RESUMEN
BACKGROUND: Lipoprotein(a) [Lp(a)] is a causal risk factor for cardiovascular diseases that has no established therapy. The attribute of Lp(a) that affects cardiovascular risk is not established. Low levels of Lp(a) have been associated with type 2 diabetes (T2D). OBJECTIVES: This study investigated whether cardiovascular risk is conferred by Lp(a) molar concentration or apolipoprotein(a) [apo(a)] size, and whether the relationship between Lp(a) and T2D risk is causal. METHODS: This was a case-control study of 143,087 Icelanders with genetic information, including 17,715 with coronary artery disease (CAD) and 8,734 with T2D. This study used measured and genetically imputed Lp(a) molar concentration, kringle IV type 2 (KIV-2) repeats (which determine apo(a) size), and a splice variant in LPA associated with small apo(a) but low Lp(a) molar concentration to disentangle the relationship between Lp(a) and cardiovascular risk. Loss-of-function homozygotes and other subjects genetically predicted to have low Lp(a) levels were evaluated to assess the relationship between Lp(a) and T2D. RESULTS: Lp(a) molar concentration was associated dose-dependently with CAD risk, peripheral artery disease, aortic valve stenosis, heart failure, and lifespan. Lp(a) molar concentration fully explained the Lp(a) association with CAD, and there was no residual association with apo(a) size. Homozygous carriers of loss-of-function mutations had little or no Lp(a) and increased the risk of T2D. CONCLUSIONS: Molar concentration is the attribute of Lp(a) that affects risk of cardiovascular diseases. Low Lp(a) concentration (bottom 10%) increases T2D risk. Pharmacologic reduction of Lp(a) concentration in the 20% of individuals with the greatest concentration down to the population median is predicted to decrease CAD risk without increasing T2D risk.
Asunto(s)
Enfermedad de la Arteria Coronaria/sangre , Variaciones en el Número de Copia de ADN , Diabetes Mellitus Tipo 2/sangre , Lipoproteína(a)/sangre , Estudios de Casos y Controles , Enfermedad de la Arteria Coronaria/genética , Diabetes Mellitus Tipo 2/genética , Humanos , Islandia , Kringles , Lipoproteína(a)/genética , Análisis de la Aleatorización Mendeliana , Peso Molecular , Isoformas de Proteínas/sangre , Factores de RiesgoRESUMEN
We expanded our genome-wide association study on atrial fibrillation (AF) in Iceland, which previously identified risk variants on 4q25, and tested the most significant associations in samples from Iceland, Norway and the United States. A variant in the ZFHX3 gene on chromosome 16q22, rs7193343-T, associated significantly with AF (odds ratio OR = 1.21, P = 1.4 x 10(-10)). This variant also associated with ischemic stroke (OR = 1.11, P = 0.00054) and cardioembolic stroke (OR = 1.22, P = 0.00021) in a combined analysis of five stroke samples.
Asunto(s)
Fibrilación Atrial/genética , Isquemia Encefálica/genética , Cromosomas Humanos Par 16/genética , Predisposición Genética a la Enfermedad , Proteínas de Homeodominio/genética , Mutación/genética , Accidente Cerebrovascular/genética , Fibrilación Atrial/complicaciones , Secuencia de Bases , Isquemia Encefálica/complicaciones , Humanos , Accidente Cerebrovascular/complicacionesRESUMEN
Variants of the gene ALOX5AP (also known as FLAP) encoding arachidonate 5-lipoxygenase activating protein are known to be associated with risk of myocardial infarction. Here we show that a haplotype (HapK) spanning the LTA4H gene encoding leukotriene A4 hydrolase, a protein in the same biochemical pathway as ALOX5AP, confers modest risk of myocardial infarction in an Icelandic cohort. Measurements of leukotriene B4 (LTB4) production suggest that this risk is mediated through upregulation of the leukotriene pathway. Three cohorts from the United States also show that HapK confers a modest relative risk (1.16) in European Americans, but it confers a threefold larger risk in African Americans. About 27% of the European American controls carried at least one copy of HapK, as compared with only 6% of African American controls. Our analyses indicate that HapK is very rare in Africa and that its occurrence in African Americans is due to European admixture. Interactions with other genetic or environmental risk factors that are more common in African Americans are likely to account for the greater relative risk conferred by HapK in this group.
Asunto(s)
Población Negra/genética , Negro o Afroamericano/genética , Epóxido Hidrolasas/genética , Predisposición Genética a la Enfermedad , Infarto del Miocardio/genética , Población Blanca/genética , Estudios de Casos y Controles , Epóxido Hidrolasas/metabolismo , Variación Genética , Haplotipos/genética , Humanos , Islandia , Desequilibrio de Ligamiento , Datos de Secuencia MolecularRESUMEN
We mapped a gene predisposing to myocardial infarction to a locus on chromosome 13q12-13. A four-marker single-nucleotide polymorphism (SNP) haplotype in this locus spanning the gene ALOX5AP encoding 5-lipoxygenase activating protein (FLAP) is associated with a two times greater risk of myocardial infarction in Iceland. This haplotype also confers almost two times greater risk of stroke. Another ALOX5AP haplotype is associated with myocardial infarction in individuals from the UK. Stimulated neutrophils from individuals with myocardial infarction produce more leukotriene B4, a key product in the 5-lipoxygenase pathway, than do neutrophils from controls, and this difference is largely attributed to cells from males who carry the at-risk haplotype. We conclude that variants of ALOX5AP are involved in the pathogenesis of both myocardial infarction and stroke by increasing leukotriene production and inflammation in the arterial wall.
Asunto(s)
Proteínas Portadoras/genética , Proteínas de la Membrana/genética , Infarto del Miocardio/genética , Accidente Cerebrovascular/genética , Proteínas Activadoras de la 5-Lipooxigenasa , Mapeo Cromosómico , Cromosomas Humanos Par 13 , Predisposición Genética a la Enfermedad , Humanos , Leucotrieno B4/sangre , Repeticiones de Microsatélite , Polimorfismo de Nucleótido SimpleRESUMEN
We previously mapped susceptibility to stroke to chromosome 5q12. Here we finely mapped this locus and tested it for association with stroke. We found the strongest association in the gene encoding phosphodiesterase 4D (PDE4D), especially for carotid and cardiogenic stroke, the forms of stroke related to atherosclerosis. Notably, we found that haplotypes can be classified into three distinct groups: wild-type, at-risk and protective. We also observed a substantial disregulation of multiple PDE4D isoforms in affected individuals. We propose that PDE4D is involved in the pathogenesis of stroke, possibly through atherosclerosis, which is the primary pathological process underlying ischemic stroke.
Asunto(s)
3',5'-AMP Cíclico Fosfodiesterasas/genética , Isquemia Encefálica/enzimología , Isquemia Encefálica/genética , Cromosomas Humanos Par 5 , Desequilibrio de Ligamiento , Regiones no Traducidas 5'/genética , Secuencia de Bases , Mapeo Cromosómico , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3 , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Predisposición Genética a la Enfermedad , Humanos , Isoenzimas/genética , Repeticiones de Microsatélite , Datos de Secuencia Molecular , Polimorfismo Genético , Polimorfismo de Nucleótido SimpleRESUMEN
Stroke is one of the most complex diseases, with several subtypes, as well as secondary risk factors, such as hypertension, hyperlipidemia, and diabetes, which, in turn, have genetic and environmental risk factors of their own. Here, we report the results of a genomewide search for susceptibility genes for the common forms of stroke. We cross-matched a population-based list of patients with stroke in Iceland with an extensive computerized genealogy database clustering 476 patients with stroke within 179 extended pedigrees. Linkage to 5q12 was detected, and the LOD score at this locus meets the criteria for genomewide significance (multipoint allele-sharing LOD score of 4.40, P=3.9 x 10(-6)). A 20-cM region on 5q was physically and genetically mapped to obtain accurate marker order and intermarker distances. This locus on 5q12, which we have designated as "STRK1," does not correspond to known susceptibility loci for stroke or for its risk factors and represents the first mapping of a locus for common stroke.