Genetic basis for the heterogeneity of systemic lupus erythematosus (SLE) : population difference and female predominance

Abstract

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a strong genetic basis, showing significant disparities between populations and extreme female predominance.

Owing to the advent of high-throughput genotyping and computation technologies, significant advances have been made in understanding the genetic predisposition of SLE over the past decades. The application of genome-wide association studies (GWAS) have identified more than 90 loci conferring SLE susceptibility, which has significantly improved our understanding of the disease. However, while Asians and other non-European populations are known to have higher prevalence and suffer from more severe disease outcomes, previous SLE genetic studies have focused disproportionally on European populations. Therefore, the genetic basis for the population heterogeneity of SLE have not been thoroughly investigated. In addition, epidemiological studies have shown that females have a significantly higher incidence and prevalence of SLE in almost all ethnicities concerned and in all age groups. Sex differences in severity, mortality, and clinical manifestations were also observed. Although some theories about hormonal modulations have been proposed to explain this, little is known about the genetic basis for the female predominance of the disease.

In the current thesis, I have made effort to reveal the genetic basis for the heterogeneity of SLE, on both the population differences and female predominance of the disease. To better understand the genetic basis for population heterogeneity of SLE, I performed a genome-wide association study, increasing the sample size of East Asian populations to a comparable level of existing European studies. Trans-ethnic meta-analysis have identified 38 novel loci associated with SLE. By comparing the results from respective meta-analysis in East Asian and European populations, I observed nine disease loci presented with clear population heterogeneity, which suggested that antibody production might be a potential mechanism for population difference. To decipher the genetic basis for the female predominance of SLE, I performed a X chromosomal-focused association analysis on four cohorts of both East Asian and European origin. A single-nucleotide polymorphism (SNP), rs13440883 located in GPR173 gene, was identified as significantly associated with SLE. Conditional analysis revealed evidence of a potential independent signal in L1CAM-IRAK1-MECP2 as well. These findings highlighted the contribution of X chromosome to SLE aetiology and its potential role in SLE female predominance.

In summary, by increasing sample size of East Asian populations and by doing a X chromosome-specific analysis, I have detected novel genetic loci associated with SLE, some of which have demonstrated clear differences between East Asians and Europeans. These findings may help improve our understanding of the genetic basis for population differences and female predominance of SLE. These findings and future functional studies of them will help provide additional insight on disease risk prediction and personalized treatment of this prototype autoimmune disorder.