Background/Purpose: Systemic lupus erythematosus (SLE) is a complex chronic autoimmune disease with multi-organ involvement and a strong female predominance. Prior studies demonstrated sex dimorphism in SLE manifestations, with female SLE patients more commonly having malar rash and arthritis, and male SLE patients with a higher prevalence of renal disease. Genetics play a role in SLE risk, but few studies have tested sex chromosome loci for differences in disease manifestations. This study aimed to identify X chromosome loci for SLE sub-phenotypes in a multi-ethnic cohort of children and adults with SLE.

Methods: Our study included patients with childhood-onset (cSLE) and adult-onset (aSLE) from 9 tertiary care centers in North America and Europe who met American College of Rheumatology (ACR) or Systemic Lupus International Collaborating Clinics (SLICC) SLE classification criteria and were genotyped on a multi-ethnic array. Ungenotyped SNPs were imputed using TopMed as a referent. Principal Components (PCs) were generated to account for ancestral variation. Phenotypic variables derived from SLE classification criteria were tested for sex dimorphism in the entire cohort and age stratified groups, with significance set at P < 0.05. An X chromosome analysis was performed for significant SLE phenotypes, controlling for sex and 5 PCs. X-wide significance was set at P < 5 × 10^-8.

Results: Our study included 1553 participants and 88% were female. A total of 819 (53%) were cSLE patients with a median age at diagnosis of 14.1 years (IQR: 11.8 – 15.9), while the median age at diagnosis for aSLE patients was 31.2 years (IQR: 24.8 – 42.4). Among females there was a higher prevalence of arthritis, mucocutaneous features, and hematologic features, while lupus nephritis and anti-Smith, anti-Ro, and anti-RNP antibodies were more prevalent among males. [Table 1.] Chromosome X analyses identified significant loci for hematologic features (rs2768083, OR = 1.92, 95%CI: 1.64 – 2.24; P = 1.39 × 10^-16 and rs139494182, OR = 0.57, 95%CI: 0.47 – 0.69; P = 1.18 × 10^-8), mucocutaneous features (rs1751732, OR = 1.82, 95%CI: 1.53 – 2.15; P = 8.27 × 10^-12), and Ro antibody (rs5939599, OR = 1.69, 95%CI: 1.41 – 2.03; P = 1.83 × 10^-8 and rs34494682, OR = 0.49, 95%CI: 0.38 – 0.63; P = 3.62 × 10^-8). [Figure 1.] Three SNPs on the long arm of Chromosome X associated with hematologic abnormalities, mucocutaneous features, and anti-Ro antibody positivity appear to be in varying degrees of linkage disequilibrium (D’ > 0.9, R² between 0.3 and 0.7).

Conclusion: Our multi-ancestral study of children and adults with SLE identified X chromosome SNPs associated with sex dimorphic SLE features: hematologic abnormalities, mucocutaneous features, and anti-Ro antibody positivity. To further investigate genetics of sexual dimorphism in SLE manifestations, we will complete stratified analyses by ancestry as well as studies into whether any of these loci are expression quantitative trait loci.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genetics-of-sex-dimorphism-in-clinical-manifestations-of-systemic-lupus-erythematosus/