RESUMO
BACKGROUND: Family history of venous thromboembolism (VTE) has been suggested to be more useful in risk assessment than thrombophilia testing. OBJECTIVES: We investigated established genetic susceptibility variants for association with VTE and evaluated a genetic risk score in isolation and combined with known trigger factors, including family history of VTE. PATIENTS/METHOD: A total of 18 single nucleotide polymorphisms (SNPs) selected from the literature were genotyped in 2835 women participating in a Swedish nationwide case-control study (the ThromboEmbolism Hormone Study [TEHS]). Association with VTE was assessed by odds ratios (ORs) with 95% confidence interval (CI) using logistic regression. Clinical and genetic predictors that contributed significantly to the fit of the logistic regression model were included in the prediction models. SNP-SNP interactions were investigated and incorporated into the models if found significant. Risk scores were evaluated by calculating the area under the receiver-operating characteristics curve (AUC). RESULTS: Seven SNPs (F5 rs6025, F2 rs1799963, ABO rs514659, FGG rs2066865, F11 rs2289252, PROC rs1799810 and KNG1 rs710446) with four SNP-SNP interactions contributed to the genetic risk score for VTE, with an AUC of 0.66 (95% CI, 0.64-0.68). After adding clinical risk factors, which included family history of VTE, the AUC reached 0.84 (95% CI, 0.82-0.85). The goodness of fit of the genetic and combined scores improved when significant SNP-SNP interaction terms were included. CONCLUSION: Prediction of VTE in high-risk individuals was more accurate when a combination of clinical and genetic predictors with SNP-SNP interactions was included in a risk score.
Assuntos
Polimorfismo de Nucleotídeo Único , Trombose Venosa/genética , Adulto , Área Sob a Curva , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Razão de Chances , Linhagem , Fenótipo , Valor Preditivo dos Testes , Curva ROC , Medição de Risco , Fatores de Risco , Fatores Sexuais , Suécia/epidemiologia , Trombose Venosa/diagnóstico , Trombose Venosa/epidemiologiaRESUMO
BACKGROUND: ß2 -Glycoprotein I (ß2 -GPI), also designated apolipoprotein H, is a 50-kDa protein that circulates in blood at high concentrations, playing important roles in autoimmune diseases, hemostasis, atherogenesis, and angiogenesis, as well as in host defense against bacteria and in protein/cellular waste removal. Plasma ß2 -GPI levels have a significant genetic component (heritability of ~ 80%). OBJECTIVES: To present the results of a genome-wide association study for plasma ß2 -GPI levels in a set of extended pedigrees from the Genetic Analysis of Idiopathic Thrombophilia (GAIT) Project. PATIENTS/METHODS: A total of 306 individuals for whom ß2 -GPI plasma measurements were available were typed for 307,984 single-nucleotide polymorphisms (SNPs) with the Infinium 317k Beadchip (Illumina). Association with the ß2 -GPI phenotype was investigated through variance component analysis, and the most significant results were followed up for association with coronary artery disease (CAD) in an independent in silico analysis involving 5765 CAD cases from the PROCARDIS Project and 7264 controls from the PROCARDIS Project and the Wellcome Trust Case Control Consortium (WTCCC) collection. RESULTS: After correction for multiple testing, three SNPs located in/around two genes (ELF5 and SCUBE2) reached genome-wide significance. Moreover, an SNP in the APOH gene showed suggestive association with the ß2 -GPI phenotype. Some of the identified genes are plausible biological candidates, as they are actually or potentially involved in inflammatory processes. CONCLUSIONS: Our results represent a first step towards identifying common variants reflecting the genetic architecture influencing plasma ß2 -GPI levels, and warrant further validation by functional experiments, as the functions of some of the discovered loci are still unknown.
Assuntos
Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/genética , Polimorfismo de Nucleotídeo Único , beta 2-Glicoproteína I/sangue , beta 2-Glicoproteína I/genética , Proteínas Adaptadoras de Transdução de Sinal , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/sangue , Doenças Autoimunes/genética , Proteínas de Ligação ao Cálcio , Estudos de Casos e Controles , Criança , Pré-Escolar , Proteínas de Ligação a DNA , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Lactente , Modelos Lineares , Modelos Logísticos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Linhagem , Fenótipo , Proteínas Proto-Oncogênicas c-ets/genética , Espanha , Trombofilia/sangue , Trombofilia/genética , Fatores de Transcrição , Adulto JovemAssuntos
Fosfatase Alcalina/genética , Fucosiltransferases/genética , Polimorfismo de Nucleotídeo Único , Tromboembolia Venosa/genética , Trombose Venosa/genética , Estudos de Casos e Controles , Europa (Continente) , Feminino , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Razão de Chances , Fenótipo , Medição de Risco , Fatores de Risco , Tromboembolia Venosa/enzimologia , Trombose Venosa/enzimologia , Galactosídeo 2-alfa-L-FucosiltransferaseRESUMO
One of the main goals of human genetics is to find genetic markers related to complex diseases. In blood coagulation process, it is known that genetic variability in F7 gene is the most responsible for observed variations in FVII levels in blood. In this work, we propose a method for selecting sets of Single Nucleotide Polymorphisms (SNPs) significantly correlated with a phenotype (FVII levels). This method employs a feature selection algorithm (variant of Sequential Forward Selection, SFS) based on a criterion of statistical significance of a mutual information functional. This algorithm is applied to a sample of independent individuals from the GAIT project. Main SNPs found by the algorithm are in correspondence with previous results published using family-based techniques.
Assuntos
Fator VII/genética , Genômica/métodos , Polimorfismo de Nucleotídeo Único/genética , Algoritmos , Inteligência Artificial , Análise por Conglomerados , Bases de Dados Genéticas , Humanos , Modelos Genéticos , Modelos Estatísticos , Modelos Teóricos , FenótipoRESUMO
Delineating the genetic variability of loci coding for complex diseases helps to understand the individual variation in disease susceptibility and drug response. We present the allelic architecture of the F7 gene. This gene is the major determinant of FVII plasma levels, and these plasma levels constitute an important intermediate risk factor for cardiovascular disease. As part of the Genetic Analysis of Idiopathic Thrombophila Project, we completely re-sequenced the F7 locus (promoter, exons, introns, and 3'-untranslated region) in 40 unrelated individuals. We found 49 polymorphisms with only two amino acid changes suggesting that regulatory non-coding and intronic variants are responsible for the FVII variability. These results are important for mapping susceptibility alleles of complex diseases, because differences in pair-wise linkage disequilibrium patterns between DNA variants and haplotype frequency distributions may help to detect disease-associated alleles. In addition, we present the results of an in silico search that established genomic comparisons among different species. In conclusion, our study of the F7 DNA sequence variations is an example of a strategy for analyzing the genetic architecture of a quantitative trait locus. Furthermore, it provides a model for future analyses of genetic factors that contribute to the susceptibility of complex diseases in humans.