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1.
Diabetes Care ; 42(3): 406-415, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30659077

RESUMO

OBJECTIVE: Genetic risk scores (GRS) have been developed that differentiate individuals with type 1 diabetes from those with other forms of diabetes and are starting to be used for population screening; however, most studies were conducted in European-ancestry populations. This study identifies novel genetic variants associated with type 1 diabetes risk in African-ancestry participants and develops an African-specific GRS. RESEARCH DESIGN AND METHODS: We generated single nucleotide polymorphism (SNP) data with the ImmunoChip on 1,021 African-ancestry participants with type 1 diabetes and 2,928 control participants. HLA class I and class II alleles were imputed using SNP2HLA. Logistic regression models were used to identify genome-wide significant (P < 5.0 × 10-8) SNPs associated with type 1 diabetes in the African-ancestry samples and validate SNPs associated with risk in known European-ancestry loci (P < 2.79 × 10-5). RESULTS: African-specific (HLA-DQA1*03:01-HLA-DQB1*02:01) and known European-ancestry HLA haplotypes (HLA-DRB1*03:01-HLA-DQA1*05:01-HLA-DQB1*02:01, HLA-DRB1*04:01-HLA-DQA1*03:01-HLA-DQB1*03:02) were significantly associated with type 1 diabetes risk. Among European-ancestry defined non-HLA risk loci, six risk loci were significantly associated with type 1 diabetes in subjects of African ancestry. An African-specific GRS provided strong prediction of type 1 diabetes risk (area under the curve 0.871), performing significantly better than a European-based GRS and two polygenic risk scores in independent discovery and validation cohorts. CONCLUSIONS: Genetic risk of type 1 diabetes includes ancestry-specific, disease-associated variants. The GRS developed here provides improved prediction of type 1 diabetes in African-ancestry subjects and a means to identify groups of individuals who would benefit from immune monitoring for early detection of islet autoimmunity.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Diabetes Mellitus Tipo 1/etnologia , Diabetes Mellitus Tipo 1/genética , Testes Genéticos , Antígenos HLA-D/genética , Grupo com Ancestrais do Continente Africano/estatística & dados numéricos , Alelos , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Testes Genéticos/métodos , Testes Genéticos/normas , Estudo de Associação Genômica Ampla , Cadeias alfa de HLA-DQ/genética , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Haplótipos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Projetos de Pesquisa , Fatores de Risco
2.
Diabetes ; 68(4): 847-857, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30655385

RESUMO

The risk for autoimmunity and subsequently type 1 diabetes is 10-fold higher in children with a first-degree family history of type 1 diabetes (FDR children) than in children in the general population (GP children). We analyzed children with high-risk HLA genotypes (n = 4,573) in the longitudinal TEDDY birth cohort to determine how much of the divergent risk is attributable to genetic enrichment in affected families. Enrichment for susceptible genotypes of multiple type 1 diabetes-associated genes and a novel risk gene, BTNL2, was identified in FDR children compared with GP children. After correction for genetic enrichment, the risks in the FDR and GP children converged but were not identical for multiple islet autoantibodies (hazard ratio [HR] 2.26 [95% CI 1.6-3.02]) and for diabetes (HR 2.92 [95% CI 2.05-4.16]). Convergence varied depending upon the degree of genetic susceptibility. Risks were similar in the highest genetic susceptibility group for multiple islet autoantibodies (14.3% vs .12.7%) and diabetes (4.8% vs. 4.1%) and were up to 5.8-fold divergent for children in the lowest genetic susceptibility group, decreasing incrementally in GP children but not in FDR children. These findings suggest that additional factors enriched within affected families preferentially increase the risk of autoimmunity and type 1 diabetes in lower genetic susceptibility strata.


Assuntos
Autoimunidade/fisiologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Autoanticorpos/imunologia , Autoimunidade/genética , Predisposição Genética para Doença/genética , Genótipo , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/imunologia , Humanos , Ilhotas Pancreáticas/metabolismo , Modelos de Riscos Proporcionais , Fatores de Risco
3.
Curr Opin Genet Dev ; 50: 7-16, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29453110

RESUMO

Type 1 diabetes is the most common autoimmune disorder in childhood, characterized by the development of autoimmunity through unknown environmental insults in genetically susceptible individuals. There are now over 50 regions of the genome that harbor type 1 diabetes susceptibility genes, with much of the genetic risk now well-defined in youth of Northern European ancestry. The impact of these genetic variants on initiation and progression of the autoimmune process (islet autoimmunity) is now being understood; however, studies are only now being conducted to understand the function of the variants associated with type 1 diabetes risk. The characteristics of genetic risk of type 1 diabetes across the age spectrum suggests extensive complexity in biological and environmental mechanisms. We propose that both genetic and environmental factors attributed to type 1 and type 2 diabetes may contribute to beta-cell death through multiple mechanisms, leading to the clinical outcome of type 1 diabetes.


Assuntos
Autoimunidade/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/genética , Genoma Humano/genética , Morte Celular/genética , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/patologia , Predisposição Genética para Doença , Humanos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Fatores de Risco
5.
Nephrol Dial Transplant ; 32(6): 983-990, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-27190333

RESUMO

Background: Individuals of African ancestry harboring two variant alleles within apolipoprotein L1 ( APOL1 ) are classified with a high-risk (HR) genotype. Adults with an HR genotype have increased risk of focal segmental glomerulosclerosis and chronic kidney disease compared with those with a low-risk (LR) genotype (0 or 1 variants). The role of APOL1 risk genotypes in children with glomerular disease is less well known. Methods: This study characterized 104 African-American children with a glomerular disease by APOL1 genotype in two cohorts: the Chronic Kidney Disease in Children (CKiD) and Nephrotic Syndrome Study Network (NEPTUNE). Results: Among these subjects, 46% had an HR genotype with a similar age at cohort enrollment. For APOL1 HR children, the median age of disease onset was older (CKiD: 4.5 versus 11.5 years for LR versus HR; NEPTUNE: 11 versus 14 years for LR versus HR, respectively) and preterm birth was more common [CKiD: 27 versus 4%; NEPTUNE: 26 versus 12%; combined odds ratio 4.6 (95% confidence interval: 1.4, 15.5)]. Within studies, HR children had lower initial estimated glomerular filtration rate (eGFR) (CKiD: 53 versus 69 mL/min/1.73 m 2 ; NEPTUNE: 74 versus 94 mL/min/1.73 m 2 ). Longitudinal eGFR decline was faster among HR children versus LR (CKiD: -18 versus -8% per year; NEPTUNE: -13 versus -3% per year). Conclusions: Children with an HR genotype in CKiD and NEPTUNE seem to have a more aggressive form of glomerular disease, in part due to a higher prevalence of focal segmental glomerulosclerosis. These consistent findings across independent cohorts suggest a common natural history for children with APOL1 -associated glomerular disease. Further study is needed to determine the generalizability of these findings.


Assuntos
Apolipoproteína L1/genética , Síndrome Nefrótica/genética , Adolescente , Afro-Americanos/genética , Idade de Início , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Síndrome Nefrótica/patologia , Síndrome Nefrótica/fisiopatologia , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Estados Unidos
6.
Nephrol Dial Transplant ; 32(12): 2051-2058, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27638911

RESUMO

Background: Two genetic variants in apolipoprotein L1 (APOL1) are associated with increased risk of focal segmental glomerulosclerosis as well as other glomerular phenotypes. These risk variants are common in individuals of African ancestry but absent in other racial groups. Yet, the majority of individuals with two APOL1 risk alleles [high-risk (HR) genotype] do not have renal disease. It is critical to identify environmental and secondary genetic influences that, when combined with these alleles, lead to kidney disease. In a recent study of black children with glomerular disease enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) and Chronic Kidney Disease in Children Study (n = 104), we found that subjects with an HR genotype had a 4.6-fold increase in the odds of preterm birth as compared to those with a low risk (LR) genotype [odds ratio 4.6 (CI 1.4-15.5)]. There are known racial disparities in preterm birth, which itself is a known risk factor for chronic kidney disease and focal segmental glomerulosclerosis. Thus, we questioned whether an HR APOL1 genotype is associated with prematurity in the general African American population. Methods: We analyzed two publically available genetic datasets of preterm birth in African Americans, including 867 infants and 519 mothers from the Gene Environment Association Studies (GENEVA) study of preterm delivery and 960 mothers from the Boston Medical Center genome-wide association study of preterm birth. We performed multivariable analyses testing for association between HR APOL1 and birth outcomes. Results: In both studies, there was no association between HR APOL1 in mothers and prematurity, gestational age or birthweight. Additionally, in the GENEVA study, we saw no association between infant HR APOL1 and prematurity, gestational age or birthweight. Conclusion: From these data, we conclude that the previously observed association between HR APOL1 and prematurity is specific to those with glomerular disease, suggesting prematurity may act as an additional risk factor in APOL1-associated renal disease.


Assuntos
Afro-Americanos/genética , Apolipoproteína L1/genética , Variação Genética , Glomerulosclerose Segmentar e Focal/complicações , Nascimento Prematuro/genética , Insuficiência Renal Crônica/complicações , Adulto , Estudos de Casos e Controles , Criança , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Glomerulosclerose Segmentar e Focal/genética , Humanos , Fenótipo , Nascimento Prematuro/diagnóstico , Nascimento Prematuro/etiologia , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/genética , Fatores de Risco , Estados Unidos/epidemiologia , Adulto Jovem
7.
Pediatr Nephrol ; 32(3): 467-476, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27766458

RESUMO

BACKGROUND: More than 30 genes can harbor rare exonic variants sufficient to cause nephrotic syndrome (NS), and the number of genes implicated in monogenic NS continues to grow. However, outside the first year of life, the majority of affected patients, particularly in ancestrally mixed populations, do not have a known monogenic form of NS. Even in those children classified with a monogenic form of NS, there is phenotypic heterogeneity. Thus, we have only discovered a fraction of the heritability of NS-the underlying genetic factors contributing to phenotypic variation. Part of the "missing heritability" for NS has been posited to be explained by patients harboring coding variants across one or more previously implicated NS genes, insufficient to cause NS in a classical Mendelian manner, but that nonetheless have a sufficient impact on protein function to cause disease. However, systematic evaluation in patients with NS for rare or low-frequency risk alleles within single genes, or in combination across genes ("oligogenicity"), has not been reported. To determine whether, compared with a reference population, patients with NS have either a significantly increased burden of protein-altering variants ("risk-alleles"), or a unique combination of them ("oligogenicity"), in a set of 21 genes implicated in Mendelian forms of NS. METHODS: In 303 patients with NS enrolled in the Nephrotic Syndrome Study Network (NEPTUNE), we performed targeted amplification paired with next-generation sequencing of 21 genes implicated in monogenic NS. We created a high-quality variant call set and compared it with a variant call set of the same genes in a reference population composed of 2,535 individuals from phase 3 of the 1000 Genomes Project. We created both a "stringent" and a "relaxed" pathogenicity-filtering pipeline, applied them to both cohorts, and computed the burden of variants in the entire gene set per cohort, the burden of variants in the entire gene set per individual, the burden of variants within a single gene per cohort, and unique combinations of variants across two or more genes per cohort. RESULTS: With few exceptions when using the relaxed filter, and which are likely the result of confounding by population stratification, NS patients did not have a significantly increased burden of variants in Mendelian NS genes in comparison to a reference cohort, nor was there any evidence for oligogenicity. This was true when using both the relaxed and the stringent variant pathogenicity filter. CONCLUSION: In our study, there were no significant differences in the burden or particular combinations of low-frequency or rare protein-altering variants in a previously implicated Mendelian NS genes cohort between North American patients with NS and a reference population. Studies in larger independent cohorts or meta-analyses are needed to assess the generalizability of our discoveries and also address whether there is in fact small but significant enrichment of risk alleles or oligogenicity in NS cases that was undetectable with this current sample size. It is still possible that rare protein-altering variants in these genes, insufficient to cause Mendelian disease, still contribute to NS as risk alleles and/or via oligogenicity. However, we suggest that more accurate bioinformatic analyses and the incorporation of functional assays would be necessary to identify bona fide instances of this form of genetic architecture as a contributor to the heritability of NS.


Assuntos
Alelos , Síndrome Nefrótica/genética , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Frequência do Gene , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Fenótipo , Valores de Referência , Risco , Adulto Jovem
8.
BMC Bioinformatics ; 17(1): 233, 2016 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-27287006

RESUMO

BACKGROUND: Targeted sequencing of discrete gene sets is a cost effective strategy to screen subjects for monogenic forms of disease. One method to achieve this pairs microfluidic PCR with next generation sequencing. The PCR step of this pipeline creates challenges in accurate variant calling. This includes that most reads targeting a specific exon are duplicates that have been amplified from the PCR step. To reduce false positive variant calls from these experiments, previous studies have used threshold-based filtering of alternative allele depth ratio and manual inspection of the alignments. However even after manual inspection and filtering, many variants fail to be validated via Sanger sequencing. To improve the accuracy of variant calling from these experiments, we are challenged to design a variant filtering strategy that sufficiently models microfluidic PCR-specific issues. RESULTS: We developed an open source variant filtering pipeline, targeted sequencing support vector machine ("tarSVM"), that uses a Support Vector Machine (SVM) and a new score the normalized allele dosage test to identify high quality variants from microfluidic PCR data. tarSVM maximizes training knowledge by selecting variants that are likely true and likely false variants by incorporating knowledge from the 1000 Genomes and the Exome Aggregation Consortium projects. tarSVM improves on previous approaches by synthesizing variant features from the Genome Analysis Toolkit and allele dosage information. We compared the accuracy of tarSVM versus existing variant quality filtering strategies on two cohorts (n = 474 and n = 1152), and validated our method on a third cohort (n = 75). In the first cohort, our method achieved 84.5 % accuracy of predicting whether or not a variant would be validated with Sanger sequencing versus 78.8 % for the second most accurate method. In the second cohort, our method had an accuracy of 73.3 %, versus 61.5 % for the second best method. Finally, our method had a false discovery rate of 5 % for the validation cohort. CONCLUSIONS: tarSVM increases the accuracy of variant calling when using microfluidic PCR based targeted sequencing approaches. This results in higher confidence downstream analyses, and ultimately reduces the costs Sanger validation. Our approach is less labor intensive than existing approaches, and is available as an open source pipeline for read trimming, aligning, variant calling, and variant quality filtering on GitHub at https://github.com/christopher-gillies/TargetSpecificGATKSequencingPipeline .


Assuntos
Alelos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Microfluídica , Software , Máquina de Vetores de Suporte , Confiabilidade dos Dados , Humanos , Reação em Cadeia da Polimerase , Análise de Sequência de DNA/métodos
9.
J Am Soc Nephrol ; 27(3): 814-23, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26150607

RESUMO

APOL1 variants have been associated with renal phenotypes in blacks. To refine clinical outcomes and discover mechanisms of APOL1-associated kidney injury, we analyzed clinical and genomic datasets derived from 90 black subjects in the Nephrotic Syndrome Study Network (NEPTUNE), stratified by APOL1 risk genotype. Ninety subjects with proteinuria ≥0.5 g/d were enrolled at first biopsy for primary nephrotic syndrome and followed. Clinical outcomes were determined, and renal histomorphometry and sequencing of Mendelian nephrotic syndrome genes were performed. APOL1 variants were genotyped, and glomerular and tubulointerstitial transcriptomes from protocol renal biopsy cores were analyzed for differential and correlative gene expression. Analyses were performed under the recessive model (high-risk genotype defined by two risk alleles). APOL1 high-risk genotype was significantly associated with a 17 ml/min per 1.73 m(2) lower eGFR and a 69% reduction in the probability of complete remission at any time, independent of histologic diagnosis. Neither APOL1 risk group was enriched for Mendelian mutations. On renal biopsy, high-risk genotype was associated with increased fractional interstitial area, interstitial fibrosis, and tubular atrophy. Risk genotype was not associated with intrarenal APOL1 mRNA expression levels. Differential expression analysis demonstrated an increased steady-state level of five genes associated with the high-risk genotype (CXCL9, CXCL11, and UBD in glomerulus; SNOR14B and MUC13 in tubulointerstitium). APOL1 tubulointerstitial coexpression analysis showed coexpression of APOL1 mRNA levels with a group of intrarenal transcripts that together were associated with increased interstitial fibrosis and tubular atrophy. These data indicate the high-risk APOL1 genotype confers renal risk across histopathologic diagnoses.


Assuntos
Afro-Americanos/genética , Apolipoproteínas/genética , Genômica/métodos , Túbulos Renais/patologia , Lipoproteínas HDL/genética , Síndrome Nefrótica/genética , Síndrome Nefrótica/patologia , Adolescente , Adulto , Alelos , Apolipoproteína L1 , Atrofia/genética , Biópsia , Quimiocina CXCL11/genética , Quimiocina CXCL9/genética , Criança , Feminino , Fibrose , Expressão Gênica , Genótipo , Taxa de Filtração Glomerular/genética , Humanos , Glomérulos Renais/fisiopatologia , Túbulos Renais/metabolismo , Túbulos Renais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mucinas/genética , Síndrome Nefrótica/fisiopatologia , Proteinúria/genética , RNA Mensageiro/metabolismo , Fatores de Risco , Transcriptoma , Ubiquitinas/genética , Adulto Jovem
10.
J Am Soc Nephrol ; 27(7): 1970-83, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26534921

RESUMO

To maximize clinical benefits of genetic screening of patients with nephrotic syndrome (NS) to diagnose monogenic causes, reliably distinguishing NS-causing variants from the background of rare, noncausal variants prevalent in all genomes is vital. To determine the prevalence of monogenic NS in a North American case cohort while accounting for background prevalence of genetic variation, we sequenced 21 implicated monogenic NS genes in 312 participants from the Nephrotic Syndrome Study Network and 61 putative controls from the 1000 Genomes Project (1000G). These analyses were extended to available sequence data from approximately 2500 subjects from the 1000G. A typical pathogenicity filter identified causal variants for NS in 4.2% of patients and 5.8% of subjects from the 1000G. We devised a more stringent pathogenicity filtering strategy, reducing background prevalence of causal variants to 1.5%. When applying this stringent filter to patients, prevalence of monogenic NS was 2.9%; of these patients, 67% were pediatric, and 44% had FSGS on biopsy. The rate of complete remission did not associate with monogenic classification. Thus, we identified factors contributing to inaccurate monogenic classification of NS and developed a more accurate variant filtering strategy. The prevalence and clinical correlates of monogenic NS in this sporadically affected cohort differ substantially from those reported for patients referred for genetic analysis. Particularly in unselected, population-based cases, considering putative causal variants in known NS genes from a probabilistic rather than a deterministic perspective may be more precise. We also introduce GeneVetter, a web tool for monogenic assessment of rare disease.


Assuntos
Genética Populacional , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Humanos , Pessoa de Meia-Idade , Adulto Jovem
11.
Bioinformatics ; 31(22): 3682-4, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26209433

RESUMO

UNLABELLED: When performing DNA sequencing to diagnose affected individuals with monogenic forms of rare diseases, accurate attribution of causality to detected variants is imperative but imperfect. Even if a gene has variants already known to cause a disease, rare disruptive variants predicted to be causal are not always so, mainly due to imperfect ability to predict the pathogenicity of variants. Existing population-scale sequence resources such as 1000 Genomes are useful to quantify the 'background prevalence' of an unaffected individual being falsely predicted to carry causal variants. We developed GeneVetter to allow users to quantify the 'background prevalence' of subjects with predicted causal variants within specific genes under user-specified filtering parameters. GeneVetter helps quantify uncertainty in monogenic diagnosis and design genetic studies with support for power and sample size calculations for specific genes with specific filtering criteria. GeneVetter also allows users to analyze their own sequence data without sending genotype information over the Internet. Overall, GeneVetter is an interactive web tool that facilitates quantifying and accounting for the background prevalence of predicted pathogenic variants in a population. AVAILABILITY AND IMPLEMENTATION: GeneVetter is available at http://genevetter.org/ CONTACT: mgsamps@med.umich.edu or hmkang@umich.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Internet , Doenças Raras/genética , Software , Diabetes Mellitus Tipo 2/genética , Humanos , Síndrome Nefrótica/genética , Análise de Sequência de DNA
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