Genetically determined Amerindian ancestry correlates with increased frequency of risk alleles for systemic lupus erythematosus.

OBJECTIVE To assess whether genetically determined Amerindian ancestry predicts increased presence of risk alleles of known susceptibility genes for systemic lupus erythematosus (SLE). METHODS Single-nucleotide polymorphisms (SNPs) within 16 confirmed genetic susceptibility loci for SLE were genotyped in a set of 804 Mestizo lupus patients and 667 Mestizo healthy controls. In addition, 347 admixture informative markers were genotyped. Individual ancestry proportions were determined using STRUCTURE. Association analysis was performed using PLINK, and correlation between ancestry and the presence of risk alleles was analyzed using linear regression. RESULTS A meta-analysis of the genetic association of the 16 SNPs across populations showed that TNFSF4, STAT4, ITGAM, and IRF5 were associated with lupus in a Hispanic Mestizo cohort enriched for European and Amerindian ancestry. In addition, 2 SNPs within the major histocompatibility complex region, previously shown to be associated in a genome-wide association study in Europeans, were also associated in Mestizos. Using linear regression, we predicted an average increase of 2.34 risk alleles when comparing an SLE patient with 100% Amerindian ancestry versus an SLE patient with 0% Amerindian ancestry (P < 0.0001). SLE patients with 43% more Amerindian ancestry were predicted to carry 1 additional risk allele. CONCLUSION Our results demonstrate that Amerindian ancestry is associated with an increased number of risk alleles for SLE.

[1]  M. Alarcón‐Riquelme,et al.  Lower expression levels of the programmed death 1 receptor on CD4+CD25+ T cells and correlation with the PD-1.3A genotype in patients with systemic lupus erythematosus. , 2010, Arthritis and rheumatism.

[2]  A. Delgado-Vega,et al.  Replication of the TNFSF4 (OX40L) promoter region association with systemic lupus erythematosus , 2009, Genes and Immunity.

[3]  J. Molineros,et al.  Admixture in Hispanic-Americans: Its impact on ITGAM association and implications for admixture mapping in SLE , 2009, Genes and Immunity.

[4]  Gabriel Silva,et al.  Ancestry informative marker sets for determining continental origin and admixture proportions in common populations in America , 2009, Human mutation.

[5]  N. Eriksson,et al.  STAT4 associates with systemic lupus erythematosus through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk , 2008, Annals of the rheumatic diseases.

[6]  J. Belmont,et al.  Amerindian ancestry in Argentina is associated with increased risk for systemic lupus erythematosus , 2008, Genes and Immunity.

[7]  David Reich,et al.  Principal component analysis of genetic data , 2008, Nature Genetics.

[8]  J. Wojcik,et al.  Corrigendum: Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus , 2008, Nature Genetics.

[9]  Geoffrey Hom,et al.  Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. , 2008, The New England journal of medicine.

[10]  Sandra D'Alfonso,et al.  Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus , 2008, Nature Genetics.

[11]  Wei Chen,et al.  A nonsynonymous functional variant in integrin-αM (encoded by ITGAM) is associated with systemic lupus erythematosus , 2008, Nature Genetics.

[12]  Marta E Alarcón-Riquelme,et al.  Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci , 2008, Nature Genetics.

[13]  P. Lipsky,et al.  Genetic association of interleukin-21 polymorphisms with systemic lupus erythematosus , 2007, Annals of the rheumatic diseases.

[14]  David Altshuler,et al.  Polymorphism at the TNF superfamily gene TNFSF4 confers susceptibility to systemic lupus erythematosus , 2008, Nature Genetics.

[15]  Wentian Li,et al.  STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. , 2007, The New England journal of medicine.

[16]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[17]  Annette Lee,et al.  A genomewide single-nucleotide-polymorphism panel for Mexican American admixture mapping. , 2007, American journal of human genetics.

[18]  L. Orozco,et al.  Genetic association of IRF5 with SLE in Mexicans: higher frequency of the risk haplotype and its homozygozity than Europeans , 2007, Human Genetics.

[19]  Michael P Epstein,et al.  A simple and improved correction for population stratification in case-control studies. , 2007, American journal of human genetics.

[20]  J. Belmont,et al.  Argentine population genetic structure: large variance in Amerindian contribution. , 2007, American journal of physical anthropology.

[21]  Jesús K. Estrada-Gil,et al.  Association of PDCD1 polymorphisms with childhood-onset systemic lupus erythematosus , 2007, European Journal of Human Genetics.

[22]  P. Lipsky,et al.  OR.81Genetic Association of IL-21 Polymorphisms with Systemic Lupus Erythematosus , 2007 .

[23]  D. Reich,et al.  Population Structure and Eigenanalysis , 2006, PLoS genetics.

[24]  J. Wojcik,et al.  A Fast, Unbiased and Exact Allelic Test for Case-Control Association Studies , 2006, Human Heredity.

[25]  N. Bottini,et al.  Role of PTPN22 in type 1 diabetes and other autoimmune diseases. , 2006, Seminars in immunology.

[26]  D. Reich,et al.  Principal components analysis corrects for stratification in genome-wide association studies , 2006, Nature Genetics.

[27]  Marta E Alarcón-Riquelme,et al.  A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus , 2006, Nature Genetics.

[28]  J. Reveille,et al.  Systemic lupus erythematosus in a multi-ethnic cohort (LUMINA): contributions of admixture and socioeconomic status to renal involvement , 2006 .

[29]  Gudmundur A. Thorisson,et al.  The International HapMap Project Web site. , 2005, Genome research.

[30]  J. Heward,et al.  HLA, CTLA-4 and PTPN22: the shared genetic master-key to autoimmunity? , 2005, Expert Reviews in Molecular Medicine.

[31]  Hongzhe Li,et al.  Examination of ancestry and ethnic affiliation using highly informative diallelic DNA markers: application to diverse and admixed populations and implications for clinical epidemiology and forensic medicine , 2005, Human Genetics.

[32]  M. Feldmann,et al.  Molecular therapeutic targets in rheumatoid arthritis , 2005, Expert Reviews in Molecular Medicine.

[33]  J. Kere,et al.  Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. , 2005, American journal of human genetics.

[34]  M. Ward,et al.  Ethnic and socioeconomic disparities in health among patients with rheumatic disease , 2005, Current opinion in rheumatology.

[35]  C. Qualls,et al.  The effect of race on disease activity in systemic lupus erythematosus. , 2004, Journal of Rheumatology.

[36]  E. Soriano,et al.  The GLADEL Multinational Latin American Prospective Inception Cohort of 1,214 Patients With Systemic Lupus Erythematosus: Ethnic and Disease Heterogeneity Among “Hispanics” , 2004, Medicine.

[37]  J. Reveille,et al.  Early clinical manifestations, disease activity and damage of systemic lupus erythematosus among two distinct US Hispanic subpopulations. , 2003, Rheumatology.

[38]  J. Sánchez-Román,et al.  CTLA4 polymorphism in Spanish patients with systemic lupus erythematosus. , 2003, Human immunology.

[39]  M. Stephens,et al.  Inference of population structure using multilocus genotype data: linked loci and correlated allele frequencies. , 2003, Genetics.

[40]  J. Reveille,et al.  Clinical, immunogenetic and outcome features of Hispanic systemic lupus erythematosus patients of different ethnic ancestry , 2003, Lupus.

[41]  R. Jonsson,et al.  A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans , 2002, Nature Genetics.

[42]  C. Langefeld,et al.  Genetic linkage and association of Fcgamma receptor IIIA (CD16A) on chromosome 1q23 with human systemic lupus erythematosus. , 2002, Arthritis and rheumatism.

[43]  J. Reveille,et al.  Systemic lupus erythematosus in three ethnic groups. IX. Differences in damage accrual. , 2001, Arthritis and rheumatism.

[44]  J. Reveille,et al.  Systemic lupus erythematosus in three ethnic groups. VIII. Predictors of early mortality in the LUMINA cohort , 2001 .

[45]  J. Reveille,et al.  Low-binding alleles of Fcgamma receptor types IIA and IIIA are inherited independently and are associated with systemic lupus erythematosus in Hispanic patients. , 2001, Arthritis and rheumatism.

[46]  A. Svejgaard,et al.  Mannose-binding lectin polymorphisms and susceptibility to infection in systemic lupus erythematosus. , 1999, Arthritis and rheumatism.

[47]  M. Hochberg,et al.  Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. , 1997, Arthritis and rheumatism.

[48]  F. Arnett,et al.  Fc gamma RIIA alleles are heritable risk factors for lupus nephritis in African Americans. , 1996, The Journal of clinical investigation.

[49]  C. Drake,et al.  Genetic Contributions to Lupus‐like Disease in (NZB×NZW)F1 Mice , 1995, Immunological reviews.

[50]  W. Thomson,et al.  Mannose-binding protein gene polymorphism in systemic lupus erythematosus. , 1995, Arthritis and rheumatism.

[51]  C. Drake,et al.  Genetic analysis of the NZB contribution to lupus-like autoimmune disease in (NZB x NZW)F1 mice. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[52]  N. Breslow,et al.  Estimation of multiple relative risk functions in matched case-control studies. , 1978, American journal of epidemiology.