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1.
Mol Psychiatry ; 28(10): 4451-4462, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37666928

RESUMO

The APOE 2/3/4 polymorphism is the greatest genetic risk factor for Alzheimer's disease (AD). This polymorphism is also associated with variation in plasma ApoE level; while APOE*4 lowers, APOE*2 increases ApoE level. Lower plasma ApoE level has also been suggested to be a risk factor for incident dementia. To our knowledge, no large genome-wide association study (GWAS) has been reported on plasma ApoE level. This study aimed to identify new genetic variants affecting plasma ApoE level as well as to test if baseline ApoE level is associated with cognitive function and incident dementia in a longitudinally followed cohort of the Ginkgo Evaluation of Memory (GEM) study. Baseline plasma ApoE concentration was measured in 3031 participants (95.4% European Americans (EAs)). GWAS analysis was performed on 2580 self-identified EAs where both genotype and plasma ApoE data were available. Lower ApoE concentration was associated with worse cognitive function, but not with incident dementia. As expected, the risk for AD increased from E2/2 through to E4/4 genotypes (P for trend = 4.8E-75). In addition to confirming the expected and opposite associations of APOE*2 (P = 4.73E-79) and APOE*4 (P = 8.73E-12) with ApoE level, GWAS analysis revealed nine additional independent signals in the APOE region, and together they explained about 22% of the variance in plasma ApoE level. We also identified seven new loci on chromosomes 1, 4, 5, 7, 11, 12 and 20 (P range = 5.49E-08 to 5.36E-10) that explained about 9% of the variance in ApoE level. Plasma ApoE level-associated independent variants, especially in the APOE region, were also associated with AD risk and amyloid deposition in the brain, indicating that genetically determined ApoE level variation may be a risk factor for developing AD. These results improve our understanding of the genetic determinants of plasma ApoE level and their potential value in affecting AD risk.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/genética , Estudo de Associação Genômica Ampla , Apolipoproteínas E/genética , Genótipo , Polimorfismo Genético , Apolipoproteína E4/genética
2.
Alzheimers Dement ; 20(2): 1038-1049, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37855447

RESUMO

INTRODUCTION: This study aimed to investigate the influence of the overall Alzheimer's disease (AD) genetic architecture on Down syndrome (DS) status, cognitive measures, and cerebrospinal fluid (CSF) biomarkers. METHODS: AD polygenic risk scores (PRS) were tested for association with DS-related traits. RESULTS: The AD risk PRS was associated with disease status in several cohorts of sporadic late- and early-onset and familial late-onset AD, but not in familial early-onset AD or DS. On the other hand, lower DS Mental Status Examination memory scores were associated with higher PRS, independent of intellectual disability and APOE (PRS including APOE, PRSAPOE , p = 2.84 × 10-4 ; PRS excluding APOE, PRSnonAPOE , p = 1.60 × 10-2 ). PRSAPOE exhibited significant associations with Aß42, tTau, pTau, and Aß42/40 ratio in DS. DISCUSSION: These data indicate that the AD genetic architecture influences cognitive and CSF phenotypes in DS adults, supporting common pathways that influence memory decline in both traits. HIGHLIGHTS: Examination of the polygenic risk of AD in DS presented here is the first of its kind. AD PRS influences memory aspects in DS individuals, independently of APOE genotype. These results point to an overlap between the genes and pathways that leads to AD and those that influence dementia and memory decline in the DS population. APOE ε4 is linked to DS cognitive decline, expanding cognitive insights in adults.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Síndrome de Down , Adulto , Humanos , Doença de Alzheimer/diagnóstico , Síndrome de Down/genética , Estratificação de Risco Genético , Apolipoproteínas E/genética , Fenótipo , Disfunção Cognitiva/diagnóstico , Biomarcadores/líquido cefalorraquidiano , Cognição , Transtornos da Memória , Peptídeos beta-Amiloides/líquido cefalorraquidiano
3.
Alzheimers Dement ; 19(11): 5010-5022, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37089073

RESUMO

INTRODUCTION: Cognitive abilities have substantial heritability throughout life, as shown by twin- and population-based studies. However, there is limited understanding of the genetic factors related to cognitive decline in aging across neurocognitive domains. METHODS: We conducted a meta-analysis on 3045 individuals aged ≥65, derived from three population-based cohorts, to identify genetic variants associated with the decline of five neurocognitive domains (attention, memory, executive function, language, visuospatial function) and global cognitive decline. We also conducted gene-based and functional bioinformatics analyses. RESULTS: Apolipoprotein E (APOE)4 was significantly associated with decline of memory (p = 5.58E-09) and global cognitive function (p = 1.84E-08). We identified a novel association with attention decline on chromosome 9, rs6559700 (p = 2.69E-08), near RASEF. Gene-based analysis also identified a novel gene, TMPRSS11D, involved in the activation of SARS-CoV-2, to be associated with the decline in global cognitive function (p = 4.28E-07). DISCUSSION: Domain-specific genetic studies can aid in the identification of novel genes and pathways associated with decline across neurocognitive domains. HIGHLIGHTS: rs6559700 was associated with decline of attention. APOE4 was associated with decline of memory and global cognitive decline. TMPRSS11D, a gene involved in the activation of SARS-CoV-2, was implicated in global cognitive decline. Cognitive domain abilities had both unique and shared molecular pathways across the domains.


Assuntos
COVID-19 , Disfunção Cognitiva , Humanos , COVID-19/genética , SARS-CoV-2 , Cognição/fisiologia , Disfunção Cognitiva/genética , Atenção , Apolipoproteína E4/genética , Testes Neuropsicológicos
4.
Mol Psychiatry ; 26(1): 309-321, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-30361487

RESUMO

Deposition of amyloid plaques in the brain is one of the two main pathological hallmarks of Alzheimer's disease (AD). Amyloid positron emission tomography (PET) is a neuroimaging tool that selectively detects in vivo amyloid deposition in the brain and is a reliable endophenotype for AD that complements cerebrospinal fluid biomarkers with regional information. We measured in vivo amyloid deposition in the brains of ~1000 subjects from three collaborative AD centers and ADNI using 11C-labeled Pittsburgh Compound-B (PiB)-PET imaging followed by meta-analysis of genome-wide association studies, first to our knowledge for PiB-PET, to identify novel genetic loci for this endophenotype. The APOE region showed the most significant association where several SNPs surpassed the genome-wide significant threshold, with APOE*4 being most significant (P-meta = 9.09E-30; ß = 0.18). Interestingly, after conditioning on APOE*4, 14 SNPs remained significant at P < 0.05 in the APOE region that were not in linkage disequilibrium with APOE*4. Outside the APOE region, the meta-analysis revealed 15 non-APOE loci with P < 1E-05 on nine chromosomes, with two most significant SNPs on chromosomes 8 (P-meta = 4.87E-07) and 3 (P-meta = 9.69E-07). Functional analyses of these SNPs indicate their potential relevance with AD pathogenesis. Top 15 non-APOE SNPs along with APOE*4 explained 25-35% of the amyloid variance in different datasets, of which 14-17% was explained by APOE*4 alone. In conclusion, we have identified novel signals in APOE and non-APOE regions that affect amyloid deposition in the brain. Our data also highlights the presence of yet to be discovered variants that may be responsible for the unexplained genetic variance of amyloid deposition.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Compostos de Anilina/análise , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Estudo de Associação Genômica Ampla , Tomografia por Emissão de Pósitrons , Tiazóis/análise , Doença de Alzheimer/genética , Apolipoproteína E4/genética , Endofenótipos , Feminino , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética
5.
Theor Appl Genet ; 133(8): 2477-2497, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32462429

RESUMO

KEY MESSAGE: This study uses simulations to explore statistical power and false-positive rates for eQTL mapping in allopolyploid organisms and provides guidelines to apply eQTL mapping in these organisms. In recent years, RNA-seq has become the dominant technology for eQTL studies. However, most work has been in diploid organisms. Many species of economic and environmental importance are polyploid, and approaches for eQTL mapping in polyploids are not well developed. High similarity between duplicated genes in polyploids will cause misassignment of sequence reads and may cause false-positive results and/or lack of power to detect eQTL. In this paper, we first explore the similarity of homoeologous transcripts in polyploid organisms. We find that 5-20% of genes (varying with organism) in important agricultural plants such as wheat, soybean, and switchgrass are not sufficiently diverged between duplicated genomes to allow unambiguous assignment of reads. Second, we examine the impact of misassigned reads on eQTL mapping and show that both false-positive and false-negative rates can be greatly inflated. Third, we compare four strategies for dealing with ambiguous reads: (1) dividing ambiguous reads evenly between homoeologous transcripts, (2) assigning them proportionally, (3) using all reads for all genes, and (4) discarding ambiguous reads. We find that the strategy of discarding ambiguous reads gives the best balance of false-positive and false-negative rates for most genes. However, for genes that are very similar between genomes, using all reads is the only choice. This leads to reduced power, but false-positive rates will be maintained. We also discuss QTL mapping in polyploids using allele-specific expression (ASE) and show how the proportion of ASE-informative reads varies according to the divergence between homoeologous genes.


Assuntos
Mapeamento Cromossômico/métodos , Produtos Agrícolas/genética , Poliploidia , Análise de Sequência de RNA/métodos , Alelos , Diploide , Panicum/genética , Panicum/metabolismo , Filogenia , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Glycine max/genética , Glycine max/metabolismo , Triticum/genética , Triticum/metabolismo
6.
N Engl J Med ; 368(5): 436-45, 2013 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-23363497

RESUMO

BACKGROUND: The purpose of this analysis was to compare long-term urinary, bowel, and sexual function after radical prostatectomy or external-beam radiation therapy. METHODS: The Prostate Cancer Outcomes Study (PCOS) enrolled 3533 men in whom prostate cancer had been diagnosed in 1994 or 1995. The current cohort comprised 1655 men in whom localized prostate cancer had been diagnosed between the ages of 55 and 74 years and who had undergone either surgery (1164 men) or radiotherapy (491 men). Functional status was assessed at baseline and at 2, 5, and 15 years after diagnosis. We used multivariable propensity scoring to compare functional outcomes according to treatment. RESULTS: Patients undergoing prostatectomy were more likely to have urinary incontinence than were those undergoing radiotherapy at 2 years (odds ratio, 6.22; 95% confidence interval [CI], 1.92 to 20.29) and 5 years (odds ratio, 5.10; 95% CI, 2.29 to 11.36). However, no significant between-group difference in the odds of urinary incontinence was noted at 15 years. Similarly, although patients undergoing prostatectomy were more likely to have erectile dysfunction at 2 years (odds ratio, 3.46; 95% CI, 1.93 to 6.17) and 5 years (odds ratio, 1.96; 95% CI, 1.05 to 3.63), no significant between-group difference was noted at 15 years. Patients undergoing prostatectomy were less likely to have bowel urgency at 2 years (odds ratio, 0.39; 95% CI, 0.22 to 0.68) and 5 years (odds ratio, 0.47; 95% CI, 0.26 to 0.84), again with no significant between-group difference in the odds of bowel urgency at 15 years. CONCLUSIONS: At 15 years, no significant relative differences in disease-specific functional outcomes were observed among men undergoing prostatectomy or radiotherapy. Nonetheless, men treated for localized prostate cancer commonly had declines in all functional domains during 15 years of follow-up. (Funded by the National Cancer Institute.).


Assuntos
Disfunção Erétil/etiologia , Enteropatias/etiologia , Prostatectomia , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/cirurgia , Incontinência Urinária/etiologia , Idoso , Disfunção Erétil/epidemiologia , Seguimentos , Humanos , Enteropatias/epidemiologia , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Complicações Pós-Operatórias , Prevalência , Radioterapia/efeitos adversos , Incontinência Urinária/epidemiologia
7.
J Urol ; 193(4): 1226-31, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25451829

RESUMO

PURPOSE: Observational data suggest that androgen deprivation therapy increases the risk of diabetes and cardiovascular disease. Using data from the population based PCOS we evaluated whether age at diagnosis and comorbidity impact the association of androgen deprivation therapy with incident diabetes and cardiovascular disease. MATERIALS AND METHODS: We identified men with nonmetastatic prostate cancer diagnosed from 1994 to 1995 who were followed through 2009 to 2010. We used multivariable logistic regression models to assess the relationship of androgen deprivation therapy exposure (2 or fewer years, greater than 2 years or none) with incident diabetes and cardiovascular disease, adjusting for age at diagnosis, race, stage and comorbidity. RESULTS: Of 3,526 eligible study participants 2,985 without diabetes and 3,112 without cardiovascular disease comprised the cohorts at risk. Androgen deprivation therapy was not associated with an increased risk of diabetes or cardiovascular disease in men diagnosed with prostate cancer before age 70 years. Prolonged androgen deprivation therapy and increasing age at diagnosis in older men was associated with an increased risk of diabetes (at age 76 years OR 2.1, 95% CI 1.0-4.4) and cardiovascular disease (at age 74 years OR 1.9, 95% CI 1.0-3.5). Men with comorbidities were at greater risk for diabetes (OR 4.3, 95% CI 2.3-7.9) and cardiovascular disease (OR 8.1, 95% CI 4.3-15.5) than men without comorbidities. CONCLUSIONS: Prolonged androgen deprivation therapy exposure increases the risk of cardiovascular disease and diabetes in men diagnosed with prostate cancer who are older than approximately 75 years, especially those with other comorbidities. Older men who receive prolonged androgen deprivation therapy should be closely monitored for diabetes and cardiovascular disease.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/epidemiologia , Complicações do Diabetes/induzido quimicamente , Complicações do Diabetes/epidemiologia , Diabetes Mellitus/induzido quimicamente , Diabetes Mellitus/epidemiologia , Neoplasias da Próstata/complicações , Neoplasias da Próstata/tratamento farmacológico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/complicações , Estudos de Coortes , Complicações do Diabetes/complicações , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Risco , Sobreviventes
8.
Ann Intern Med ; 158(10): 709-17, 2013 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-23689764

RESUMO

BACKGROUND: Accurate estimation of life expectancy is essential to offering appropriate care to men with early-stage prostate cancer, but mortality risks associated with comorbidity are poorly defined. OBJECTIVE: To determine the effect of age, comorbidity, and tumor risk on other-cause and prostate cancer-specific mortality in men with early-stage disease. DESIGN: Prospective cohort study. SETTING: A nationally representative, population-based cohort. PATIENTS: 3183 men with nonmetastatic prostate cancer at diagnosis. MEASUREMENTS: Baseline self-reported comorbidity (scored as a count of 12 major comorbid conditions), tumor characteristics, initial treatment, and overall and disease-specific mortality through 14 years of follow-up. Survival analyses that accounted for competing risks were performed. RESULTS: Fourteen-year cumulative other-cause mortality rates were 24%, 33%, 46%, and 57% for men with 0, 1, 2, and 3 or more comorbid conditions, respectively. For men diagnosed at age 65 years, subhazard ratios for other-cause mortality among those with 1, 2, or 3 or more comorbid conditions (vs. none) were 1.2 (95% CI, 1.0 to 1.4), 1.7 (CI, 1.4 to 2.0), and 2.4 (CI, 2.0 to 2.8), respectively. Among men with 3 or more comorbid conditions, 10-year other-cause mortality rates were 26%, 40%, and 71% for those aged 60 years or younger, 61 to 74 years, and 75 years or older at diagnosis, respectively. Prostate cancer-specific mortality was minimal in patients with low-risk (3%) and intermediate-risk (7%) disease but appreciable in those with high-risk disease (18%) and did not vary by number of comorbid conditions (10% to 11% in all groups). LIMITATION: Comorbid conditions were self-reported. CONCLUSION: Older men with multiple major comorbid conditions are at high risk for other-cause mortality within 10 years of diagnosis and should consider this information when deciding between conservative management and aggressive treatment for low- or intermediate-risk prostate cancer. PRIMARY FUNDING SOURCE: National Cancer Institute.


Assuntos
Neoplasias da Próstata/mortalidade , Fatores Etários , Idoso , Causas de Morte , Comorbidade , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Estudos Prospectivos , Neoplasias da Próstata/patologia , Fatores de Risco
9.
Blood ; 118(4): 1140-4, 2011 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-21628416

RESUMO

B-cell activating factor (BAFF) single nucleotide polymorphisms (SNPs) are associated with autoimmune diseases. Because patients with classic and overlap chronic GVHD (cGVHD) have features of autoimmune diseases, we studied the association of recipient and/or donor BAFF SNPs with the phenotype of GVHD after allogeneic stem cell transplantation. Twenty tagSNPs of the BAFF gene were genotyped in 164 recipient/donor pairs. GVHD after day 100 occurred in 124 (76%) patients: acute GVHD (aGVHD) subtypes (n = 23), overlap GVHD (n = 29), and classic cGVHD (n = 72). In SNP analyses, 9 of the 20 tag SNPs were significant comparing classic/overlap cGVHD versus aGVHD subtypes/no GVHD. In multivariate analyses, 4 recipient BAFF SNPs (rs16972217 [odds ratio = 2.72, P = .004], rs7993590 [odds ratio = 2.35, P = .011], rs12428930 [odds ratio2.53, P = .008], and rs2893321 [odds ratio = 2.48, P = .009]) were independent predictors of GVHD subtypes, adjusted for conventional predictors of cGVHD. This study shows that genetic variation of BAFF modulates GVHD phenotype after allogeneic stem cell transplantation.


Assuntos
Fator Ativador de Células B/genética , Doença Enxerto-Hospedeiro/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Feminino , Genótipo , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Transplante Homólogo , Adulto Jovem
10.
J Hand Surg Am ; 38(1): 40-8, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23218558

RESUMO

PURPOSE: To assess the ability of volar locked plating to achieve and maintain normal radiographic parameters for articular stepoff, volar tilt, radial inclination, ulnar variance, and radial height in distal radius fractures. METHODS: We performed a retrospective review of 185 distal radius fractures that underwent volar locked plating with a single plate design over a 5-year period. We reviewed radiographs and recorded measurements for volar tilt, radial inclination, ulnar variance, radial height, and articular stepoff. We used logistic regression to determine the association between return to radiographic standard norms and fracture type. RESULTS: At the first and final postoperative follow-up visits, we observed articular congruence less than 2 mm in 92% of fractures at both times. Normal volar tilt (11°) was restored in 46% at the first follow-up and 48% at the final one. Radial inclination (22°) was achieved in 44% at the first follow-up and 43% at the final one, and ulnar variance (01 ± 2 mm) was achieved in 53% at the first follow-up and 53% at the final one. In addition, radial height (14 ± 1mm) was restored in 14% at the first follow-up and 12% at the final one. More complex, intra-articular fractures (AO class B and C and Frykman types 3, 4, 7, and 8) were less likely to be restored to normal radiographic parameters. However, because of the small sample size for some fracture types, it was difficult to discover significant associations between fracture type and radiographic outcome. CONCLUSIONS: Volar locked plating for distal radius fractures achieved articular stepoff less than 2 mm in most fractures but only restored and maintained normal radiographic measurements for volar tilt, radial inclination, and ulnar variance in 50% of fractures. The ability of volar locked plating to restore and maintain ulnar variance and volar tilt decreased with more complex intra-articular fracture types. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.


Assuntos
Placas Ósseas , Fraturas do Rádio/diagnóstico por imagem , Fraturas do Rádio/cirurgia , Adolescente , Adulto , Idoso , Feminino , Fixação Interna de Fraturas , Humanos , Fraturas Intra-Articulares/diagnóstico por imagem , Fraturas Intra-Articulares/cirurgia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Radiografia , Estudos Retrospectivos , Resultado do Tratamento , Articulação do Punho/diagnóstico por imagem , Adulto Jovem
11.
medRxiv ; 2023 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-36993271

RESUMO

Determining the genetic architecture of Alzheimer's disease (AD) pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we performed a genome-wide association study of cortical tau quantified by positron emission tomography in 3,136 participants from 12 independent studies. The CYP1B1-RMDN2 locus was associated with tau deposition. The most significant signal was at rs2113389, which explained 4.3% of the variation in cortical tau, while APOE4 rs429358 accounted for 3.6%. rs2113389 was associated with higher tau and faster cognitive decline. Additive effects, but no interactions, were observed between rs2113389 and diagnosis, APOE4 , and Aß positivity. CYP1B1 expression was upregulated in AD. rs2113389 was associated with higher CYP1B1 expression and methylation levels. Mouse model studies provided additional functional evidence for a relationship between CYP1B1 and tau deposition but not Aß. These results may provide insight into the genetic basis of cerebral tau and novel pathways for therapeutic development in AD.

12.
Acta Neuropathol Commun ; 11(1): 68, 2023 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-37101235

RESUMO

Amyloid PET imaging has been crucial for detecting the accumulation of amyloid beta (Aß) deposits in the brain and to study Alzheimer's disease (AD). We performed a genome-wide association study on the largest collection of amyloid imaging data (N = 13,409) to date, across multiple ethnicities from multicenter cohorts to identify variants associated with brain amyloidosis and AD risk. We found a strong APOE signal on chr19q.13.32 (top SNP: APOE ɛ4; rs429358; ß = 0.35, SE = 0.01, P = 6.2 × 10-311, MAF = 0.19), driven by APOE ɛ4, and five additional novel associations (APOE ε2/rs7412; rs73052335/rs5117, rs1081105, rs438811, and rs4420638) independent of APOE ɛ4. APOE ɛ4 and ε2 showed race specific effect with stronger association in Non-Hispanic Whites, with the lowest association in Asians. Besides the APOE, we also identified three other genome-wide loci: ABCA7 (rs12151021/chr19p.13.3; ß = 0.07, SE = 0.01, P = 9.2 × 10-09, MAF = 0.32), CR1 (rs6656401/chr1q.32.2; ß = 0.1, SE = 0.02, P = 2.4 × 10-10, MAF = 0.18) and FERMT2 locus (rs117834516/chr14q.22.1; ß = 0.16, SE = 0.03, P = 1.1 × 10-09, MAF = 0.06) that all colocalized with AD risk. Sex-stratified analyses identified two novel female-specific signals on chr5p.14.1 (rs529007143, ß = 0.79, SE = 0.14, P = 1.4 × 10-08, MAF = 0.006, sex-interaction P = 9.8 × 10-07) and chr11p.15.2 (rs192346166, ß = 0.94, SE = 0.17, P = 3.7 × 10-08, MAF = 0.004, sex-interaction P = 1.3 × 10-03). We also demonstrated that the overall genetic architecture of brain amyloidosis overlaps with that of AD, Frontotemporal Dementia, stroke, and brain structure-related complex human traits. Overall, our results have important implications when estimating the individual risk to a population level, as race and sex will needed to be taken into account. This may affect participant selection for future clinical trials and therapies.


Assuntos
Doença de Alzheimer , Amiloidose , Humanos , Feminino , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Doença de Alzheimer/complicações , Peptídeos beta-Amiloides/genética , Estudo de Associação Genômica Ampla , Amiloidose/diagnóstico por imagem , Amiloidose/genética , Amiloide , Apolipoproteínas E/genética
13.
Biol Blood Marrow Transplant ; 18(7): 1069-75, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22178694

RESUMO

Relapse remains a major cause of death after allogeneic hematopoietic cell transplantation (allo-HCT). Graft-versus-tumor effect is primarily mediated by donor T cells. Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a critical inhibitor of T cell proliferation. Single nucleotide polymorphisms (SNPs) in CTLA-4 may affect immune responses. We hypothesized that CTLA-4 SNPs will be associated with disease control after allo-HCT. One hundred sixty-four adult patients with the availability of pretransplantation recipient and donor DNA samples were included in this analysis. Ten tagSNPs of the CTLA-4 gene were identified. Donor CTLA-4 SNP rs4553808 was associated with decreased relapse-free survival (RFS) (P = .019) and overall survival (OS) (P = .033). In multivariable analysis of an additive genetic model, genotype of CTLA-4 SNP rs4553808 was an independent risk factor for inferior RFS (hazard ratio [HR] = 1.73, 95% confidence interval [CI] 1.10-2.71, P = .017) and OS (HR = 1.84, 95% CI 1.13-3.0, P = .015). CTLA-4 SNPs can be used to identify high-risk patient subsets that may benefit from preemptive immunomodulation to decrease relapse rates and improve survival.


Assuntos
Antígeno CTLA-4/genética , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Idoso , Antígeno CTLA-4/imunologia , Feminino , Efeito Enxerto vs Tumor/imunologia , Neoplasias Hematológicas/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/imunologia , Fatores de Risco , Prevenção Secundária , Análise de Sobrevida , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/imunologia , Doadores de Tecidos , Transplante Homólogo , Resultado do Tratamento
14.
Genes (Basel) ; 13(12)2022 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-36553504

RESUMO

Structural variations such as copy number variants (CNVs) have been associated with multiple autoimmune diseases. In this study, we explored the association of the Fc gamma receptor 3B gene (FCGR3B) copy number variation (CNV) with rheumatoid arthritis (RA) susceptibility and related serological traits in the Pakistani population. We also performed a meta-analysis of four published FCGR3B CNV studies along with the current study. A total of 927 subjects (597 RA cases, 330 healthy controls) were recruited from three rheumatology centers in Pakistan. Anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor (RF) were measured in RA patients. FCGR3B copy number was assayed using the TaqMan® CN assay (Hs04211858_cn, Applied Biosystems, Foster City, CA, USA) and the copy number was estimated by using CopyCaller® software (version 2.1; Applied Biosystems, USA). Logistic regression was applied to calculate the odds ratio (OR) of RA risk associated with FCGR3B CNV using sex and age as covariates in R. Meta-analysis on four previously published studies and the current study was performed using the random-effect model. We observed a significant association between FCGR3B copy number < 2 and RA susceptibility (OR = 1.53; 95% CI: 1.05 to 2.22; p = 0.0259) and anti-CCP seropositivity (OR 2.56; 95% CI: 1.34 to 4.89; p = 0.0045). A non-significant association of FCGR3B copy number < 2 was also observed between increased rheumatoid factor (RF) seropositivity (OR = 1.74; 95% CI:0.93 to 3.26; p = 0.0816). Meta-analysis on 13,915 subjects (7005 RA cases and 6907 controls) also showed significant association of copy number < 2 with the increased risk of RA (OR = 1.30; 95% CI: 1.07 to 1.56; p = 0.00671). FCGR3B copy number < 2 is associated with increased RA risk and anti-CCP seropositivity.


Assuntos
Artrite Reumatoide , Variações do Número de Cópias de DNA , Receptores de IgG , Humanos , Anticorpos Antiproteína Citrulinada , Artrite Reumatoide/genética , Autoanticorpos , Variações do Número de Cópias de DNA/genética , Dosagem de Genes , Predisposição Genética para Doença , Receptores de IgG/genética , Fator Reumatoide/genética
15.
J Alzheimers Dis ; 88(2): 787-798, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35694926

RESUMO

BACKGROUND: Alzheimer's disease (AD) is a complex disease influenced by the environment and genetics; however, much of the genetic component remains unaccounted for. OBJECTIVE: The purpose of this work was to use genome-wide association analyses to detect genetic associations with incident AD in a sample of older adults aged 75 and above. METHODS: We performed a genome-wide association study (GWAS) on genome-wide genotyped and imputed data (14,072,053 variants) on the Gingko Evaluation of Memory (GEM) study sample consisting of 424 incident dementia (mean age = 84.46±3.91) and 2,206 non-demented (mean age = 84.55±3.23) subjects. RESULTS: The established association of APOE*4 carriers with AD was confirmed in this community-based sample of older subjects (odds ratio (OR) = 2.22; p = 9.36E-14) and was stronger in females (OR = 2.72; p = 1.74E-10) than in males (OR = 1.88; p = 2.43E-05). We observed a novel genome-wide significant (GWS) locus on chromosome 12 near ncRNA LOC105369711/rs148377161 (OR = 3.31; p = 1.66E-08). In addition, sex-stratified analyses identified two novel associations in males: one near ncRNA LOC729987/rs140076909 on chromosome 1 (OR = 4.51; p = 3.72E-08) and the other approaching GWS near ncRNA LOC105375138/rs117803234 on chromosome 7 (OR = 3.76; p = 6.93E-08). CONCLUSION: The use of community-based samples of older individuals and incident dementia as a phenotype may be a helpful approach for the identification of novel genes for AD, which may not be detected in standard case-control studies. Replication of these signals and further studies of these regions and genes will help to provide a clearer picture for their role in AD.


Assuntos
Doença de Alzheimer , Estudo de Associação Genômica Ampla , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética
16.
Gene ; 783: 145563, 2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-33705809

RESUMO

Genome-wide association studies (GWAS) have identified multiple type 2 diabetes (T2D) loci, mostly among populations of European descent. There is a high prevalence of T2D among Pakistanis. Both genetic and environmental factors may be responsible for this high prevalence. In order to understand the shared genetic basis of T2D among Pakistanis and Europeans, we examined 77 genome-wide significant variants previously implicated among European populations. We genotyped 77 single-nucleotide polymorphisms (SNPs) by iPLEX® Gold or TaqMan® assays in a case-control sample of 1,683 individuals. Association analysis was performed using logistic regression. A total of 16 SNPs (TCF7L2/rs7903146, GLIS3/rs7041847, CHCHD9/rs13292136, PLEKHA1/rs2292626, FTO/rs9936385, CDKAL1/rs7756992, KCNJ11/rs5215, LOC105372155/rs12970134, KCNQ1/rs163182, CTRB1/rs7202877, ST6GAL1/rs16861329, ADAMTS9-AS2/rs6795735, LOC105370275/rs1359790, C5orf67/rs459193, ZBED3-AS1/rs6878122 and UBE2E2/rs7612463) showed statistically significant associations after controlling for the false discovery rate. While KCNQ1/rs163182 and ZBED3-AS1/rs6878122 showed opposite allelic effects, the remaining significant SNPs had the same allelic effects as reported previously. Our data indicate that a selected number of T2D loci previously identified among populations of European descent also affect the risk of T2D in the Pakistani population.


Assuntos
Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla , Feminino , Predisposição Genética para Doença , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Paquistão , Polimorfismo de Nucleotídeo Único , Medição de Risco
17.
PLoS One ; 15(9): e0239426, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32946523

RESUMO

Rheumatoid arthritis (RA) is a multifactorial autoimmune disease. The interaction of genetic and environmental factors is likely necessary for RA. Among potential genetic factors, many major histocompatibility complex (MHC) and non-MHC variants may be involved in RA susceptibility. CTLA4 is involved in the regulation of T-cell response during an immune reaction, and multiple CTLA4 single nucleotide polymorphisms (SNPs) have been associated with numerous autoimmune diseases, including RA. To our knowledge, the genetic association of CTLA4 with RA risk has not been examined previously in the Pakistani population. In this study, we sequenced the entire CTLA4 gene and flanking regions in 95 Pakistani RA cases followed the screening of identified variants in Study 1 sample consisting of 350 RA cases and controls. Four common significant variants identified in Study 1 sample were further examined in a larger Study 2 replication sample comprising 1,678 independent RA cases and controls. We report significant associations of three variants from the combined analysis: rs3087243 (OR = 1.26, p = 4.47E-03), rs5742909 (OR = 1.78, p = 4.60E-03), and rs11571319 (OR = 1.48, p = 6.64E-03); the latter is a novel association in the Pakistani sample.


Assuntos
Artrite Reumatoide/genética , Antígeno CTLA-4/genética , Análise de Sequência , Adulto , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Paquistão , Polimorfismo de Nucleotídeo Único
18.
Dis Markers ; 2020: 7189626, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33101545

RESUMO

OBJECTIVE: Copy number variation (CNV) is a structural variation in the human genome that has been associated with multiple clinical phenotypes. B cells are important components of rheumatoid arthritis- (RA-) mediated immune response; hence, CNV in the regulators of B cells (such as VPREB1) can influence RA susceptibility. In this study, we aimed to explore the association of CNV in the VPREB1 gene with RA susceptibility in the Pakistani population. METHODS: A total of 1,106 subjects (616 RA cases, 490 healthy controls) were selected from three rheumatology centers in Pakistan. VPREB1 CNV was determined using the TaqMan® CN assay (Hs02879734_cn, Applied Biosystems, Foster City, CA, USA), and CNV was estimated by using CopyCaller® (version 2.1; Applied Biosystems, USA) software. Odds ratio (OR) was calculated by logistic regression with sex and age as covariates in R. RESULTS: A significant association between >2 VPREB1 CNV and RA risk was observed with an OR of 3.92 (95% CI: 1.27 - 12.12; p = 0.01746) in the total sample. Whereas <2 CNV showed a significantly protective effect against RA risk in women with an OR of 0.48 (95% CI: 0.29-0.79; p = 0.00381). CONCLUSION: CNV > 2 of VPREB1 is a risk factor for RA in the total Pakistani population, while CNV < 2 is protective in women.


Assuntos
Artrite Reumatoide/genética , Variações do Número de Cópias de DNA , Cadeias Leves Substitutas da Imunoglobulina/genética , Adulto , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Paquistão
19.
J Alzheimers Dis ; 76(4): 1553-1565, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32651314

RESUMO

The genetics of late-onset Alzheimer's disease (AD) is complex due to the heterogeneous nature of the disorder. APOE*4 is the strongest genetic risk factor for AD. Genome-wide association studies have identified more than 30 additional loci, each having relatively small effect size. Known AD loci explain only about 30% of the genetic variance, and thus much of the genetic variance remains unexplained. To identify some of the missing heritability of AD, we analyzed whole-exome sequencing (WES) data focusing on non-APOE*4 carriers from two WES datasets: 720 cases and controls from the University of Pittsburgh and 7,252 cases and controls from the Alzheimer's Disease Sequencing Project. Following separate WES analyses in each dataset, we performed meta-analysis for overlapping markers present in both datasets. Among the four variants reaching the exome-wide significance threshold, three were from known AD loci: APOE/rs7412 (odds ratio (OR) = 0.40; p = 5.46E-24), TOMM40/rs157581 (OR = 1.49; p = 4.04E-07), and TREM2/rs75932628 (OR = 4.00; p = 1.15E-07). The fourth significant variant, rs199533, was from a novel locus on chromosome 17 in the NSF gene (OR = 0.78; p = 2.88E-07). NSF was also significant in the gene-based analysis (p = 1.20E-05). In the GTEx data, NSF/rs199533 is a cis-eQTL for multiple genes in the brain and blood, including NSF that is highly expressed across all brain tissues, including regions that typically show amyloid-ß accumulation. Further characterization of genes that are affected by NSF/rs199533 may help to shed light on the roles of these genes in AD etiology.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Apolipoproteínas E/genética , Predisposição Genética para Doença/genética , Idoso , Exoma/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Proteínas de Membrana Transportadoras/genética , Polimorfismo de Nucleotídeo Único/genética
20.
Dis Markers ; 2020: 1910215, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32831971

RESUMO

Rheumatoid arthritis (RA) is a complex and multifactorial autoimmune disorder with the involvement of multiple genetic and environmental factors. Genome-wide association studies (GWAS) have identified more than 50 RA genetic loci in European populations. Given the anticipated overlap of RA-relevant genes and pathways across different ethnic groups, we sought to replicate 58 GWAS-implicated SNPs reported in Europeans in Pakistani subjects. 1,959 unrelated subjects comprising 1,222 RA cases and 737 controls were collected from three rheumatology facilities in Pakistan. Genotyping was performed using iPLEX or TaqMan® methods. A total of 50 SNPs were included in the final association analysis after excluding those that failed assay design/run or postrun QC analysis. Fourteen SNPs (LINC00824/rs1516971, PADI4/rs2240336, CEP57/rs4409785, CTLA4/rs3087243, STAT4/rs13426947, HLA-B/MICA/rs2596565, C5orf30/rs26232, CCL21/rs951005, GATA3/rs2275806, VPS37C/rs595158, HLA-DRB1/rs660895, EOMES/rs3806624, SPRED2/rs934734, and RUNX1/rs9979383) were replicated in our Pakistani sample at false discovery rate (FDR) of <0.20 with nominal p values ranging from 4.73E-06 to 3.48E-02. Our results indicate that several RA susceptibility loci are shared between Pakistani and European populations, supporting the role of common genes/pathways.


Assuntos
Artrite Reumatoide/genética , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Adulto , Estudos de Casos e Controles , Europa (Continente)/etnologia , Feminino , Predisposição Genética para Doença/etnologia , Humanos , Masculino , Pessoa de Meia-Idade , Paquistão
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