwab for their assistance with the L-TMLE software, as well as Maya Petersen, Alex Luedtke and Alice Baker for their thoughtful feedback. We also thank Paola Bronson for her assistance in developing the genetic risk score, and Lily Hoang for her help with this project. This work was supported by the Lupus Foundation of America (to MAG); Rheumatology Research Foundation (to MAG); National Institutes of Health (Grants P60 AR053308 and K24-AR-02175 to LAC); University of California, San Francisco General Clinical Research Center (Grant R01-AR-44804 to LAC); National Center for Advancing Translational Sciences (Grant UL1-TR-000004 to LAC); and Alliance for Lupus Research (to LAC).

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Author notes

  1. L A Criswell and L F Barcellos: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Epidemiology, University of California, Berkeley, CA, USA

    M A Gianfrancesco, A W Singer & L F Barcellos

  2. Division of Biostatistics, University of California, Berkeley, CA, USA

    L Balzer

  3. Department of Medicine, Rosalind Russell/Ephraim P. Engleman Rheumatology Research Center, University of California, San Francisco, CA, USA

    K E Taylor, L Trupin, J Nititham & L A Criswell

  4. Department of Biochemistry and Molecular Medicine, University of California, Davis, CA, USA

    M F Seldin

Authors
  1. M A Gianfrancesco
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  2. L Balzer
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  3. K E Taylor
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  4. L Trupin
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  8. L A Criswell
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Correspondence to L F Barcellos.

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Gianfrancesco, M., Balzer, L., Taylor, K. et al. Genetic risk and longitudinal disease activity in systemic lupus erythematosus using targeted maximum likelihood estimation. Genes Immun 17, 358–362 (2016). https://doi.org/10.1038/gene.2016.33

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