Comment on: Meta-analysis of 208370 East Asians identifies 113 susceptibility loci for systemic lupus erythematosus. Xianyong Yin, Kwangwoo Kim, Hiroyuki Suetsugu et al. Ann Rheum Dis 2020 Dec 3;annrheumdis-2020-219209. doi: 10.1136/annrheumdis-2020-219209. Online ahead of print.
Commented by: Maria G. Tektonidou, First Department of Propaedeutic Internal Medicine, Laiko Hospital, Medical School, National and Kapodistrian University of Athens, Greece.
Over the past decades, an enormous progress has been made in the identification of genetic factors that contribute to the development of SLE (1). Despite the fact that more than 100 genetic loci have been found to be more prevalent in SLE compared to the general population, these explain only about 30% of SLE heritability. In many of the GWAS conducted, there is low representation of specific groups like East Asians although epidemiological studies showed a high prevalence of SLE in these groups (2, 3). Given the genetic and phenotypic differences between Europeans and East Asians, Yin et al conducted a large genome-wide meta-analysis (GWAS) study in East Asian individuals with SLE.
In this study, 3 different case-control cohorts from 3 East Asian countries (China, Korea and Japan) were combined, reaching a total number of 10.029 SLE cases and 180.167 healthy controls. Additional data from 3348 SLE cases and 14 826 controls published previously in East Asian SLE GWAS were analysed. In total, 13.377 SLE cases and 194.993 controls were included in the meta-analysis; 26.379 genetic variants in 113 loci reached the level of statistical significance for GWAS (p<5×10−8) and 46 of them were novel. Noteworthy, in 7 of these novel loci, minor allele frequency (MAF) of the lead SNP was 10-times higher in East Asians compared to Europeans.
New exonic variants were identified at two novel (CHD23 and LRRK1) and three known (CSK, IKBKB and TYK2) loci. In the latter, the new exonic variants were not correlated with those previously reported in the same genes. From the exonic variants reported, those pertain to the newly identified loci (CHD23 and LRRK1) are implicated in cell migration, B-cell proliferation and NFκΒ activation. Using GCTA analysis based on linkage disequilibrium (LD) estimated from 7021 unrelated Chinese non-SLE individuals, 233 independent association signals were recorded. From these, 110 putative causal variants for 57 SLE loci were identified and 10 [four known: ATXN2,BACH2, DRAM1/WASHC3 and NCF2 and six novel: 17p13.1, ELF3, GTF2H1, LRRK1, LOC102724596/PHB and STIM1) most likely putative causal variants with posterior probability ≥0.8 were further prioritized. In addition, significant positive genetic correlations were found between SLE and two other autoimmune disorders, rheumatoid arthritis (rg =0.437) and Graves’ disease (rg=0.318). Significant genetic correlations were also found between SLE and albumin/globulin ratio (rg =−0.242) and non-albumin protein(rg=0.238).
In summary, this is the largest GWAS study for SLE in East Asian populations identifying 46 novel susceptibility loci for SLE risk that can also help to better understand the phenotypic diversity of SLE between Asians and Europeans. A limitation of the study highlighted also by the authors is the small linkage disequilibrium reference panel from single population in the in the Bayesian statistical fine-mapping analysis. The study demonstrated for the first time significant genetic correlations between SLE, albumin/globulin ratio and higher serum globulin suggesting a common pathway underlying the SLE risk and kidney function.
- Bentham J, Morris DL, Graham DSC, et al. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat Genet 2015;47:1457–6
- Morris DL, Yujun Sheng Y, Yan Zhang Y, et al. Genome-wide association meta-analysis in Chinese and European individuals identifies ten new loci associated with systemic lupus erythematosus. Nat Genet. 2016 Aug;48(8):940-946. doi: 10.1038/ng.3603.
- Osio-Salido E, Manapat-Reyes H: Epidemiology of systemic lupus erythematosus in Asia. Lupus 2010; 19: 1365–1373.