RESUMO
BACKGROUND AND PURPOSE: Genetic variability in DNM3 has been shown to modify age of onset of Parkinson's disease (PD) among LRRK2 Gly2019Ser carriers in North African Arab-Berber populations. In Asian populations, the Gly2019Ser mutation is rare or absent but two other LRRK2 variants, Gly2385Arg and Arg1628PPro, increase PD risk. We aimed to determine whether the DNM3 locus was associated with age of PD onset in both carriers and non-carriers of LRRK2 risk variants in Asians. METHODS: We analyzed the association of DNM3 rs2421947 genotypes with age of PD onset in 3645 Chinese samples, of which 369 carried at least one of two Asian LRRK2 risk variants. RESULTS: DNM3 rs2421947 genotypes were not associated with age of PD onset in Chinese samples. We observed no heterogeneity in the effect of rs2421947 between the Asian LRRK2 risk variant carriers and non-carriers. CONCLUSIONS: DNM3 rs2421947 was not associated with age of PD onset in LRRK2 risk variant carriers and non-carriers in Chinese samples. Further studies in other Asian populations will be of interest.
Assuntos
Idade de Início , Dinamina III/genética , Doença de Parkinson/epidemiologia , Doença de Parkinson/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Ásia/epidemiologia , Povo Asiático , China/epidemiologia , Feminino , Predisposição Genética para Doença , Variação Genética , Genótipo , Heterozigoto , Humanos , Estimativa de Kaplan-Meier , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Masculino , Pessoa de Meia-Idade , MutaçãoRESUMO
BACKGROUND: Pemphigus is an autoimmune blistering disease with pemphigus vulgaris (PV) and foliaceus (PF) as the two major histological subtypes. Associations with HLA molecules have been suggested, but specific HLA risk variants as well as non-HLA risk variants remain to be discovered. METHODS: We performed a two-stage genome-wide association study in the Chinese Han population through a genome-wide discovery analysis and follow-up validation analysis in a total number of 210 PV, 159 PF and 2493 healthy controls. HLA imputation as well as high coverage next generation sequencing based HLA genotyping was employed to investigate the association of classical HLA alleles and amino acid change. RESULTS: We have discovered independent novel associations with PF at rs2178077 on 12q24.33, located next to RAN (PPF = 1.57 × 10-9 ) and rs3888722 within the MHC region (P = 6.73 × 10-9 ). For the HLA variants, we confirmed independent genome-wide level risk associations in HLA-DQB1 and HLA-DRB1, with DQB1*05:03 to be the strongest association with PV (P = 8.59 × 10-68 , OR = 31.16) and PF (P = 4.84 × 10-17 , OR = 5.64). In addition, DRB1*14 was demonstrated to be a second independent variants (P = 4.2 × 10-63 , OR = 35.47) for PV, while DRB1*04:06 was demonstrated to be the second independent signal (P = 7.44 × 10-13 , OR = 5.58) for PF. CONCLUSIONS: These findings advance our understanding of the genetic basis of pemphigus susceptibility and may offer opportunities for risk prediction and preventive treatment for pemphigus, in particular for PV.
Assuntos
Predisposição Genética para Doença/epidemiologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Pênfigo/epidemiologia , Pênfigo/genética , Povo Asiático/genética , Estudos de Casos e Controles , Causalidade , China/epidemiologia , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Humanos , Masculino , Pênfigo/patologia , Prevalência , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Dapsone is used in the treatment of infections and inflammatory diseases. The dapsone hypersensitivity syndrome, which is associated with a reported mortality of 9.9%, develops in about 0.5 to 3.6% of persons treated with the drug. Currently, no tests are available to predict the risk of the dapsone hypersensitivity syndrome. METHODS: We performed a genomewide association study involving 872 participants who had received dapsone as part of multidrug therapy for leprosy (39 participants with the dapsone hypersensitivity syndrome and 833 controls), using log-additive tests of single-nucleotide polymorphisms (SNPs) and imputed HLA molecules. For a replication analysis, we genotyped 24 SNPs in an additional 31 participants with the dapsone hypersensitivity syndrome and 1089 controls and performed next-generation sequencing for HLA-B and HLA-C typing at four-digit resolution in an independent series of 37 participants with the dapsone hypersensitivity syndrome and 201 controls. RESULTS: Genomewide association analysis showed that SNP rs2844573, located between the HLA-B and MICA loci, was significantly associated with the dapsone hypersensitivity syndrome among patients with leprosy (odds ratio, 6.18; P=3.84×10(-13)). HLA-B*13:01 was confirmed to be a risk factor for the dapsone hypersensitivity syndrome (odds ratio, 20.53; P=6.84×10(-25)). The presence of HLA-B*13:01 had a sensitivity of 85.5% and a specificity of 85.7% as a predictor of the dapsone hypersensitivity syndrome, and its absence was associated with a reduction in risk by a factor of 7 (from 1.4% to 0.2%). HLA-B*13:01 is present in about 2 to 20% of Chinese persons, 1.5% of Japanese persons, 1 to 12% of Indians, and 2 to 4% of Southeast Asians but is largely absent in Europeans and Africans. CONCLUSIONS: HLA-B*13:01 was associated with the development of the dapsone hypersensitivity syndrome among patients with leprosy. (Funded by the National Natural Science Foundation of China and others.).
Assuntos
Dapsona/efeitos adversos , Hipersensibilidade a Drogas/genética , Antígenos HLA-B/genética , Hansenostáticos/efeitos adversos , Hanseníase/tratamento farmacológico , Adulto , Dapsona/uso terapêutico , Quimioterapia Combinada , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Hansenostáticos/uso terapêutico , Hanseníase/genética , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Análise de Sequência de DNARESUMO
BACKGROUND AND PURPOSE: Mutations in the PRRT2 gene have been identified in patients with paroxysmal kinesigenic dyskinesias (PKD); however, not many detailed clinico-genetic correlations have been performed. METHODS: To investigate PRRT2 mutations in a mixed Asian PKD population and perform clinico-genetic correlations, we recruited patients between 2002 and 2011 and administered a standardized questionnaire. RESULTS: Amongst 29 unrelated patients with PKD recruited, five PRRT2 mutations were present in 15 patients. Three mutations (c.649dupC, c.649delC, c.649C>T) were previous reported, while three were novel mutations (c.604delT; c.609_611delACC/p.Ser202Hisfs; c.697_698delAG/p.Ser233Trp fsX5). Clinico-genetic correlations revealed that a history of seizures was more common in patients with PRRT2 mutations, although this did not reach statistical significance (P= 0.08). A younger age of onset, non-Chinese, and the presence of premonitory sensations were significantly associated with PRRT2 mutations in the univariate analysis. Multivariate logistic regression analysis demonstrated that age of onset [odds ratio (OR) = 0.59, P = 0.025] and premonitory sensation (OR = 10.67, P = 0.028) were independently associated with positive PRRT2 mutation. CONCLUSIONS: PRRT2 mutations are common in patients with PKD, and a double PRRT2 mutation is reported for the first time. PRRT2 mutations are significantly associated with a younger age of onset and the presence of premonitory sensation in our population.