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Antecedentes. HDL es cuantitativamente la lipoproteína más importante en la mayoría de las especies y la evidencia mecanicista sugiere que HDL tendría un papel en la función inmunológica normal. Probamos la hipótesis que sugiere que las concentraciones plasmáticas de HDL están asociadas con el riesgo de enfermedades autoinmunes. Métodos. Se incluyeron 107.954 y 9.387 individuos con mediciones basales de colesterol-HDL provenientes de 2 estudios de la población general: el Estudio de la Población General de Copenhague y el Estudio del Corazón de Copenhague. Los pacientes fueron seguidos mediante el Registro Nacional Danés de pacientes desde el inicio del período 2003-2015 o 1991-1994 hasta 2017, tiempo durante el cual 4.078 y 1.101 individuos desarrollaron enfermedad autoinmune en los 2 estudios respectivamente. Resultados. En el Estudio de la Población General de Copenhague, en comparación a los individuos con colesterol de HDL =2,0 mmol/L (77 mg/dL), los índices de riesgo para cualquier enfermedad autoinmune, ajustados de manera multifactorial fueron 1,06 (IC 95%, 0,94-1,19) para individuos con colesterol-HDL entre 1,5 y 1,99 mmol/L (58 a 77 mg/dL), 1,18 (IC 95%, 1,04-1,35) para individuos con colesterol-HDL entre 1,0 y 1,49 mmol/L (39 a 58 mg/dL) y 1,84 (IC 95%, 1,52- 2,22) para individuos con colesterol-HDL <1,0 mmol/L (39 mg/dL) (p<0,001 para tendencia). Estos resultados fueron similares cuando: se excluyeron los eventos dentro de los 5 años del inicio del estudio, tanto en mujeres como hombres por separado, eventos en el inicio del estudio, independientemente de la inflamación de bajo grado o concentraciones de triglicéridos, para diferentes niveles de apolipoproteína A1 y para definiciones de punto final más restrictivas. Finalmente, el Estudio del Corazón de Copenhague proporcionó una confirmación independiente. Conclusiones: Los bajos niveles de colesterol-HDL se asocian con un alto riesgo de enfermedad autoinmune en individuos de la población general. Nuestros hallazgos observacionales no pueden determinar la causalidad.

Background. HDL is quantitatively the most important lipoprotein in most species and mechanistic evidence points toward a role for HDL in normal immune function. We tested the hypothesis that concentrations of HDL cholesterol are associated with risk of autoimmune disease. Methods. From 2 studies of the general population-the Copenhagen General Population Study and the Copenhagen City Heart study-we included 107,954 and 9,387 individuals with baseline measurements of HDL cholesterol. These were followed with the national Danish Patient Registry from baseline in 2003-2015 or 1991-1994 through 2017, during which time 4078 and 1101 individuals developed autoimmune disease in the 2 studies. Results. In the Copenhagen General Population Study, compared to individuals with HDL cholesterol =2.0 mmol/L (77 mg/dL), the multifactorially adjusted hazard ratios for any autoimmune disease were 1.06 (95% CI, 0.94-1.19) for individuals with HDL cholesterol of 1.5-1.99 mmol/L (58-77 mg/dL), 1.18 (95% CI, 1.04-1.35) for individuals with HDL cholesterol of 1.0-1.49 mmol/L (39-58 mg/dL), and 1.84 (95% CI, 1.52-2.22) for individuals with HDL cholesterol <1.0 mmol/L (39 mg/dL) (p for trend <0.001). These results were similar when excluding events within 5 years of baseline, in women and men separately, for events at baseline, irrespective of low-grade inflammation or triglyceride concentrations, for the apolipoprotein A1 part of HDL, and for more restrictive end point definitions. Finally, the Copenhagen City Heart Study provided independent confirmation. Conclusions. Low HDL cholesterol level is associated with high risk of autoimmune disease in individuals from the general population. Our observational findings cannot determine causality.

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Objetivos: Evaluar criticamente las implicaciones clinicas de la utilizacion del perfil lipidico sin ayuno en lugar de perfiles de lipidos con ayuno y proporcionar orientacion para la elaboracion de informes de laboratorio sobre perfiles lipidicos anormales con ayuno y sin ayuno. Metodos y Resultados: Abundantes datos observacionales, en los que perfiles lipidicos medidos aleatoriamente sin ayuno se han comparado con perfiles lipidicos determinados en condiciones de ayuno, indican que las variaciones medias maximas de 1-6 h despues de ingestas habituales no son clinicamente significativas [+0,3 mmol/L (+26 mg/dL) para trigliceridos; -0,2 mmol/L (-8 mg/dL) para colesterol total; -0,2 mmol/L (-8 mg/dL) para colesterol-LDL; +0,2 mmol/L (+8 mg/dL) para colesterol de remanentes calculado; -0,2 mmol/L (-8 mg/dL) para el colesterol no-HDL calculado]; las concentraciones de colesterol-HDL, apolipoproteina A1, apolipoproteina B, y lipoproteina(a) no se ven afectados por el estado de ayuno/ no ayuno. Ademas, las concentraciones en ayunas y sin ayuno varian de manera similar con el tiempo y son comparables en la prediccion de la enfermedad cardiovascular. Para mejorar el cumplimiento del paciente con las condiciones para la determinacion del perfil lipidico, por lo tanto, se recomienda el uso rutinario de los perfiles lipidicos sin ayuno, mientras que se puede considerar la toma de muestra en ayunas cuando los trigliceridos sin ayuno son >5 mmol/L (440 mg/dL). Para las muestras sin ayuno, los informes de laboratorio deberian marcar como concentraciones anormales a trigliceridos ≥2 mmol/L (175 mg/dL), colesterol total ≥5 mmol/L (190 mg/dL), colesterol-LDL ≥3 mmol/L (115 mg/dL), colesterol remanente calculado ≥0,9 mmol/L (35 mg/dL), colesterol no-HDL calculado ≥3.9 mmol/L (150 mg/dL), HDL colesterol ≤1 mmol/L (40 mg/dL), apolipoproteina A1 ≤1,25 g/L (125 mg/dL), apolipoproteina B ≥1,0 g/L (100 mg/dL), y lipoproteina(a) ≥50 mg/dL (percentil 80); para muestras con ayuno, las concentraciones anormales corresponden a trigliceridos ≥1,7 mmol/L (150 mg/dL). Aquellas concentraciones que ponen en peligro la vida requieren derivacion inmediata debido al riesgo de pancreatitis cuando los trigliceridos son >10 mmol/L (880 mg/dL), de hipercolesterolemia familiar homocigotica cuando el colesterol-LDL es >13 mmol/L (500 mg/dL) o hipercolesterolemia familiar heterocigota cuando el colesterol-LDL es >5 mmol/L (190 mg/dL), y debido al riesgo cardiovascular muy alto cuando la lipoproteina(a) es >150 mg/dL (percentil 99). Conclusiones: Recomendamos la utilizacion de rutina de muestras de sangre sin ayuno para la evaluacion del perfil lipidico plasmatico. Los informes de laboratorio deberian marcar resultados anormales basandose en valores de corte deseables. Las determinaciones con ayuno y sin ayuno deben ser complementarias, pero no se excluyen mutuamente.

Aims: To critically evaluate the clinical implications of the use of non-fasting rather than fasting lipid profiles and to provide guidance for the laboratory reporting of abnormal non-fasting or fasting lipid profiles. Methods and Results: Extensive observational data, in which random non-fasting lipid profiles have been compared with those determined under fasting conditions, indicate that the maximal mean changes at 1-6 h after habitual meals are not clinically significant [+0.3 mmol/L (26 mg/dL) for triglycerides; -0.2 mmol/L (8 mg/dL) for total cholesterol; -0.2 mmol/L (8 mg/dL) for LDL cholesterol; +0.2 mmol/L (8 mg/dL) for calculated remnant cholesterol; -0.2 mmol/L (8 mg/dL) for calculated non-HDL cholesterol]; concentrations of HDL cholesterol, apolipoprotein A1, apolipoprotein B, and lipoprotein(a) are not affected by fasting/nonfasting status. In addition, non-fasting and fasting concentrations vary similarly over time and are comparable in the prediction of cardiovascular disease. To improve patient compliance with lipid testing, we therefore recommend the routine use of non-fasting lipid profiles, whereas fasting sampling may be considered when non-fasting triglycerides are >5 mmol/L (440 mg/dL). For nonfasting samples, laboratory reports should flag abnormal concentrations as triglycerides ≥2 mmol/L (175 mg/dL), total cholesterol ≥5 mmol/L (190 mg/dL), LDL cholesterol ≥3 mmol/L (115 mg/dL), calculated remnant cholesterol ≥0.9 mmol/L (35 mg/dL), calculated non-HDL cholesterol ≥3.9 mmol/L (150 mg/dL), HDL cholesterol ≤1 mmol/L (40 mg/dL), apolipoprotein A1 ≤1.25 g/L (125 mg/dL), apolipoprotein B ≥1.0 g/L (100 mg/dL), and lipoprotein(a) ≥50 mg/dL (80th percentile); for fasting samples, abnormal concentrations correspond to triglycerides ≥1.7 mmol/L (150 mg/dL). Life-threatening concentrations require separate referral for the risk of pancreatitis when triglycerides are >10 mmol/L (880 mg/dL), for homozygous familial hypercholesterolemia when LDL cholesterol is >13 mmol/L (500 mg/dL), for heterozygous familial hypercholesterolemia when LDL cholesterol is >5 mmol/L (190 mg/dL), and for very high cardiovascular risk when lipoprotein(a) >150 mg/dL (99th percentile). Conclusions: We recommend that non-fasting blood samples be routinely used for the assessment of plasma lipid profiles. Laboratory reports should flag abnormal values on the basis of desirable concentration cutpoints. Non-fasting and fasting measurements should be complementary but not mutually exclusive.

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BACKGROUND: The reason why lipoprotein(a) concentrations are raised in individuals with clinical familial hypercholesterolaemia is unclear. We tested the hypotheses that high lipoprotein(a) cholesterol and LPA risk genotypes are a possible cause of clinical familial hypercholesterolaemia, and that individuals with both high lipoprotein(a) concentrations and clinical familial hypercholesterolaemia have the highest risk of myocardial infarction. METHODS: We did a prospective cohort study that included data from 46 200 individuals from the Copenhagen General Population Study who had lipoprotein(a) measurements and were genotyped for common familial hypercholesterolaemia mutations. Individuals receiving cholesterol-lowering drugs had their concentrations of LDL and total cholesterol multiplied by 1·43, corresponding to an estimated 30% reduction in LDL cholesterol from the treatment. In lipoprotein(a) cholesterol-adjusted analyses, total cholesterol and LDL cholesterol were adjusted for the lipoprotein(a) cholesterol content by subtracting 30% of the individuals' lipoprotein(a) total mass before total and LDL cholesterol were used for diagnosis of clinical familial hypercholesterolaemia. We used modified Dutch Lipid Clinic Network (DLCN), Simon Broome, and Make Early Diagnosis to Prevent Early Death (MEDPED) criteria to clinically diagnose familial hypercholesterolaemia. Cox proportional hazard regression calculated hazard ratios (95% CI) of myocardial infarction. FINDINGS: Using unadjusted LDL cholesterol, mean lipoprotein(a) concentrations were 23 mg/dL in individuals unlikely to have familial hypercholesterolaemia, 32 mg/dL in those with possible familial hypercholesterolaemia, and 35 mg/dL in those with probable or definite familial hypercholesterolaemia (ptrend<0·0001). However, when adjusting LDL cholesterol for lipoprotein(a) cholesterol content the corresponding values were 24 mg/dL for individuals unlikely to have familial hypercholesterolaemia, 22 mg/dL for those with possible familial hypercholesterolaemia, and 21 mg/dL for those with probable or definite familial hypercholesterolaemia (ptrend=0·46). High lipoprotein(a) cholesterol accounted for a quarter of all individuals diagnosed with clinical familial hypercholesterolaemia and LPA risk genotypes were more frequent in clinical familial hypercholesterolaemia, whereas lipoprotein(a) concentrations were similar in those with and without familial hypercholesterolaemia mutations. The hazard ratios (HRs) for myocardial infarction compared with individuals unlikely to have familial hypercholesterolaemia and lipoprotein(a) concentration of 50 mg/dL or less were 1·4 (95% CI 1·1-1·7) in those unlikely to have familial hypercholesterolaemia and lipoprotein(a) concentrations of more than 50 mg/dL, 3·2 (2·5-4·1) in those with possible, probable, or definite familial hypercholesterolaemia and lipoprotein(a) concentration of 50 mg/dL or less, and 5·3 (3·6-7·6) in those with possible, probable, or definite familial hypercholesterolaemia and lipoprotein(a) concentration of more than 50 mg/dL. In analyses using Simon Broome or MEDPED criteria, results were similar to those using DLCN criteria to diagnose clinical familial hypercholesterolaemia. INTERPRETATION: High lipoprotein(a) concentrations and corresponding LPA risk genotypes represent novel risk factors for clinical familial hypercholesterolaemia. Our findings suggest that all individuals with familial hypercholesterolaemia should have their lipoprotein(a) measured in order to identify those with the highest concentrations, and as a result, the highest risk of myocardial infarction. FUNDING: Danish Heart Association and IMK General Fund, Denmark.

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BACKGROUND: Survival after a diagnosis of breast cancer varies considerably between patients, and some of this variation may be because of germline genetic variation. We aimed to identify genetic markers associated with breast cancer-specific survival. METHODS: We conducted a large meta-analysis of studies in populations of European ancestry, including 37954 patients with 2900 deaths from breast cancer. Each study had been genotyped for between 200000 and 900000 single nucleotide polymorphisms (SNPs) across the genome; genotypes for nine million common variants were imputed using a common reference panel from the 1000 Genomes Project. We also carried out subtype-specific analyses based on 6881 estrogen receptor (ER)-negative patients (920 events) and 23059 ER-positive patients (1333 events). All statistical tests were two-sided. RESULTS: We identified one new locus (rs2059614 at 11q24.2) associated with survival in ER-negative breast cancer cases (hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.55 to 2.47, P = 1.91 x 10(-8)). Genotyping a subset of 2113 case patients, of which 300 were ER negative, provided supporting evidence for the quality of the imputation. The association in this set of case patients was stronger for the observed genotypes than for the imputed genotypes. A second locus (rs148760487 at 2q24.2) was associated at genome-wide statistical significance in initial analyses; the association was similar in ER-positive and ER-negative case patients. Here the results of genotyping suggested that the finding was less robust. CONCLUSIONS: This is currently the largest study investigating genetic variation associated with breast cancer survival. Our results have potential clinical implications, as they confirm that germline genotype can provide prognostic information in addition to standard tumor prognostic factors.

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