RESUMO
A genetic contribution to the development of systemic lupus erythematosus (SLE) is well established. Several genome-wide linkage scans have identified a number of putative susceptibility loci for SLE, some of which have been replicated in independent samples. This study aimed to identify the regions showing the most consistent evidence for linkage by applying the genome scan meta-analysis (GSMA) method. The study identified two genome-wide suggestive regions on 6p21.1-q15 and 20p11-q13.13 (P-value=0.0056 and P-value=0.0044, respectively) and a region with P-value<0.01 on 16p13-q12.2. The region on chromosome 6 contains the human leukocyte antigen cluster, and the chromosome 16 and 20 regions have been replicated in several cohorts. The potential importance of the identified genomic regions are also highlighted. These results, in conjunction with data emerging from dense single nucleotide polymorphism typing of specific regions or future genome-wide association studies will help guide efforts to identify the actual predisposing genetic variation contributing to this complex genetic disease.
Assuntos
Ligação Genética , Lúpus Eritematoso Sistêmico/genética , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 20/genética , Cromossomos Humanos Par 6/genética , Feminino , Predisposição Genética para Doença , Genoma Humano , Antígenos HLA/genética , Humanos , Lúpus Eritematoso Sistêmico/imunologia , MasculinoRESUMO
The aim of this study was to analyze in families with SLE for the presence of linkage and the structure and transmission of haplotypes containing alleles for the low-affinity Fcgamma receptors. The Fcgamma receptor polymorphisms FcgammaRIIA-131R/H, FcgammaRIIIA-176F/V and FcgammaRIIIB-NA1/2 and a polymorphism in the FcgammaRIIB gene were genotyped with RFLP, allele-specific PCR or pyrosequencing. Individual SNPs and haplotypes were tested for linkage in multicase families and for association using contingency tables, transmission disequilibrium test and affected family-based control groups in Swedish and Mexican single-case families. No linkage or association could be detected using the FcgammaR polymorphisms in the multicase families. However, an association was found for both FcgammaRIIA-131R and IIIA-176F alleles in the single-case families, but not for IIIB or IIB. Allelic association to SLE was found for a haplotype that included both risk alleles, but not in haplotypes where only one or the other was present. We propose that FcgammaRIIA-131R and FcgammaRIIIA-176F are both risk alleles for SLE transmitted primarily, but not exclusively on a single major haplotype that behaves functionally in a situation similar to that of compound heterozygozity.
Assuntos
Alelos , Antígenos CD/genética , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Receptores de IgG/genética , Ligação Genética/genética , Genótipo , Haplótipos/genética , Humanos , México , Polimorfismo de Fragmento de Restrição , Polimorfismo de Nucleotídeo Único , SuéciaRESUMO
The development of systemic lupus erythematosus has a strong genetic basis. The techniques to study the genetics of SLE have improved, and family-based studies have been gaining importance due to advances in the human genome project. Recently, complete genome scans with microsatellite markers and linkage analysis have been performed in human systemic lupus erythematosus in various populations. These studies represent the first step of a process towards the identification of susceptibility genes in SLE. We review here the results of the human genome scans performed until now and provide an update of the latest advances on the genetics of SLE in linkage studies and association analyses of candidate genes.
Assuntos
Ligação Genética , Genoma Humano , Lúpus Eritematoso Sistêmico/genética , Repetições de Microssatélites/genética , Proteínas do Tecido Nervoso/genética , Feminino , Testes Genéticos , Humanos , Masculino , Proteínas do Tecido Nervoso/análise , Linhagem , Sensibilidade e EspecificidadeRESUMO
To identify chromosomal regions containing susceptibility loci for systemic lupus erythematosus (SLE), we performed genome scans in families with multiple SLE patients from Iceland, a geographical and genetic isolate, and from Sweden. A number of chromosomal regions showed maximum lod scores (Z) indicating possible linkage to SLE in both the Icelandic and Swedish families. In the Icelandic families, five regions showed lod scores greater than 2.0, three of which (4p15-13, Z=3.20; 9p22, Z=2.27; 19q13, Z=2.06) are homologous to the murine regions containing the lmb2, sle2 and sle3 loci, respectively. The fourth region is located on 19p13 (D19S247, Z=2.58) and the fifth on 2q37 (D2S125, Z=2.06). Only two regions showed lod scores above 2.0 in the Swedish families: on chromosome 2q11 (D2S436, Z=2. 13) and 2q37 (D2S125, Z=2.18). The combination of both family sets gave a highly significant lod score at D2S125 of Z=4.24 in favor of linkage for 2q37. This region represents a new locus for SLE. Our results underscore the importance of studying well-defined populations for genetic analysis of complex diseases such as SLE.
Assuntos
Cromossomos Humanos Par 2/genética , Lúpus Eritematoso Sistêmico/genética , Animais , Feminino , Ligação Genética , Marcadores Genéticos , Genótipo , Humanos , Islândia , Escore Lod , Masculino , Camundongos , Linhagem , SuéciaRESUMO
We have described suggestive linkage between microsatellite markers within the cytogenetic region 18q21-23 and SLE, a region where linkage with other autoimmune diseases has also been detected. The Bcl-2 gene located within this region, is a candidate gene because of its role in apoptosis, a physiological mechanism that could be deregulated in autoimmune disease. Furthermore, several studies have found abnormalities of Bcl-2 expression in SLE patients. We therefore sought to determine if the Bcl-2 gene is involved in SLE by studying members of a large cohort of Mexican SLE patients (n = 378) and 112 Swedish simplex families. Using a microsatellite marker and two single nucleotide polymorphisms located within the gene, we were unable to detect association between Bcl-2 and SLE in either population. We also tested whether combinations of alleles of the Bcl-2 and IL-10.G microsatellites would increase the risk for SLE. Our results do not support such hypothesis. Our findings suggest that linkage between SLE and the 18q21-23 region is due to a gene other than Bcl-2.
Assuntos
Genes bcl-2 , Lúpus Eritematoso Sistêmico/genética , Alelos , Sequência de Bases , Estudos de Casos e Controles , Estudos de Coortes , Primers do DNA/genética , Feminino , Frequência do Gene , Ligação Genética , Genótipo , Humanos , Interleucina-10/genética , Lúpus Eritematoso Sistêmico/imunologia , Masculino , México , Repetições de Microssatélites , Polimorfismo de Nucleotídeo Único , SuéciaRESUMO
OBJECTIVE: To study the contribution of the IL10 gene to the susceptibility to systemic lupus erythematosus (SLE). METHODS: Analysis by fluorescent-semiautomated genotyping of a dinucleotide repeat located in the promoter region of the IL10 locus (microsatellite G). RESULTS: No significant difference was found in the frequencies of the microsatellite alleles of 330 Mexican patients with SLE compared to 368 controls from the same population. Two-point linkage analyses were carried out using 13 Mexican, 13 Swedish, and 8 Icelandic families with 2 or more cases with SLE. No linkage was revealed between IL10 and SLE, using a variety of parameter settings. CONCLUSION: Our results do not support that the IL10 gene contributes to the susceptibility to SLE in the populations we studied.
Assuntos
Interleucina-10/genética , Lúpus Eritematoso Sistêmico/genética , Repetições de Dinucleotídeos/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Masculino , México , Repetições de Microssatélites , Regiões Promotoras Genéticas/genéticaRESUMO
Systemic lupus erythematosus is a disease of unknown etiology. Multiple genetic factors are believed to be involved in its pathogenesis. In addition, and due to genetic heterogeneity, these factors and/or their combinations may be different in different ethnic groups, while some might be shared between populations. We have performed genome scans in multicase families from three different population groups, two from Northern Europe, with a high degree of homogeneity, and the third from a recently admixed population of Mexican Mestizos. Although our family material is relatively small, the results presented here show that using family sets from well defined populations are sufficient to detect susceptibility loci for SLE. Our results also reveal the chromosomal regions most likely to contain susceptibility genes for SLE.
Assuntos
Genoma Humano , Lúpus Eritematoso Sistêmico/genética , Etnicidade/genética , Feminino , Técnicas Genéticas , Genética Populacional , Humanos , Islândia/epidemiologia , Indígenas Norte-Americanos/genética , Escore Lod , Lúpus Eritematoso Sistêmico/epidemiologia , Masculino , México/epidemiologia , Suécia/epidemiologia , Estados Unidos/epidemiologia , População Branca/genéticaRESUMO
The social organization of most mammals is characterized by female philopatry and male dispersal. Such sex-biased dispersal can cause the genetic structure of populations to differ between the maternally inherited mitochondrial DNA (mtDNA) and the bi-parental nuclear genome. Here we report on the global genetic structure of oceanic populations of the sperm whale, one of the most widely distributed mammalian species. Groups of females and juveniles are mainly found at low latitudes, while males reach polar waters, returning to tropical and subtropical waters to breed. In comparisons between oceans, we did not find significant heterogeneity in allele frequencies of microsatellite loci (exact test; p = 0.23). Estimates of GST = 0.001 and RST = 0.005 also indicated negligible if any nuclear DNA differentiation. We have previously reported significant differentiation between oceans in mtDNA sequences. These contrasting patterns suggest that interoceanic movements have been more prevalent among males than among females, consistent with observations of females being the philopatric sex and having a more limited latitudinal distribution than males. Consequently, the typical mammalian dispersal pattern may have operated on a global scale in sperm whales.
