RESUMEN
Genetic analysis of admixed populations raises special concerns with regard to study design and data processing, particularly to avoid population stratification biases. The point mutation responsible for sickle cell anaemia codes for a variant hemoglobin, sickle hemoglobin or HbS, whose presence drives the pathophysiology of disease. Here we propose to explore ancestry and population structure in a genome-wide study with particular emphasis on chromosome 11 in two SCA admixed cohorts obtained from urban populations of Brazil (Pernambuco and São Paulo) and the United States (Pennsylvania). Ancestry inference showed different proportions of European, African and American backgrounds in the composition of our samples. Brazilians were more admixed, had a lower African background (43% vs. 78% on the genomic level and 44% vs. 76% on chromosome 11) and presented a signature of positive selection and Iberian introgression in the HbS region, driving a high differentiation of this locus between the two cohorts. The genetic structures of the SCA cohorts from Brazil and US differ considerably on the genome-wide, chromosome 11 and HbS mutation locus levels.
Asunto(s)
Anemia de Células Falciformes/genética , Cromosomas Humanos Par 11/genética , Genética de Población/métodos , Genotipo , Hemoglobina Falciforme/genética , Grupos de Población , Grupos Raciales/genética , Brasil , Estudios de Cohortes , Frecuencia de los Genes , Genoma , Estudio de Asociación del Genoma Completo , Haplotipos , Humanos , Estados UnidosRESUMEN
Sickle cell anemia (SCA) is an autosomal recessive disorder, with Mendelian inheritance pattern, caused by a missense mutation in the ß-polypeptide chain of the hemoglobin B. SCA preferentially affects populations in countries where malaria was/is present (e.g. Africa, USA, Brazil). Thereby, in USA, the incidence of SCA is relatively high, around 1/500, and the prevalence is about 1/1000. In Brazil, SCA represents a major public health problem with an incidence ranging from 1/2000 to 1/600 depending on the regions. Homozygotic patients present more severe medical conditions and reduced life expectancy than heterozygous individuals who generally are asymptomatic. Eventually, this life-threatening disease displays a complex etiology owing to heterogeneous phenotypes and clinical outcomes, subsequently affecting the management of the patients. One of the most critical complications associated with SCA is stroke, a leading neurologic cause of death and disability. About 24% of SCA patients have a stroke by the age of 45 and 11% by the age of 20. From the general population, twin and familial aggregation studies as well as genome-wide association studies (GWAS), mostly in pediatric populations with ischemic stroke, showed that the risk of stroke has a substantial genetic component. Nevertheless, to fully characterize genomic contributors of stroke and permit reliable personalized medicine, multidisciplinary studies incorporating knowledge from clinical medicine, epidemiology, genetics, and molecular biology, are required. In this manuscript, stroke in SCA patients is extensively reviewed with emphasis to the US and Brazilian populations. Recent advances in genomics analysis of stroke in SCA patients are highlighted.
Asunto(s)
Anemia de Células Falciformes , Estudio de Asociación del Genoma Completo , Hemoglobinas/genética , Comunicación Interdisciplinaria , Accidente Cerebrovascular , Anemia de Células Falciformes/epidemiología , Anemia de Células Falciformes/genética , Anemia de Células Falciformes/terapia , Humanos , Incidencia , Prevalencia , Factores de Riesgo , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/terapiaRESUMEN
MYOC encodes a secretary glycoprotein of 504 amino acids named myocilin. MYOC is the first gene to be linked to juvenile open-angle glaucoma (JOAG) and some forms of adult-onset primary open-angle glaucoma (POAG). The gene was identified as an up-regulated molecule in cultured trabecular meshwork (TM) cells after treatment with dexamethasone and was originally referred to as trabecular meshwork-inducible glucocorticoid response (TIGR). Elevated intraocular pressure (IOP), due to decreased aqueous outflow, is the strongest known risk factor for POAG. Increasing evidence showed that the modulation of the wild-type (wt) myocilin protein expression is not causative of glaucoma while some misfolded and self-assembly aggregates of mutated myocilin may be associated with POAG in related or unrelated populations. The etiology of the disease remains unclear. Consequently, a better understanding of the molecular mechanisms underlying POAG is required to obtain early diagnosis, avoid potential disease progression, and develop new therapeutic strategies. In the present study, we review and discuss the most relevant studies regarding structural characterizations, expressions, molecular interactions, putative functions of MYOC gene and/or its corresponding protein in POAG etiology.