RESUMEN
Previously, a single nucleotide polymorphism (SNP), rs9939609, in the FTO gene showed a much stronger association with all-cause mortality than expected from its association with body mass index (BMI), body fat mass index (FMI) and waist circumference (WC). This finding implies that the SNP has strong pleiotropic effects on adiposity and adiposity-independent pathological pathways that leads to increased mortality. To investigate this further, we conducted a meta-analysis of similar data from 34 longitudinal studies including 169,551 adult Caucasians among whom 27,100 died during follow-up. Linear regression showed that the minor allele of the FTO SNP was associated with greater BMI (n = 169,551; 0.32 kg m(-2) ; 95% CI 0.28-0.32, P < 1 × 10(-32) ), WC (n = 152,631; 0.76 cm; 0.68-0.84, P < 1 × 10(-32) ) and FMI (n = 48,192; 0.17 kg m(-2) ; 0.13-0.22, P = 1.0 × 10(-13) ). Cox proportional hazard regression analyses for mortality showed that the hazards ratio (HR) for the minor allele of the FTO SNPs was 1.02 (1.00-1.04, P = 0.097), but the apparent excess risk was eliminated after adjustment for BMI and WC (HR: 1.00; 0.98-1.03, P = 0.662) and for FMI (HR: 1.00; 0.96-1.04, P = 0.932). In conclusion, this study does not support that the FTO SNP is associated with all-cause mortality independently of the adiposity phenotypes.
Asunto(s)
Adiposidad/genética , Obesidad/mortalidad , Polimorfismo de Nucleótido Simple , Proteínas/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Índice de Masa Corporal , Predisposición Genética a la Enfermedad , Variación Genética , Estudio de Asociación del Genoma Completo , Humanos , Obesidad/genética , Estudios Observacionales como Asunto , Circunferencia de la CinturaRESUMEN
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.
Asunto(s)
Polimorfismo de Nucleótido Simple , Trombosis de la Vena/genética , Adulto , Área Bajo la Curva , Estudios de Casos y Controles , Femenino , Estudios de Asociación Genética , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Humanos , Modelos Logísticos , Persona de Mediana Edad , Oportunidad Relativa , Linaje , Fenotipo , Valor Predictivo de las Pruebas , Curva ROC , Medición de Riesgo , Factores de Riesgo , Factores Sexuales , Suecia/epidemiología , Trombosis de la Vena/diagnóstico , Trombosis de la Vena/epidemiologíaRESUMEN
Growth hormone (GH) signaling via the growth hormone receptor (GHR) forms a major part of the GH-IGF-I axis, which is crucial for controlling metabolism and anabolism. Two common variants of the GHR differ by the presence (full length or GHR(fl)) or absence of exon 3 (exon 3 deleted or GHR(d3)), the function of which is unknown. However, differential response to GH treatment has been observed with carriers of the GHR(d3) variant conferring a greater growth rate. This study investigates these GHR variants in subjects with normal glucose tolerance (NGT) and impaired glucose tolerance (IGT), including Type 2 diabetes mellitus (T2DM). DNA was extracted from blood samples from subjects with NGT (n=158), IGT (n=116) and T2DM (n=194). The T2DM subjects in set 1 (n= 39) were newly diagnosed, whilst those in set 2 (n=155) had a mean duration of 7 years. Set 1 also included NGT and IGT subjects. Genotyping by standard PCR and gel electrophoresis were carried out. A significant difference was observed between T2DM and NGT (p<0.0001) with a significantly lower frequency of GHR(d3) in T2DM (3.6% compared to 17% in NGT). Both sets of T2DM subjects with at least one GHR(d3) allele had significantly higher BMI. In the larger subset of T2DM, GHR(d3) was associated with higher CRP levels as well as age adjusted IGF-I, with a trend of higher C-peptide secretion and impaired lipid levels, indicating a phenotype with metabolic disorder when compared to the GHR(fl/fl) T2DM subjects. In conclusion, homozygosity for the GHR(d3) allele appears to be preventive of T2DM. However, when other factors cause overt T2DM, the GHR(d3) allele confers a phenotype indicative of metabolic disorder. This study supports the hypothesis that the two GHR alleles by their inclusion or exclusion of exon 3 are functionally different.
