ABSTRACT
BACKGROUND: Studies utilising genotyping methods report the prevalence of familial hypercholesterolaemia to be as high as one in 137 of the adult population. AIM: To estimate the prevalence of familial hypercholesterolaemia measured by clinically coded diagnosis, associated treatments, and lipid measurements observed in UK primary care. DESIGN AND SETTING: This was a retrospective analysis using the Clinical Practice Research Datalink (CPRD) GOLD database. METHOD: Patients aged ≥18 years and actively registered on the index date (30 June 2018) formed the study cohort. Point prevalence of familial hypercholesterolaemia for 2018 was estimated overall and for each nation of the UK. Patients with familial hypercholesterolaemia were stratified into primary and secondary prevention groups, defined as those with/without a prior diagnosis of atherosclerotic cardiovascular disease. Prevalence estimates and extrapolations were replicated for these subgroups. Baseline demographic, lipid, and clinical characteristics for the prevalent cohort were presented. RESULTS: In total, 4048 patients with familial hypercholesterolaemia formed the study cohort. The estimated familial hypercholesterolaemia prevalence for the UK was 16.4 per 10 000 (95% confidence interval [CI] = 16.0 to 16.9). Of these, 2646 (65.4%) patients with familial hypercholesterolaemia had a recent prescription for lipid-lowering therapy. Mean lipid levels were lower for those treated with lipid-lowering therapy compared with those untreated: 5.34 mmol/L (SD 1.50) versus 6.25 mmol/L (SD 1.55) for total cholesterol and 3.15 mmol/L (SD 1.34) versus 3.96 mmol/L (SD 1.36) for low-level density lipoprotein cholesterol. CONCLUSION: The estimated prevalence of familial hypercholesterolaemia was one in 608 of the population, less than expected from other studies, which may indicate that familial hypercholesterolaemia is under-recognised in UK primary care. Over one-third of diagnosed patients were undertreated and many did not achieve target goals, placing them at risk of cardiovascular events.
ABSTRACT
PURPOSE: To evaluate the impact of DNMT3A mutations on outcome in younger patients with cytogenetic intermediate-risk acute myeloid leukemia. PATIENTS AND METHODS: Diagnostic samples from 914 patients (97% < 60 years old) were screened for mutations in DNMT3A exons 13 to 23. Clinical outcome was evaluated according to presence or absence of a mutation and stratified according to type of mutation (R882, non-R882 missense, or truncation). RESULTS: DNMT3A mutations (DNMT3A(MUT)) were identified in 272 patients (30%) and associated with a poorer prognosis than wild-type DNMT3A, but the difference was only seen when the results were stratified according to NPM1 genotype. This example of Simpson's paradox results from the high coincidence of DNMT3A and NPM1 mutations (80% of patients with DNMT3A(MUT) had NPM1 mutations), where the two mutations have opposing prognostic impact. In the stratified analyses, relapse in patients with DNMT3A(MUT) was higher (hazard ratio, 1.35; 95% CI, 1.07 to 1.72; P = .01), and overall survival was lower (hazard ratio, 1.37; 95% CI, 1.12 to 1.87; P = .002). The impact of DNMT3A(MUT) did not differ according to NPM1 genotype (test for heterogeneity: relapse, P = .4; overall survival, P = .9). Further analysis according to the type of DNMT3A mutation indicated that outcome was comparable in patients with R882 and non-R882 missense mutants, whereas in those with truncation mutants, it was comparable to wild-type DNMT3A. CONCLUSION: These data confirm that presence of a DNMT3A mutation should be considered as a poor-risk prognostic factor, irrespective of the NPM1 genotype, and suggest that further consideration should be given to the type of DNMT3A mutation.