Genome‐Wide Association Study in an Amerindian Ancestry Population Reveals Novel Systemic Lupus Erythematosus Risk Loci and the Role of European Admixture

Abstract

OBJECTIVES Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a strong genetic component. Our aim was to perform the first genome-wide association study on individuals from the Americas enriched for Native American heritage. MATERIALS and METHODS We analyzed 3,710 individuals from four countries of Latin America and the Unites States diagnosed with SLE and healthy controls. Samples were genotyped with the HumanOmni1 BeadChip. Data of out-of-study controls was obtained for the HumanOmni2.5. Statistical analyses were performed using SNPTEST and SNPGWA. Data was adjusted for genomic control and FDR. Imputation was done using IMPUTE2, and HiBAG for classical HLA alleles. RESULTS The IRF5-TNPO3 region showed the strongest association and largest odds ratio (OR) (rs10488631, Pgcadj = 2.61×10−29, OR = 2.12, 95% CI: 1.88–2.39) followed by the HLA class II on the DQA2-DQB1 loci (rs9275572, Pgcadj = 1.11 × 10−16, OR = 1.62, 95% CI: 1.46–1.80; rs9271366, Pgcadj=6.46 × 10−12, OR = 2.06, 95% CI: 1.71–2.50). Other known SLE loci associated were ITGAM, STAT4, TNIP1, NCF2 and IRAK1. We identified a novel locus on 10q24.33 (rs4917385, Pgcadj =1.4×10−8) with a eQTL effect (Peqtl=8.0 × 10−37 at USMG5/miR1307), and describe novel loci. We corroborate SLE-risk loci previously identified in European and Asians. Local ancestry estimation showed that HLA allele risk contribution is of European ancestral origin. Imputation of HLA alleles suggested that autochthonous Native American haplotypes provide protection. CONCLUSIONS Our results show the insight gained by studying admixed populations to delineate the genetic architecture that underlies autoimmune and complex diseases.

The VEGFA ‐1154G/A polymorphism is associated with reduced risk of rheumatoid arthritis but not with systemic lupus erythematosus in Mexican women

“…In addition, in the GWAS, several hundred or thousands of markers are removed, particularly by high error rates, including SNPs with an excessive missing genotype . Hence, we cannot discard the possibility that the controversial results found in the present study and those observed in GWAS (which included Mexican patients with SLE) are influenced by the aforementioned aspects . However, it is necessary to carry out additional studies in Mexican patients (and other Latin American populations) with RA or SLE to confirm our findings.…”

“…43 Hence, we cannot discard the possibility that the controversial results found in the present study and those observed in GWAS (which included Mexican patients with SLE) are influenced by the aforementioned aspects. 34,35 However, it is necessary to carry out additional studies in Mexican patients (and other Latin American populations) with RA or SLE to confirm our findings. It should be noted that the statistical power of the present study was 92% for RA and 93% for SLE [taking into account the frequency of the VEGFA -1154A allele and the prevalence of RA (1.6%) and SLE (0.06%) in Mexicans].…”

Multiple variants in 5q31.1 are associated with systemic lupus erythematosus susceptibility and subphenotypes in the Han Chinese population

“…1,11 Consequently, candidate gene studies and genome-wide association studies (GWAS) have been performed and identified over 70 risk genes associated with SLE that achieve genome-wide significance level (P < 5 9 10 À8 ). [12][13][14][15][16][17][18][19][20][21] Many of these genes participate in known pathways relevant to SLE pathogenesis that are key to innate and adaptive immune responses, lymphocyte activation, and clearance of immune complexes and apoptotic cells. 22 In 2011, a single-nucleotide polymorphism (SNP) rs7704116 in PPP2CA on chromosome 5q31.1 was found to be associated across multi-ancestral SLE cohorts that included Hispanic American, European American and Asian populations (Korea).…”

“…The heritability of SLE was estimated to be 43·9%, suggesting a strong genetic component to its pathogenesis . Consequently, candidate gene studies and genome‐wide association studies (GWAS) have been performed and identified over 70 risk genes associated with SLE that achieve genome‐wide significance level ( P < 5 × 10 −8 ) . Many of these genes participate in known pathways relevant to SLE pathogenesis that are key to innate and adaptive immune responses, lymphocyte activation, and clearance of immune complexes and apoptotic cells …”

The association of the UHRF1BP1 gene with systemic lupus erythematosus was replicated in a Han Chinese population from mainland China

“…Although the exact etiology of SLE is not fully understood, the familial aggregation of SLE suggests an important contribution of genetics to SLE susceptibility (Kuo et al., ). To date, genome‐wide association studies (GWAS) and candidate gene studies have discovered more than 80 genetic loci with SLE risk that achieve genome‐wide significance ( P < 5 × 10 −8 ) (Alarcon‐Riquelme et al., ; Bentham et al., ; Han et al., ; Langefeld et al., ; Lessard et al., ; Morris et al., ; Sun et al., ; Wen et al., 2017, ). So far, most of the genetic risk loci are shared across borders and ethnicities.…”