RESUMEN
HLA-DRB1 codes for a major histocompatibility complex class II cell surface receptor. Genetic variants in and around this gene have been linked to numerous autoimmune diseases. Most notably, an association between HLA-DRB1*1501 haplotype and multiple sclerosis (MS) has been defined. Utilizing electronic health records and 4235 individuals within Marshfield Clinic's Personalized Medicine Research Project, a reverse genetic screen coined phenome-wide association study (PheWAS) tested association of rs3135388 genotype (tagging HLA-DRB1*1501) with 4841 phenotypes. As expected, HLA-DRB1*1501 was associated with MS (International Classification of Disease version 9-CM (ICD9) 340, P=0.023), whereas the strongest association was with alcohol-induced cirrhosis of the liver (ICD9 571.2, P=0.00011). HLA-DRB1*1501 also demonstrated association with erythematous conditions (ICD9 695, P=0.0054) and benign neoplasms of the respiratory and intrathoracic organs (ICD9 212, P=0.042), replicating previous findings. This study not only builds on the feasibility/utility of the PheWAS approach, represents the first external validation of a PheWAS, but may also demonstrate the complex etiologies associated with the HLA-DRB1*1501 loci.
Asunto(s)
Estudios de Asociación Genética/métodos , Predisposición Genética a la Enfermedad/genética , Cadenas HLA-DRB1/genética , Esclerosis Múltiple/genética , Polimorfismo de Nucleótido Simple , Eritema/genética , Estudios de Factibilidad , Genotipo , Haplotipos , Humanos , Clasificación Internacional de Enfermedades , Hepatopatías Alcohólicas/genética , Persona de Mediana Edad , Fenotipo , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: The variable clinical features of hereditary sensory and autonomic neuropathy (HSAN I) suggest heterogeneity. Some cases of idiopathic sensory neuropathy could be caused by missense mutations of SPTLC1 and RAB7 and not be recognised as familial. OBJECTIVE: To screen persons with dominantly inherited HSAN I and others with idiopathic sensory neuropathies for known mutations of SPTLC1 and RAB7. PATIENTS: DNA was examined from well characterised individuals of 25 kindreds with adult onset HSAN I for mutations of SPTLC1 and RAB7; 92 patients with idiopathic sensory neuropathy were also screened for known mutations of these genes. RESULTS: Of the 25 kindreds, only one had a mutation (SPTLC1 399T-->G). This kindred, and 10 without identified mutations, had prominent mutilating foot injuries with peroneal weakness. Of the remainder, 12 had foot insensitivity with injuries but no weakness, one had restless legs and burning feet, and one had dementia with hearing loss. No mutation of RAB7 was found in any of these. No known mutations of SPTLC1 or RAB7 were found in cases of idiopathic sensory neuropathy. CONCLUSIONS: Adult onset HSAN I is clinically and genetically heterogeneous and further work is required to identify additional genetic causes. Known SPTLC1or RAB7 mutations were not found in idiopathic sensory neuropathy.
Asunto(s)
Aciltransferasas/genética , Análisis Mutacional de ADN , Genes Dominantes , Neuropatías Hereditarias Sensoriales y Autónomas/genética , Proteínas de Unión al GTP rab/genética , Adulto , Cartilla de ADN/genética , Diagnóstico Diferencial , Exones , Enfermedad de Fabry/diagnóstico , Enfermedad de Fabry/genética , Femenino , Tamización de Portadores Genéticos , Genotipo , Neuropatías Hereditarias Sensoriales y Autónomas/diagnóstico , Humanos , Masculino , Datos de Secuencia Molecular , Sistemas de Lectura Abierta , Linaje , Polineuropatías/diagnóstico , Polineuropatías/genética , Análisis de Secuencia de ADN , Serina C-Palmitoiltransferasa , Proteínas de Unión a GTP rab7RESUMEN
Regions on chromosomes 7 and 19 were recently reported to contain susceptibility loci that regulate tumor aggressiveness of prostate cancer. To confirm these findings, we analyzed genome scan data from 161 pedigrees affected with prostate cancer. Using the Gleason score as a quantitative measure of tumor aggressiveness, we regressed the squared trait difference, as well as the mean-corrected cross product, on the estimated proportion of alleles shared identical-by-descent at each marker position. Our results confirm the previous linkage results for chromosome 19q (D19S902, P<.00001). In addition, we report suggestive evidence for linkage on chromosome 4 (D4S403, P=.00012). The results of previous findings, together with our results, provide strong evidence that chromosome 19 harbors a gene for tumor aggressiveness.