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Marta E Alarcón-Riquelme

Publications and source records attributed to Marta E Alarcón-Riquelme.

15 recordsLinked to original sources
PubMed2006

A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by activation of the type I interferon (IFN) pathway. Here we convincingly replicate association of the IFN regulatory factor 5 (IRF5) rs2004640 T allele with SLE in four independent case-control cohorts (P = 4.4 x 10(-16)) and by family-based transmission disequilibrium test analysis (P = 0.0006). The rs2004640 T allele creates a 5' donor splice site in an alternate exon 1 of IRF5, allowing expression of several unique IRF5 isoforms. We also identify an independent cis-acting variant associated with elevated expression of IRF5 and linked to the exon 1B splice site. Haplotypes carrying the variant associated with elevated expression and lacking the exon 1B donor site do not confer risk of SLE. Thus, a common IRF5 haplotype driving elevated expression of multiple unique isoforms of IRF5 is an important genetic risk factor for SLE, establishing a causal role for type I IFN pathway genes in human autoimmunity.

Case-Control Studies↗
PubMed2005

The genetics of systemic lupus erythematosus.

For years the identification of candidate genes has been approached in various ways. The latest technology allows for whole genome SNP analysis in genetic association studies. These studies pose new challenges but also new possibilities. I hereby review what is known to date on lupus genetics and what challenges we are to overcome with the new available methods.

Animals↗
PubMed2005

Familial aggregation of systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases in 1,177 lupus patients from the GLADEL cohort.

OBJECTIVE: To determine whether there is familial aggregation of systemic lupus erythematosus (SLE) and/or other autoimmune diseases in SLE patients and to identify clinical differences between patients with and those without familial autoimmunity. METHODS: We interviewed members of the Grupo Latinoamericano de Estudio del Lupus Eritematoso (GLADEL) inception cohort of 1,214 SLE patients to ascertain whether they had relatives with SLE and/or other autoimmune diseases. Identified relatives were studied. Familial aggregation was tested using reported highest and intermediate population prevalence data for SLE, rheumatoid arthritis (RA), or all autoimmune diseases, and studies were performed to identify the genetic model applicable for SLE. RESULTS: We identified 116 first-, second-, or third-degree relatives with SLE, 79 with RA, 23 with autoimmune thyroiditis, 3 with scleroderma, 1 with polymyositis, and 16 with other autoimmune diseases, related to 166 of the 1,177 SLE patients in the GLADEL cohort who agreed to participate. Forty-two SLE patients had 2 or more relatives with an autoimmune disease. We found a lambda(sibling) of 5.8 and 29.0 for SLE and of 3.2-5.3 for RA, when comparing with their reported high or intermediate population prevalence, respectively. We also found familial aggregation for autoimmune disease in general (lambda(sibling) = 1.5) and determined that for SLE, a polygenic additive genetic model, rather than a multiplicative one, is applicable. CONCLUSION: In SLE there is familial aggregation of SLE, RA, and autoimmune disease in general. A polygenic additive model applies for SLE. American Indian-white Mestizo SLE patients and those with higher socioeconomic level were more likely to have familial autoimmunity.

Arthritis, Rheumatoid↗
PubMed2005

IgG Fc receptor polymorphisms and association with autoimmune disease.

The aim of this study was to investigate whether a genetic polymorphism of Fc gammaRIII exists in mice, which could explain the different susceptibility to pathogenic IgG anti-collagen type II (CII) antibodies in mice carrying the collagen-induced arthritis (CIA)-susceptible H-2q haplotype. The gene for Fc gammaRIII was sequenced in 11 common mouse strains, and the results revealed three different haplotypes of mouse Fc gammaRIII: Fc gammaRIII:V, Fc gammaRIII:H and Fc gammaRIII:T. To study the consequences of this polymorphism, we generated mice carrying the Fc gammaRIII:H haplotype from the CIA-susceptible, H-2q-positive DBA/1 mouse or the Fc gammaRIII:V haplotype from the CIA-resistant, H-2q-positive SWR mouse. After CII immunization or transfer of IgG anti-CII antibodies, Fc gammaRIII:H-expressing mice, but not Fc gammaRIII:V-expressing mice, developed progressively severe arthritis. We also investigated if C5, in addition to Fc gammaRIII polymorphism, could affect the susceptibility to the pathogenic IgG anti-CII antibodies in H-2q-positive mice. Here we show that SWR mice, naturally deficient in C5, can develop CIA when supplemented with C5 and that anti-C5 antibody treatment of Fc gammaRIII:H-expressing mice inhibits arthritis development. These data demonstrate for the first time a genetic polymorphism of Fc gammaRIII in mice that may, together with C5, regulate induction of autoimmune disease.

Amino Acid Sequence↗
PubMed2005

The genetics of shared autoimmunity.

Researchers have long suspected that genetic susceptibility is shared among autoimmune diseases. With the increased understanding of genetic risks and disease etiology, we are beginning to comprehend the nature of shared autoimmunity. This article briefly describes the most recent advances in the genetics of autoimmunity and the novel genes discovered.

Animals↗
PubMed2004

Chromosome 17p12-q11 harbors susceptibility loci for systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoantibodies against intracellular components, the formation of immune complexes, and inflammation in various organs, typically the skin and kidney glomeruli. The etiology of the disease is not well understood but is most likely the result of the interaction between genetic and environmental factors. In order to identify susceptibility loci for SLE, we have performed genome scans with microsatellite markers covering the whole genome in families from Argentina, Italy, and Europe. The results reveal a heterogeneous disease with different susceptibility loci in different family sets. We have found significant linkage to chromosome 17p12-q11 in the Argentine set of families. The maximum LOD score was given by marker D17S1294 in combination with D17S1293, when assuming a dominant inheritance model (Z = 3.88). We also analyzed a repeat in the promoter region of the NOS2A gene, a strong candidate gene in the region, but no association was found. The locus on chromosome 17 has previously been identified in genetic studies of multiple sclerosis families. Several other interesting regions were found at 1p35, 1q31, 3q26, 5p15, 11q23 and 19q13, confirming previously identified loci for SLE or other autoimmune diseases.

Adult↗
PubMed2004

Role of RUNX in autoimmune diseases linking rheumatoid arthritis, psoriasis and lupus.

Recent studies investigating the genetic susceptibility of systemic lupus erythematosus, rheumatoid arthritis and psoriasis have revealed a potential role for the RUNX proteins in the development of autoimmune disease. A new pathway of disease pathogenesis opens new avenues of research with thousands of questions that remain to be answered. In this review I attempt to propose how the RUNX proteins might be involved in these diseases and review current knowledge on this very interesting trio of transcription factors that was previously only suspected to be involved in cancer.

Animals↗
PubMed2004

Regulatory SNPs in complex diseases: their identification and functional validation.

Finding the genetic causes for complex diseases is a challenge. Expression studies have shown that the level of expression of many genes is altered in disease compared with normal conditions, but what lies behind these changes? Linkage studies provide hints as to where in the genome the genetic triggers--the mutations--might be located. Fine-mapping and association studies can give yet more information about which genes, and which changes in the genes, are involved in the disease. Recent examples show that single-nucleotide polymorphisms (SNPs), which are variations at the single-nucleotide level within an individual's DNA, in the regulatory regions of some genes constitute susceptibility factors in many complex diseases. This article discusses the nature of regulatory SNPs (rSNPs) and techniques for their functional validation, and looks towards what rSNPs can tell us about complex diseases.

Alleles↗
PubMed2003

Increased salivary gland tissue expression of Fas, Fas ligand, cytotoxic T lymphocyte-associated antigen 4, and programmed cell death 1 in primary Sjögren's syndrome.

OBJECTIVE: To assess salivary gland tissues obtained from patients with primary Sjögren's syndrome (SS) for the gene expression profile of the candidate genes TNFRSF6 (Fas), TNFSF6 (FasL), SSA1 (Ro52 alpha and the splice variant Ro52 beta), SSB (La), CTLA4, PDCD1 (PD-1), and ORM2, which were selected on the basis of their putative participation in salivary gland inflammation. METHODS: Quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) was used to examine the expression of messenger RNA (mRNA). Tissue localization of the expressed proteins was detected by immunohistochemistry. RESULTS: Expression of mRNA was increased for Fas (5.1-fold; P < 0.001), FasL (8.8-fold; P < 0.05), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) (11.2-fold; P < 0.01), programmed cell death 1 (PD-1) (15.2-fold; P < 0.05), Ro52 alpha (3.0-fold; P < 0.01), La (2.3-fold; P < 0.05), and orosomucoid 2 (ORM2) (4.4-fold; P < 0.05) in patients compared with controls when GAPDH was used as endogenous standard in duplex runs. In single runs using 2 other endogenous standards (18S and beta-actin), statistically significant differences between patients and controls were confirmed for expression of Fas, FasL, CTLA-4, and PD-1, but this difference was not observed for Ro52 alpha, La, and ORM2. Expression of Ro52 beta mRNA was similar in patients and controls. CONCLUSION: The present study demonstrates a substantial increase in expression of the negative regulator molecules PD-1 and CTLA-4 and the apoptotic signal molecules Fas and FasL in patients with primary SS compared with controls, which corresponded to the immunomorphologic pattern. The results strongly indicate that these molecules have central roles in the inflammatory process in the salivary glands of patients with primary SS.

Abatacept↗
PubMed2003

Finding genes for SLE: complex interactions and complex populations.

Many years of work, multiplex family collection and endless genotyping finally give fruit. The original aim cannot be lost. The aim is not only to identify mutations involved in susceptibility for systemic lupus erythematosus (SLE) but to elucidate the disease pathogenesis as well. After genetics comes the biology. We review our recent findings on the genetics of lupus, provide possible mechanisms for disease susceptibility and present some facts on the problematic of identifying susceptibility mutations for complex diseases in complex human populations.

Antigens, CD↗
PubMed2003

Functional genomics in the study of autoimmune diseases.

Functional genomics can be defined as a series of new biotechnological tools based on whole-genome information that can be used to understand basic mechanisms of gene regulation, structure and function. Most of these tools have been used and modeled in research of lower organisms such as the yeast C. Elegans. The time has come for their use in human genome research and there is hope that the new technologies and possibilities will provide with new knowledge on disease pathogenesis and the development of new drugs.

Autoimmune Diseases↗
PubMed2002

A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans.

Systemic lupus erythematosus (SLE, OMIM 152700) is a complex autoimmune disease that affects 0.05% of the Western population, predominantly women. A number of susceptibility loci for SLE have been suggested in different populations, but the nature of the susceptibility genes and mutations is yet to be identified. We previously reported a susceptibility locus (SLEB2) for Nordic multi-case families. Within this locus, the programmed cell death 1 gene (PDCD1, also called PD-1) was considered the strongest candidate for association with the disease. Here, we analyzed 2,510 individuals, including members of five independent sets of families as well as unrelated individuals affected with SLE, for single-nucleotide polymorphisms (SNPs) that we identified in PDCD1. We show that one intronic SNP in PDCD1 is associated with development of SLE in Europeans (found in 12% of affected individuals versus 5% of controls; P = 0.00001, r.r. (relative risk) = 2.6) and Mexicans (found in 7% of affected individuals versus 2% of controls; P = 0.0009, r.r. = 3.5). The associated allele of this SNP alters a binding site for the runt-related transcription factor 1 (RUNX1, also called AML1) located in an intronic enhancer, suggesting a mechanism through which it can contribute to the development of SLE in humans.

3' Untranslated Regions↗
PubMed2002

A major susceptibility locus for systemic lupus erythemathosus maps to chromosome 1q31.

A set of 87 multicase families with systemic lupus erythemathosus (SLE) from European (Iceland, Sweden, England, Norway, Italy, and Greece) and recently admixed (Mexico, Colombia, and the United States) populations were genotyped and analyzed for 62 microsatellite markers on chromosome 1. By parametric two-point linkage analysis, six regions (1p36, 1p21, 1q23, 1q25, 1q31, and 1q43) were identified that have LOD scores of Z>or=1.50, with different contributions, depending on the population of origin of the families (European or admixed American). All of the regions have been described previously and have therefore been confirmed in this analysis. The locus at 1q31 showed a significant three-point LOD score of Z=3.79 and was contributed by families from all populations, with several markers and under the same parametric model. Analysis of a known mutation in the CD45 gene did not support the role that this mutation plays in disease. We conclude that the locus at 1q31 contains a major susceptibility gene, important to SLE in general populations.

Americas↗