VALIDATION OF THE SLE SUSCEPTIBLE GENE LOCI IN THE MULTI-ETHNIC MALAYSIAN SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) COHORT AND THEIR ASSOCIATIONS WITH CLINICAL MANIFESTATION

BackgroundSystemic Lupus erythematous (SLE) is an autoimmune disease with a wide spectrum of clinical manifestations. Asian patients including Malaysia tend to have more severe disease with renal involvement. The differences could be due to the interactions between genetic and environmental factors. Thus, identifying the genetic associations from diverse populations provides a better understanding on the genetic architecture of this heterogeneous disease.ObjectivesThe primary objective of this study was to validate the previously described SLE susceptibility gene loci among other population in the multi-ethnic Malaysian SLE patients. The secondary objective was to determine the association between the gene loci with organ-specific involvement across different Malaysian ethnicities.MethodsThis was a case-control study involving the recruitment of SLE patients who attended the outpatient clinic in Universiti Kebangsaan Malaysia Medical Centre (UKMMC) from July 2019 until March 2021. Their medical records were reviewed to record the socio-demographic characteristics and SLE clinical manifestations. The SLE susceptible gene loci from the NHGRI-EBI Catalog of human genome-wide association studies were reviewed. The gene loci with p values less than 5x10-8 tested in a total sample size of at least 1000 individuals were included in the genotyping study in our SLE patients. Healthy controls with frequency matching by gender and ethnicity-matched were also recruited in this study. Their peripheral blood samples were genotyped using the Agena MassARRAY system (Agena Bioscience). The genotype frequencies of susceptibility loci in all patients and controls were tested for Hardy–Weinberg equilibrium. Associations between phenotype and genotype were performed by logistic regression analysis.ResultsA total of 202 SLE patients and 206 healthy controls were recruited. The SLE cohort consisted of predominant Malay ethnicity (n=126,62.6%) followed by Malaysian Chinese (n=69, 34.2%) and Indian (n=7, 3.5%). After quality control and Hardy–Weinberg equilibrium test, a total of 27 candidate SNPs were genotyped in our study population. Meta-analysis revealed 5 gene loci at SNP rs4544377 (RNU6-546P), rs4917014 (IKZF1), rs1878186 (SLC12A1), rs4728142 (IRF5) and rs5029937 (TNFAIP3) were associated with SLE in Malaysian population (all p value <0.05). In Malay group, rs4544377 (RNU6-546P) and rs4728142 (IRF5) were found to be associated with SLE with adjusted OR 0.42 (95% CI: 0.24-0.74), p=0.002 and OR 3.08 (95% CI: 1.71-5.54), p=0.000169, respectively. In Malaysian Chinese group, rs4917014 (IKZF1) was found to be associated with SLE with OR 0.45 (95% CI: 0.23-0.86), p=0.016. Among Malay patients, rs1878186 (SLC12A1) was found to be associated with skin rash with OR 2.01 (95% CI: 1.20-3.35), p=0.008 while rs4544377 (RNU6-546P) and rs4917014 (IKZF1) were associated with lupus nephritis, with OR 0.48 (95% CI: 0.24-0.96), p=0.039 and OR 3.29 (95% CI: 1.18-9.20), p=0.023. In Malaysian Chinese patients, rs4544377 (RNU6-546P) was associated with muco-cutaneous manifestation with OR 2.82 (95% CI: 1.15-6.92), p=0.023 while rs4728142 (IRF5) was associated with haematological manifestation with OR 5.61 (95% CI: 1.69-18.60), p=0.005.ConclusionOur exploratory study demonstrates the associations of the established SLE genes in Malaysian SLE populations. There are variations in the SLE susceptible gene loci with clinical manifestations of SLE between Malay and Malaysian Chinese populations.References[1]J. E. Molineros, K. H. Chua, C. Sun, L. H. Lian, P. Motghare, X. Kim-Howard, et al. Evaluation of SLE Susceptibility Genes in Malaysians. Autoimmune Diseases 2014 Vol. 2014 Pages 305436AcknowledgementsThis study received funding from the Fundamental Research Grant Scheme (FRGS) of the Ministry of Education, Malaysia (FRGS/1/2018/SKK02/UKM/03/1)Disclosure of InterestsNone declared.