Genetic Alleles Associated with SLE Susceptibility and Clinical Manifestations in Hispanic Patients from the Dominican Republic

Abstract

Purpose: Systemic lupus erythematosus (SLE) is a complex autoimmune disease with marked disparities in prevalence and disease severity among different ethnic groups. The purpose of this study is to characterize a Latin American cohort and identify genetic risk factors for developing SLE and its end-organ manifestations in this Latin Hispanic cohort. Methods: In this cohort, SNP rs9271366 (tag SNP for HLA-DRB1*15:01) confers the highest risk for SLE among the 13 MHC gene alleles that display association with SLE (p = 8.748E-10; OR = 3.5). Among the 26 non-MHC gene alleles analyzed, SNP rs2476601 in PTPN22 gene confers the highest risk for SLE (p = 0.0001; OR = 5.6). ITGAM, TNFSF4, TNIP1, STAT4, CARD11, BLK, and TNXB gene alleles were confirmed as SLE-susceptible alleles in the DR cohort. However, IRF5 and TNFAIP3 gene alleles, established risk factors for SLE in populations of European and Asian ancestry, are not significantly associated with SLE in this cohort. We also defined a novel HLA-DRA haplotype that confers an increased risk for lupus nephritis (LN) and alleles in HLA-DRA2 and TNFSF4 genes as genetic risk factors for developing neuropsychiatric (NP) SLE. Results: In this cohort, SNP rs9271366 (tag SNP for HLA-DRB1*15:01) confers the highest risk for SLE among the 13 MHC gene alleles that display association with SLE (p = 8.748E-10; OR = 3.5). Among the 26 non-MHC gene alleles analyzed, SNP rs2476601 in PTPN22 gene confers the highest risk for SLE (p = 0.0001; OR = 5.6). ITGAM, TNFSF4, TNIP1, STAT4, CARD11, BLK, and TNXB gene alleles were confirmed as SLE-susceptible alleles in the DR cohort. However, IRF5 and TNFAIP3 gene alleles, established risk factors for SLE in populations of European and Asian ancestry, are not significantly associated with SLE in this cohort. We also defined a novel HLA-DRA haplotype that confers an increased risk for lupus nephritis (LN) and alleles in HLA-DRA2 and TNFSF4 genes as genetic risk factors for developing neuropsychiatric (NP) SLE. Conclusion: Our data suggest that the Latin American population shares some common genetic risk factors for SLE as other populations, but also has distinct risk gene alleles that contribute to SLE susceptibility and development of LN and NPSLE. This is the first study focusing on genetic risk factors for SLE in the DR, a Latin American population that has never been characterized before.

Correlations of Expression Levels of a Panel of Genes (IRF5, STAT4, TNFSF4, MECP2, and TLR7) and Cytokine Levels (IL-2, IL-6, IL-10, IL-12, IFN-γ, and TNF-α) with Systemic Lupus Erythematosus Outcomes in Jordanian Patients

“…Correlation studies between pairs of genes and between cytokines and associations of genes and cytokines with clinical manifestations indicate that STAT4 and TNFSF4 genes and cytokines such as TNF- α and IL-10 might be helpful biomarkers to assess disease activity and manage treatment protocols. This is interesting since a recent study showed that populations from different geographic regions share common genetic risk factors for SLE [57]. Finally, this work may have diagnostic and therapeutic implications and provides some insights into the pathogenesis of SLE patients and gives some guidance to clinicians in determining the disease activity and development and in managing treatment protocols based on cytokines and gene expression profiles for patients.…”

Immune cell infiltration characteristics and related core genes in lupus nephritis: results from bioinformatic analysis

“…Key mediator of angiostatic effects of inflammation and is induced by interferon (IFN)-α and IFN-γ.Liu, et al [34] 10.1007/s10067-018-4138-7 CD36BloodExpresses on the cell surface of monocyte/macrophages and involved in the recognition and uptake of pro-atherogenic oxidized low-density lipoprotein (LDL).Reiss, et al [35] 10.3181/0806-BC-194 FCER1GSpleenAssociated with multiple leukocyte receptor complexes and mediates signal transduction.Sweet, et al [36] 10.4049/jimmunol.1600861 CLEC7ABloodInvolved in the clearance of apoptotic cells, uptake and presentation of cellular antigens and triggers different cytokines and chemokines.Salazar-Aldrete, et al [37] 10.1007/s10875-012-9821-x ITGB2Bone MarrowEncodes integrin β2 protein (CD18). Plays important roles in leukocyte adhesion, immune and inflammatory reactions, immigration through endothelial and chemotaxis.Zimmer, et al [38] 10.1371/journal.pone.0013351 LILRB4BloodAssociated with increased inflammatory cytokine levels in SLE and is expressed by many leukocytes.Jensen, et al [39] 10.1136/annrheumdis-2012-202024 HLA − DRABloodSLE susceptibility genes and plays a central role in the immune system by presenting peptides derived from extracellular proteins.Liu, et al [40] 10.2174/1566524019666190424130809 PSMB9SkinUpregulates in the pathophysiology of cutaneous lesions of dermatomyositis and SLE.Nakamura, et al [41] 10.1111/bjd.14385 BTKBloodPlays an important role in both B cell and FcgammaR mediated myeloid cell activation. BTK inhibition may be a promising treatment approach for lupus nephritis.Kong, et al [42] 10.1007/s10067-017-3717-3 PYCARDBloodForms inflammasome complexes mediate the inflammatory and apoptotic signaling pathways.Shin, et al [43] 10.1002/art.40672 CFPBloodThe only positive regulator of the complement system.…”

Immune cell infiltration characteristics and related core genes in lupus nephritis: results from bioinformatic analysis

“…Through a review of documents about lupus and related genes [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48], 15 core genes related to clinical manifestation were found to be associated in autoimmune disease (Table 1). FCER1G, CLEC7A, MARCO, CLEC7A, PSMB9, and PSMB8 showed apparent correlation with clinical manifestation.…”