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Genes Immun. 2016 Sep;17(6):358-62. doi: 10.1038/gene.2016.33. Epub 2016 Jul 28.

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

Author information

1
Division of Epidemiology, University of California, Berkeley, CA, USA.
2
Division of Biostatistics, University of California, Berkeley, CA, USA.
3
Department of Medicine, Rosalind Russell/Ephraim P. Engleman Rheumatology Research Center, University of California, San Francisco, CA, USA.
4
Department of Biochemistry and Molecular Medicine, University of California, Davis, CA, USA.

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.

PMID:
27467283
PMCID:
PMC5008986
DOI:
10.1038/gene.2016.33
[Indexed for MEDLINE]
Free PMC Article

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