Early disease onset is predicted by a higher genetic risk for lupus and is associated with a more severe phenotype in lupus patients

Abstract

Background: Systemic lupus erythematosus (SLE) is a chronic, multiorgan, autoimmune disease that affects people of all ages and ethnicities.

Objectives: To explore the relationship between age at disease onset and many of the diverse manifestations of SLE. Additionally, to determine the relationship between age of disease onset and genetic risk in patients with SLE.

Methods: The relationship between the age at disease onset and SLE manifestations were explored in a multi-racial cohort of 1317 patients. Patients with SLE were genotyped across 19 confirmed genetic susceptibility loci for SLE. Logistic regression was used to determine the relationships between the number of risk alleles present and age of disease onset.

Results: Childhood-onset SLE had higher odds of proteinuria, malar rash, anti-dsDNA antibody, haemolytic anaemia, arthritis and leucopenia (OR=3.03, 2.13, 2.08, 2.50, 1.89, 1.53, respectively; p values <0.0001, 0.0004, 0.0005, 0.0024, 0.0114, 0.045, respectively). In female subjects, the odds of having cellular casts were 2.18 times higher in childhood-onset than in adult-onset SLE (p=0.0027). With age of onset ≥50, the odds of having proteinuria, cellular casts, anti-nRNP antibody, anti-Sm antibody, anti-dsDNA antibody and seizures were reduced. However, late adult-onset patients with SLE have higher odds of developing photosensitivity than early adult-onset patients. Each SLE-susceptibility risk allele carried within the genome of patients with SLE increased the odds of having a childhood-onset disease in a race-specific manner: by an average of 48% in Gullah and 25% in African-Americans, but this was not significant in Hispanic and European-American lupus patients.

Conclusions: The genetic contribution towards predicting early-onset disease in patients with SLE is quantified for the first time. A more severe SLE phenotype is found in patients with early-onset disease in a large multi-racial cohort, independent of gender, race and disease duration.

Figure 1

Estimated probability of childhood-onset systemic lupus erythematosus (SLE) predicted by the number of risk alleles present. Logistic regression modelling depicting the probability of developing childhood-onset SLE based on the number of SLE susceptibility alleles carried in patients who are European-American (green), African-American (red), Hispanic (purple), and Gullah (blue). The number of SLE risk alleles is associated with the development of childhood-onset disease in Gullah and African-American, but not in Hispanic and European-American patients with SLE.

Figure 2

Estimated number of systemic lupus erythematosus (SLE) risk alleles present as predicted by the age of disease onset. Linear regression analysis showing significant reduction in the number of risk alleles needed to develop SLE with increase age at disease onset in Gullah (blue) and African-American (red) patients with SLE (p=0.0044 and 0.011, respectively), but not Hispanic (purple) or European-American (green) patients (p=0.059 and 0.29, respectively).