Admixture in Hispanic Americans: its impact on ITGAM association and implications for admixture mapping in SLE.
ABSTRACT: Systemic Lupus Erythematosus (SLE) disproportionately affects minorities, such as Hispanic Americans (HA). Prevalence of SLE is 3-5 times higher in HA than in European-derived populations and have more active disease at the time of diagnosis, with more serious organ system involvement. HA is an admixed population, it is possible that there is an effect of admixture on the relative risk of the disease. This admixture can create substantial increase of linkage disequilibrium (LD) in both magnitude and range, which can provide a unique opportunity for admixture mapping. The main objectives of this study are to (a) estimate hidden population structure in HA individuals; (b) estimate individual ancestry proportions and its impact on SLE risk; (c) assess impact of admixture on ITGAM association, a recently identified SLE susceptibility gene; and (d) estimate power of admixture mapping in HA. Our dataset contained 1125 individuals, of whom 884 (657 SLE cases and 227 controls) were self-classified as HA. Using 107 unlinked ancestry informative markers (AIMs), we estimated hidden population structure and individual ancestry in HA. Out of 5671 possible pairwise LD, 54% were statistically significant, indicating recent population admixture. The best-fitted model for HA was a four-population model with average ancestry of European (48%), American-Indian (AI) (40%), African (8%) and a fourth population (4%) with unknown ancestry. We also identified significant higher risk associated with AI ancestry (odds ratio (OR)=4.84, P=0.0001, 95% CI (confidence interval)=2.14-10.95) on overall SLE. We showed that ITGAM is associated as a risk factor for SLE (OR=2.06, P=8.74 x 10(-5), 95% CI=1.44-2.97). This association is not affected by population substructure or admixture. We have shown that HA have great potential and are an appropriate population for admixture mapping. As expected, the case-only design is more powerful than case-control design, for any given admixture proportion or ancestry risk ratio.
Project description:Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease with a strong genetic component. African-Americans (AA) are at increased risk of SLE, but the genetic basis of this risk is largely unknown. To identify causal variants in SLE loci in AA, we performed admixture mapping followed by fine mapping in AA and European-Americans (EA). Through genome-wide admixture mapping in AA, we identified a strong SLE susceptibility locus at 2q22-24 (LOD=6.28), and the admixture signal is associated with the European ancestry (ancestry risk ratio ~1.5). Large-scale genotypic analysis on 19,726 individuals of African and European ancestry revealed three independently associated variants in the IFIH1 gene: an intronic variant, rs13023380 [P(meta) = 5.20×10(-14); odds ratio, 95% confidence interval = 0.82 (0.78-0.87)], and two missense variants, rs1990760 (Ala946Thr) [P(meta) = 3.08×10(-7); 0.88 (0.84-0.93)] and rs10930046 (Arg460His) [P(dom) = 1.16×10(-8); 0.70 (0.62-0.79)]. Both missense variants produced dramatic phenotypic changes in apoptosis and inflammation-related gene expression. We experimentally validated function of the intronic SNP by DNA electrophoresis, protein identification, and in vitro protein binding assays. DNA carrying the intronic risk allele rs13023380 showed reduced binding efficiency to a cellular protein complex including nucleolin and lupus autoantigen Ku70/80, and showed reduced transcriptional activity in vivo. Thus, in SLE patients, genetic susceptibility could create a biochemical imbalance that dysregulates nucleolin, Ku70/80, or other nucleic acid regulatory proteins. This could promote antibody hypermutation and auto-antibody generation, further destabilizing the cellular network. Together with molecular modeling, our results establish a distinct role for IFIH1 in apoptosis, inflammation, and autoantibody production, and explain the molecular basis of these three risk alleles for SLE pathogenesis.
Project description:Systemic Lupus Erythematosus (SLE) is an autoimmune inflammatory disorder for which Major Histocompatibility Complex (MHC) genes are well identified as risk factors. SLE patients present different clinical phenotypes, which are partly explained by admixture patterns variation among Mexicans. Population genetic has insight into the high genetic variability of Mexicans, mainly described through HLA gene studies with anthropological and biomedical importance. A prospective, case-control study was performed. In this study, we recruited 146 SLE patients, and 234 healthy individuals were included as a control group; both groups were admixed Mexicans from Mexico City. The HLA typing methods were based on Next Generation Sequencing and Sequence-Based Typing (SBT). The data analysis was performed with population genetic programs and statistical packages. The admixture estimations based on HLA-B and -DRB1 revealed that SLE patients have a higher Southwestern European ancestry proportion (48 ± 8%) than healthy individuals (30 ± 7%). In contrast, Mexican Native American components are diminished in SLE patients (44 ± 1%) and augmented in Healthy individuals (63 ± 4%). HLA alleles and haplotypes' frequency analysis found variants previously described in SLE patients from Mexico City. Moreover, a conserved extended haplotype that confers risk to develop SLE was found, the HLA-A<sup>∗</sup>29:02∼C<sup>∗</sup>16:01∼B<sup>∗</sup>44:03∼DRB1<sup>∗</sup>07:01∼DQB1<sup>∗</sup>02:02, <i>p</i>C = 0.02, OR = 1.41. Consistent with the admixture estimations, the origin of all risk alleles and haplotypes found in this study are European, while the protection alleles are Mexican Native American. The analysis of genetic distances supported that the SLE patient group is closer to the Southwestern European parental populace and farthest from Mexican Native Americans than healthy individuals. Heterogeneity of genetic admixture determines SLE susceptibility