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1.
Hum Mol Genet ; 23(17): 4693-702, 2014 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-24842889

RESUMO

The recent series of large genome-wide association studies in European and Japanese cohorts established that Parkinson disease (PD) has a substantial genetic component. To further investigate the genetic landscape of PD, we performed a genome-wide scan in the largest to date Ashkenazi Jewish cohort of 1130 Parkinson patients and 2611 pooled controls. Motivated by the reduced disease allele heterogeneity and a high degree of identical-by-descent (IBD) haplotype sharing in this founder population, we conducted a haplotype association study based on mapping of shared IBD segments. We observed significant haplotype association signals at three previously implicated Parkinson loci: LRRK2 (OR = 12.05, P = 1.23 × 10(-56)), MAPT (OR = 0.62, P = 1.78 × 10(-11)) and GBA (multiple distinct haplotypes, OR > 8.28, P = 1.13 × 10(-11) and OR = 2.50, P = 1.22 × 10(-9)). In addition, we identified a novel association signal on chr2q14.3 coming from a rare haplotype (OR = 22.58, P = 1.21 × 10(-10)) and replicated it in a secondary cohort of 306 Ashkenazi PD cases and 2583 controls. Our results highlight the power of our haplotype association method, particularly useful in studies of founder populations, and reaffirm the benefits of studying complex diseases in Ashkenazi Jewish cohorts.


Assuntos
Mapeamento Cromossômico , Etnicidade/genética , Genealogia e Heráldica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Doença de Parkinson/genética , Idoso , Estudos de Coortes , Demografia , Feminino , Loci Gênicos/genética , Haplótipos/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos Testes
2.
PLoS Genet ; 8(3): e1002559, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22412388

RESUMO

Crohn's disease (CD) is a complex disorder resulting from the interaction of intestinal microbiota with the host immune system in genetically susceptible individuals. The largest meta-analysis of genome-wide association to date identified 71 CD-susceptibility loci in individuals of European ancestry. An important epidemiological feature of CD is that it is 2-4 times more prevalent among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Europeans (NJ). To explore genetic variation associated with CD in AJs, we conducted a genome-wide association study (GWAS) by combining raw genotype data across 10 AJ cohorts consisting of 907 cases and 2,345 controls in the discovery stage, followed up by a replication study in 971 cases and 2,124 controls. We confirmed genome-wide significant associations of 9 known CD loci in AJs and replicated 3 additional loci with strong signal (p<5×10⁻6). Novel signals detected among AJs were mapped to chromosomes 5q21.1 (rs7705924, combined p = 2×10⁻8; combined odds ratio OR = 1.48), 2p15 (rs6545946, p = 7×10⁻9; OR = 1.16), 8q21.11 (rs12677663, p = 2×10⁻8; OR = 1.15), 10q26.3 (rs10734105, p = 3×10⁻8; OR = 1.27), and 11q12.1 (rs11229030, p = 8×10⁻9; OR = 1.15), implicating biologically plausible candidate genes, including RPL7, CPAMD8, PRG2, and PRG3. In all, the 16 replicated and newly discovered loci, in addition to the three coding NOD2 variants, accounted for 11.2% of the total genetic variance for CD risk in the AJ population. This study demonstrates the complementary value of genetic studies in the Ashkenazim.


Assuntos
Doença de Crohn/genética , Estudo de Associação Genômica Ampla , Judeus/genética , Cromossomos Humanos Par 5/genética , Estudos de Coortes , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , População Branca
3.
Am J Hematol ; 75(1): 18-21, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14695628

RESUMO

The diagnosis of thrombotic thrombocytopenic purpura (TTP) rests on evidence of microangiopathic hemolytic anemia and thrombocytopenia in the absence of disseminated intravascular coagulation and other known causes of thrombotic microangiopathy. Highly specific diagnostic tools such as serum levels of ADAMTS13 are not routinely available for immediate clinical diagnosis. The presence of schistocytes on a blood smear is the morphologic hallmark of the disease, but no guidelines exist as to the number of schistocytes required to differentiate TTP from other thrombotic microangiopathies. We studied 6 patients with TTP and compared their schistocyte counts with those of 40 normal subjects, 28 patients with chronic renal disease, 5 with preeclampsia, and 5 with normal functioning mechanical heart valves. The mean schistocyte count for the TTP patients was 8.35% versus 0.05% for normal subjects, 0.2% for renal patients, 0.25% for preeclamptic patients, and 0.18% for patients with mechanical valves (P < 0.001). Schistocytes were found on 100% of blood films of TTP patients and ranged from 1.0% to 18.4% of red cells. Schistocytes are found on the smears of 58% of normal individuals and on 80-100% of the other patient groups studied, but always comprise less than 0.5% of the red cell population. An initial schistocyte count of greater than 1% strongly suggests a diagnosis of TTP in the absence of other known causes of thrombotic microangiopathy.


Assuntos
Eritrócitos Anormais/patologia , Púrpura Trombocitopênica Trombótica/sangue , Estudos de Casos e Controles , Doença Crônica , Diagnóstico Diferencial , Contagem de Eritrócitos , Feminino , Próteses Valvulares Cardíacas , Humanos , Nefropatias/patologia , Pré-Eclâmpsia/patologia , Gravidez , Púrpura Trombocitopênica Trombótica/patologia
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