RESUMEN
Two multicentre genome-wide association (GWA) studies provided substantial evidence, implicating the complement receptor 1 gene (CR1) in Alzheimer disease (AD) genetic etiology. CR1 encodes a large transmembrane receptor with a crucial role in the immune complement cascade. We performed a genetic follow-up of the GWA CR1 association in a Flanders-Belgian cohort (n=1883), and investigated the effect of single-nucleotide polymorphisms (SNPs) located in the CR1 locus on AD risk and cerebrospinal fluid (CSF) biomarker levels. We obtained significant association (P(adj)<0.03; odds ratio (OR)=1.24 (95% confidence interval (CI): 1.02-1.51)) for one CR1 risk haplotype, and haplotype association was strongest in individuals carrying apolipoprotein E (APOE) É4 alleles (P(adj)<0.006; OR=1.50 (95% CI: 1.08-2.09)). Also, four SNPs correlated with increased CSF amyloid Aß1â42 levels, suggesting a role for the CR1 protein in Aß metabolism. Moreover, we quantified a low-copy repeat (LCR)-associated copy number variation (CNV) in CR1, producing different CR1 isoforms, CR1-F and CR1-S, and obtained significant association in carriers of CR1-S. We replicated the CR1 CNV association finding in a French cohort (n=2003) and calculated in the combined cohorts, an OR of 1.32; 95% CI: 1.10-1.59 (P=0.0025). Our data showed that the common AD risk association may well be explained by the presence of CR1-S increasing the number of C3b/C4b and cofactor activity sites and AD risk with 30% in CR1-S carriers. How precisely the different functional role of CR1-S in the immune complement cascade contributes to AD pathogenesis will need additional functional studies.
Asunto(s)
Enfermedad de Alzheimer/genética , Factor I de Complemento/metabolismo , Variaciones en el Número de Copia de ADN/genética , Polimorfismo de Nucleótido Simple/genética , Receptores de Complemento/genética , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Apolipoproteína E4/genética , Estudios de Cohortes , Femenino , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Modelos Logísticos , Masculino , Metaanálisis como Asunto , Oportunidad Relativa , Fragmentos de Péptidos/líquido cefalorraquídeo , Duplicaciones Segmentarias en el Genoma , Proteínas tau/líquido cefalorraquídeoRESUMEN
The plasmatic glycosyl proteins levels were measured in fifty non diabetic volunteers and thirty five patients with diabetes mellitus by the fructosamine test. The upper limit for healthy volunteers was estimated to 25 mumoles/g protein. A higher fructosamine concentration and greater spread of values were observed in the diabetic group. A very good correlation was noted in the diabetic group between A1C hemoglobin and fructosamine concentrations. This test is very reproducible, inexpensive and should be a good alternative to the A1C hemoglobin determination in some physiologic or pathologic disorders.
