RESUMEN
As part of a randomised trial [Genetic Risk Assessment for Familial Hypercholesterolaemia (FH) Trial] of the psychological consequences of DNA-based and non-DNA-based diagnosis of FH, 338 probands with a clinical diagnosis of FH (46% with tendon xanthomas) were recruited. In the DNA-based testing arm (245 probands), using single-strand conformation polymorphism of all exons of the low-density lipoprotein receptor (LDLR) gene, 48 different pathogenic mutations were found in 62 probands (25%), while 7 (2.9%) of the patients had the R3500Q mutation in the apolipoprotein B (APOB) gene. Compared to those with no detected mutation, mean untreated cholesterol levels in those with the APOB mutation were similar, while in those with an LDLR mutation levels were significantly higher (None=9.15+/-1.62 vs LDLR=9.13+/-1.16 vs APOB=10.26+/-2.07 mmol/l p<0.001, respectively). Thirty seven percent of the detected mutations were in exon 3/4 of LDLR, and this group had significantly higher untreated cholesterol than those with other LDLR mutations (11.71+/-2.39 mmol/l vs 9.88+/-2.44 mmol/l, p=0.03), and more evidence of coronary disease compared to those with other LDLR or APOB mutations (36 vs 13% p=0.04). Of the probands with a detected mutation, 54 first-degree relatives were identified, of whom 27 (50%) had a mutation. Of these, 18 had untreated cholesterol above the 95th percentile for their age and gender, but there was overlap with levels in the non-carrier relatives such that 12% of subjects would have been incorrectly diagnosed on lipid levels alone. In the non-DNA-based testing arm (82 probands) only 19 of the 74 relatives identified had untreated cholesterol above the 95th percentile for their age and gender, which was significantly lower (p<0.0005) than the 50% expected for monogenic inheritance. These data confirm the genetic heterogeneity of LDLR mutations in the UK and the deleterious effect of mutations in exon 3 or 4 of LDLR on receptor function, lipids and severity of coronary heart disease. In patients with a clinical diagnosis of FH but no detectable mutation, there is weaker evidence for a monogenic cause compared with relatives of probands with LDLR mutations. This supports the usefulness of DNA testing to confirm diagnosis of FH for the treatment of hyperlipidaemia and for further cascade screening.
Asunto(s)
Enfermedades Cardiovasculares/etiología , Hiperlipoproteinemia Tipo II/genética , Lípidos/sangre , Receptores de LDL/genética , Análisis Mutacional de ADN , Inglaterra/epidemiología , Femenino , Pruebas Genéticas , Humanos , Hiperlipoproteinemia Tipo II/complicaciones , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiología , Masculino , Persona de Mediana Edad , Linaje , Prevalencia , Distribución Aleatoria , Factores de RiesgoRESUMEN
This trial tests the hypothesis that confirming a clinical diagnosis of familial hypercholesterolemia (FH) by finding a genetic mutation reduces patients' perceptions of control over the disease and adherence to risk-reducing behaviors. Three hundred forty-one families, comprising 341 hypercholesterolemia probands and 128 adult relatives, were randomized to one of two groups: (a) routine clinical diagnosis; (b) routine clinical diagnosis plus genetic testing (mutation searching in probands and direct gene testing in relatives). The main outcome measures were perceptions of control over hypercholesterolemia, adherence to cholesterol-lowering medication, diet, physical activity, and smoking. There was no support for the main hypothesis: finding a mutation had no impact on perceived control or adherence to risk-reducing behavior (all P-values > 0.10). While all groups believed that lowering cholesterol was an effective way of reducing the risk of a heart attack, participants in whom a mutation was found believed less strongly in the efficacy of diet in reducing their cholesterol level (P = 0.02 at 6 months) and showed a trend in believing more strongly in the efficacy of cholesterol-lowering medication (P = 0.06 at 6 months). In conclusion, finding a mutation to confirm a clinical diagnosis of FH in a previously aware population does not reduce perceptions of control or adherence to risk-reducing behaviors. The pattern of findings leads to the new hypothesis that genetic testing does not affect the extent to which people feel they have control over a condition, but does affect their perceptions of how control is most effectively achieved. Further work is needed to determine whether similar results will be obtained in populations with little previous awareness of their risks.