RESUMO
BACKGROUND: A vaccine to interrupt the transmission of tuberculosis is needed. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 2b trial of the M72/AS01E tuberculosis vaccine in Kenya, South Africa, and Zambia. Human immunodeficiency virus (HIV)-negative adults 18 to 50 years of age with latent M. tuberculosis infection (by interferon-γ release assay) were randomly assigned (in a 1:1 ratio) to receive two doses of either M72/AS01E or placebo intramuscularly 1 month apart. Most participants had previously received the bacille Calmette-Guérin vaccine. We assessed the safety of M72/AS01E and its efficacy against progression to bacteriologically confirmed active pulmonary tuberculosis disease. Clinical suspicion of tuberculosis was confirmed with sputum by means of a polymerase-chain-reaction test, mycobacterial culture, or both. RESULTS: We report the primary analysis (conducted after a mean of 2.3 years of follow-up) of the ongoing trial. A total of 1786 participants received M72/AS01E and 1787 received placebo, and 1623 and 1660 participants in the respective groups were included in the according-to-protocol efficacy cohort. A total of 10 participants in the M72/AS01E group met the primary case definition (bacteriologically confirmed active pulmonary tuberculosis, with confirmation before treatment), as compared with 22 participants in the placebo group (incidence, 0.3 cases vs. 0.6 cases per 100 person-years). The vaccine efficacy was 54.0% (90% confidence interval [CI], 13.9 to 75.4; 95% CI, 2.9 to 78.2; P=0.04). Results for the total vaccinated efficacy cohort were similar (vaccine efficacy, 57.0%; 90% CI, 19.9 to 76.9; 95% CI, 9.7 to 79.5; P=0.03). There were more unsolicited reports of adverse events in the M72/AS01E group (67.4%) than in the placebo group (45.4%) within 30 days after injection, with the difference attributed mainly to injection-site reactions and influenza-like symptoms. Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two groups. CONCLUSIONS: M72/AS01E provided 54.0% protection for M. tuberculosis-infected adults against active pulmonary tuberculosis disease, without evident safety concerns. (Funded by GlaxoSmithKline Biologicals and Aeras; ClinicalTrials.gov number, NCT01755598 .).
Assuntos
Tuberculose Latente/terapia , Mycobacterium tuberculosis , Vacinas contra a Tuberculose , Tuberculose/prevenção & controle , Adolescente , Adulto , África , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/imunologia , Modelos de Riscos Proporcionais , Vacinas contra a Tuberculose/efeitos adversos , Vacinas contra a Tuberculose/imunologia , Adulto JovemRESUMO
Age-related macular degeneration (AMD) is a disease of the elderly in which central vision is lost because of degenerative changes of the macula. The current study investigated the association of single-nucleotide polymorphisms (SNPs) with AMD in the Pakistani population. Four SNPs were analyzed in this study: rs1061170 in the CFH, rs429608 near CFB, rs2230199 in the C3, and rs10490924 in ARMS2/HTRA1. This case-control association study was conducted on 300 AMD patients (125 wet AMD and 175 dry AMD) and 200 unaffected age- and gender-matched control individuals. The association of the SNP genotypes and allele frequency distributions were compared between patients and healthy controls, keeping age, gender, and smoking status as covariates. A significant genotype and variant allele association was found of rs10490924 in ARMS2/HTRA1 with wet AMD, while the SNPs in CFH, CFB, and C3 were not associated with AMD in the current Pakistani cohort. The lack of association of CFH, CFB, and C3 may be attributed to limited sample size. This study demonstrates that genetic causative factors of AMD differ among populations and supports the need for genetic association studies among cohorts from various populations to increase our global understanding of the disease pathogenesis.
Assuntos
Alelos , Predisposição Genética para Doença , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Degeneração Macular/diagnóstico , Degeneração Macular/genética , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Idoso , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Degeneração Macular/epidemiologia , Masculino , Pessoa de Meia-Idade , Razão de ChancesRESUMO
PURPOSE: The association of non-synonymous substitution polymorphism rs1801282 (c.34C>G, p.Pro12Ala) in exon 4 of the peroxisome proliferator activated receptor gamma gene with diabetic retinopathy (DR) has been reported inconsistently. Therefore, the purpose of the present study was to understand the population-specific role of the Pro12Ala polymorphism in DR susceptibility in Pakistani subjects. METHODS: A total of 180 subjects with DR, 193 subjects with type 2 diabetes mellitus (T2DM) with no diabetic retinopathy, and 200 healthy normoglycemic non-retinopathic Pakistani individuals were genotyped for the rs1801282 (c.34C>G) polymorphism using polymerase chain reaction-restriction fragment length polymorphism. RESULTS: We found the individuals with T2DM carrying 12Ala were at a reduced risk of developing DR (odds ratio [OR]=0.53; 95% confidence interval [CI]=0.33-0.87). Upon stratified analysis regarding disease severity, we observed this protective effect was confined to proliferative DR (OR=0.4; 95% CI=0.2-0.8) with non-significant effects on the susceptibility of non-proliferative DR (OR=0.67; 95% CI=0.37-1.19). CONCLUSIONS: We report a protective role of the 12Ala polymorphism against proliferative DR in individuals with T2DM in Pakistan.
Assuntos
Substituição de Aminoácidos/genética , Retinopatia Diabética/genética , Estudos de Associação Genética , Predisposição Genética para Doença , PPAR gama/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Estudos de Casos e Controles , Feminino , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Meta-GWAS report numerous variants associated with type 2 diabetes (T2D), however, for diabetic retinopathy (DR) no loci achieved genome-wide significance. There are limited candidate gene analyses for T2D and/or DR reported from the Pakistani population. Therefore, the current study was designed to evaluate the genetic association of 10 loci with T2D, non-proliferative DR (NPDR), and proliferative DR (PDR). In total 375 T2D cases and 205 controls were collected. The T2D cases included diabetic no retinopathy (n = 196), NPDR (n = 95), and PDR (n = 84). Genomic DNA was isolated, and 19 SNPs were genotyped. To determine association of SNPs with T2D, logistic regression analyses were performed adjusting for age and sex. Moreover, for association of SNPs with NPDR and PDR logistic regression analyses adjusting for diabetes duration and age of T2D onset were performed. In multivariate analysis, the minor alleles of rs1043618 [G > C, odds ratio (OR) 95% confidence interval (CI) = 1.45 (1.13-1.87), p = 4.00E-3], rs3807987 [G > A, 1.87 (1.22-2.94), p = 0.01], rs12672038 [G > A, 1.53 (1.04-2.30), p = 0.03] and rs2055858 [G > C, 1.70 (1.20-2.43), p = 3.00E-3] were associated with higher risk while rs1801133 (C > T, 0.59 (0.42-0.83), p = 2.28E-3) was associated with a lower risk of T2D. Moreover, minor alleles of rs2055858 [G > C, 1.77 (1.17-2.68), p = 0.02], and rs3759890 [C > G, 2.17 (1.39-3.39), p = 4.00E-3] showed an association with PDR when compared with DNR. However, only the association of rs1801133 survived multiple test correction. Hence, we report that rs1801133 is associated with T2D in the Pakistani population. In addition, out of studied 10 genes 8 proteins had higher interactions among themselves that are predicted to be partially biologically connected, as a group.
Assuntos
Diabetes Mellitus Tipo 2 , Retinopatia Diabética , Povo Asiático , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Retinopatia Diabética/genética , Humanos , Paquistão , Polimorfismo de Nucleotídeo ÚnicoRESUMO
PURPOSE: To identify the genetic defects underlying retinitis pigmentosa (RP) in Pakistani families. METHODS: Genome-wide high-density single-nucleotide-polymorphism microarray analysis was performed using the DNA of nine affected individuals from two large families with multiple consanguineous marriages. Data were analyzed to identify homozygous regions that are shared by affected sibs in each family. Sanger sequencing was performed for genes previously implicated in autosomal recessive RP and allied retinal dystrophies that resided in the identified homozygous regions. Probands from both families underwent fundus examination and electroretinogram measurements. RESULTS: The tubby-like protein 1 gene (TULP1) was present in the largest homozygous region in both families. Sequence analysis identified a previously reported mutation (c.1138A>G; p.Thr380Ala) in one family and a novel pathogenic variant (c.1445G>A; p.Arg482Gln) in the other family. Both variants were found to be present in a homozygous state in all affected individuals, were heterozygous present in the unaffected parents, and heterozygous present or absent in normal individuals. Affected individuals of both families showed an early-onset form of RP. CONCLUSIONS: Homozygosity mapping, combined with candidate-gene analysis, successfully identified genetic defects in TULP1 in two large Pakistani families with early-onset retinitis pigmentosa.
Assuntos
Proteínas do Olho/genética , Mutação , Polimorfismo de Nucleotídeo Único/genética , Retinose Pigmentar/genética , Adulto , Idade de Início , Sequência de Bases , Pré-Escolar , Consanguinidade , Eletrorretinografia , Feminino , Genes Recessivos , Ligação Genética , Genótipo , Homozigoto , Humanos , Masculino , Repetições de Microssatélites , Dados de Sequência Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Paquistão , Linhagem , Retinose Pigmentar/patologiaRESUMO
In the present study we determined the association of angiotensin converting enzyme (ACE) and plasminogen activator inhibitor-1 (PAI-1) gene polymorphisms with diabetic retinopathy (DR) and its sub-clinical classes in Pakistani type 2 diabetic patients. A total of 353 diabetic subjects including 160 DR and 193 diabetic non retinopathy (DNR) as well as 198 healthy controls were genotyped by allele specific polymerase chain reaction (PCR) for ACE Insertion/Deletion (ID) polymorphism, rs4646994 in intron 16 and PAI-1 4G/5G (deletion/insertion) polymorphism, rs1799768 in promoter region of the gene. To statistically assess the genotype-phenotype association, multivariate logistic regression analysis was applied to the genotype data of DR, DNR and control individuals as well as the subtypes of DR. The ACE genotype ID was found to be significantly associated with DR (p = 0.009, odds ratio (OR) 1.870 [95% confidence interval (CI) = 1.04-3.36]) and its sub-clinical class non-proliferative DR (NPDR) (p = 0.006, OR 2.250 [95% CI = 1.098-4.620]), while PAI polymorphism did not show any association with DR in the current cohort. In conclusion in Pakistani population the ACE ID polymorphism was observed to be significantly associated with DR and NPDR, but not with the severe form of the disease i.e. proliferative DR (PDR).