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1.
Nat Commun ; 10(1): 3842, 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31451708

RESUMO

Chronic kidney disease (CKD), defined by low estimated glomerular filtration rate (eGFR), contributes to global morbidity and mortality. Here we conduct a transethnic Genome-Wide Association Study of eGFR in 280,722 participants of the Million Veteran Program (MVP), with replication in 765,289 participants from the Chronic Kidney Disease Genetics (CKDGen) Consortium. We identify 82 previously unreported variants, confirm 54 loci, and report interesting findings including association of the sickle cell allele of betaglobin among non-Hispanic blacks. Our transcriptome-wide association study of kidney function in healthy kidney tissue identifies 36 previously unreported and nine known genes, and maps gene expression to renal cell types. In a Phenome-Wide Association Study in 192,868 MVP participants using a weighted genetic score we detect associations with CKD stages and complications and kidney stones. This investigation reinterprets the genetic architecture of kidney function to identify the gene, tissue, and anatomical context of renal homeostasis and the clinical consequences of dysregulation.

2.
Hum Genomics ; 13(1): 21, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31092297

RESUMO

BACKGROUND: End-stage kidney disease (ESKD) is a significant public health concern disproportionately affecting African Americans (AAs). Type 2 diabetes (T2D) is the leading cause of ESKD in the USA, and efforts to uncover genetic susceptibility to diabetic kidney disease (DKD) have had limited success. A prior genome-wide association study (GWAS) in AAs with T2D-ESKD was expanded with additional AA cases and controls and genotypes imputed to the higher density 1000 Genomes reference panel. The discovery analysis included 3432 T2D-ESKD cases and 6977 non-diabetic non-nephropathy controls (N = 10,409), followed by a discrimination analysis in 2756 T2D non-nephropathy controls to exclude T2D-associated variants. RESULTS: Six independent variants located in or near RND3/RBM43, SLITRK3, ENPP7, GNG7, and APOL1 achieved genome-wide significant association (P < 5 × 10-8) with T2D-ESKD. Following extension analyses in 1910 non-diabetic ESKD cases and 908 non-diabetic non-nephropathy controls, a meta-analysis of 5342 AA all-cause ESKD cases and 6977 AA non-diabetic non-nephropathy controls revealed an additional novel all-cause ESKD locus at EFNB2 (rs77113398; P = 9.84 × 10-9; OR = 1.94). Exclusion of APOL1 renal-risk genotype carriers identified two additional genome-wide significant T2D-ESKD-associated loci at GRAMD3 and MGAT4C. A second variant at GNG7 (rs373971520; P = 2.17 × 10-8, OR = 1.46) remained associated with all-cause ESKD in the APOL1-negative analysis. CONCLUSIONS: Findings provide further evidence for genetic factors associated with advanced kidney disease in AAs with T2D.

3.
Nat Genet ; 51(1): 51-62, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30578418

RESUMO

In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.


Assuntos
Pressão Sanguínea/genética , Grupos Étnicos/genética , Adolescente , Animais , Feminino , Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Túbulos Renais/fisiologia , Masculino , Camundongos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Transcriptoma/genética , Regulação para Cima/genética
4.
Kidney Int Rep ; 3(4): 867-878, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29989002

RESUMO

Introduction: Compared with European Americans, African Americans (AAs) are at higher risk for developing end-stage kidney disease (ESKD). Genome-wide association studies (GWAS) have identified >70 genetic variants associated with kidney function and chronic kidney disease (CKD) in patients with and without diabetes. However, these variants explain a small proportion of disease liability. This study examined the contribution of coding genetic variants for risk of type 2 diabetes (T2D)-attributed ESKD and advanced CKD in AAs. Methods: Exome sequencing was performed in 456 AA T2D-ESKD cases, and 936 AA nondiabetic, non-nephropathy control individuals at the discovery stage. A mixed logistic regression model was used for association analysis. Nominal associations (P < 0.05) were replicated in an additional 2020 T2D-ESKD cases and 1121 nondiabetic, non-nephropathy control individuals. A meta-analysis combining 4533 discovery and replication samples was performed. Putative T2D-ESKD associations were tested in additional 1910 nondiabetic ESKD and 219 T2D-ESKD cases, as well as 912 AA nondiabetic non-nephropathy control individuals. Results: A total of 11 suggestive T2D-ESKD associations (P < 1 x 10-4) from 8 loci (PLEKHN1, NADK, RAD51AP2, RREB1, PEX6, GRM8, PRX, APOL1) were apparent in the meta-analysis. Exclusion of APOL1 renal-risk genotype carriers identified 3 additional suggestive loci (OTUD7B, IFITM3, DLGAP5). Rs41302867 in RREB1 displayed consistent association with T2D-ESKD and nondiabetic ESKD (odds ratio: 0.47; P = 1.2 x 10-6 in 4605 all-cause ESKD and 2969 nondiabetic non-nephropathy control individuals). Conclusion: Our findings suggest that coding genetic variants are implicated in predisposition to T2D-ESKD in AAs.

5.
Genet Epidemiol ; 42(6): 559-570, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29691896

RESUMO

Although type 2 diabetes (T2D) results from metabolic defects in insulin secretion and insulin sensitivity, most of the genetic risk loci identified to date relates to insulin secretion. We reported that T2D loci influencing insulin sensitivity may be identified through interactions with insulin secretion loci, thereby leading to T2D. Here, we hypothesize that joint testing of variant main effects and interaction effects with an insulin secretion locus increases power to identify genetic interactions leading to T2D. We tested this hypothesis with an intronic MTNR1B SNP, rs10830963, which is associated with acute insulin response to glucose, a dynamic measure of insulin secretion. rs10830963 was tested for interaction and joint (main + interaction) effects with genome-wide data in African Americans (2,452 cases and 3,772 controls) from five cohorts. Genome-wide genotype data (Affymetrix Human Genome 6.0 array) was imputed to a 1000 Genomes Project reference panel. T2D risk was modeled using logistic regression with rs10830963 dosage, age, sex, and principal component as predictors. Joint effects were captured using the Kraft two degrees of freedom test. Genome-wide significant (P < 5 × 10-8 ) interaction with MTNR1B and joint effects were detected for CMIP intronic SNP rs17197883 (Pinteraction  = 1.43 × 10-8 ; Pjoint  = 4.70 × 10-8 ). CMIP variants have been nominally associated with T2D, fasting glucose, and adiponectin in individuals of East Asian ancestry, with high-density lipoprotein, and with waist-to-hip ratio adjusted for body mass index in Europeans. These data support the hypothesis that additional genetic factors contributing to T2D risk, including insulin sensitivity loci, can be identified through interactions with insulin secretion loci.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Afro-Americanos/genética , Epistasia Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Insulina/metabolismo , Receptor MT2 de Melatonina/genética , Adulto , Idoso , Índice de Massa Corporal , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/genética , Feminino , Humanos , Insulina/genética , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Polimorfismo de Nucleotídeo Único/genética
6.
Curr Protoc Hum Genet ; 95: 1.22.1-1.22.23, 2017 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-29044472

RESUMO

Population stratification (PS) is a primary consideration in studies of genetic determinants of human traits. Failure to control for PS may lead to confounding, causing a study to fail for lack of significant results, or resources to be wasted following false-positive signals. Here, historical and current approaches for addressing PS when performing genetic association studies in human populations are reviewed. Methods for detecting the presence of PS, including global and local ancestry methods, are described. Also described are approaches for accounting for PS when calculating association statistics, such that measures of association are not confounded. Many traits are being examined for the first time in minority populations, which may inherently feature PS. © 2017 by John Wiley & Sons, Inc.


Assuntos
Estudos de Associação Genética , Genética Populacional , Alelos , Mapeamento Cromossômico , Evolução Molecular , Frequência do Gene , Estudos de Associação Genética/métodos , Genética Populacional/métodos , Humanos , Desequilíbrio de Ligação , Modelos Genéticos , Modelos Estatísticos , Característica Quantitativa Herdável
7.
J Hum Genet ; 62(2): 175-184, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27535031

RESUMO

Linkage studies of complex genetic diseases have been largely replaced by genome-wide association studies, due in part to limited success in complex trait discovery. However, recent interest in rare and low-frequency variants motivates re-examination of family-based methods. In this study, we investigated the performance of two-point linkage analysis for over 1.6 million single-nucleotide polymorphisms (SNPs) combined with single variant association analysis to identify high impact variants, which are both strongly linked and associated with cardiometabolic traits in up to 1414 Hispanics from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Evaluation of all 50 phenotypes yielded 83 557 000 LOD (logarithm of the odds) scores, with 9214 LOD scores ⩾3.0, 845 ⩾4.0 and 89 ⩾5.0, with a maximal LOD score of 6.49 (rs12956744 in the LAMA1 gene for tumor necrosis factor-α (TNFα) receptor 2). Twenty-seven variants were associated with P<0.005 as well as having an LOD score >4, including variants in the NFIB gene under a linkage peak with TNFα receptor 2 levels on chromosome 9. Linkage regions of interest included a broad peak (31 Mb) on chromosome 1q with acute insulin response (max LOD=5.37). This region was previously documented with type 2 diabetes in family-based studies, providing support for the validity of these results. Overall, we have demonstrated the utility of two-point linkage and association in comprehensive genome-wide array-based SNP genotypes.


Assuntos
Diabetes Mellitus Tipo 2/genética , Ligação Genética/genética , Resistência à Insulina/genética , Laminina/genética , Fatores de Transcrição NFI/genética , Fator de Necrose Tumoral alfa/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Hispano-Americanos/genética , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Adulto Jovem
8.
Pac Symp Biocomput ; 22: 242-253, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27896979

RESUMO

Type 2 diabetes (T2D) is the result of metabolic defects in insulin secretion and insulin sensitivity, yet most T2D loci identified to date influence insulin secretion. We hypothesized that T2D loci, particularly those affecting insulin sensitivity, can be identified through interaction with known T2D loci implicated in insulin secretion. To test this hypothesis, single nucleotide polymorphisms (SNPs) nominally associated with acute insulin response to glucose (AIRg), a dynamic measure of first-phase insulin secretion, and previously associated with T2D in genome-wide association studies (GWAS) were identified in African Americans from the Insulin Resistance Atherosclerosis Family Study (IRASFS; n=492 subjects). These SNPs were tested for interaction, individually and jointly as a genetic risk score (GRS), using GWAS data from five cohorts (ARIC, CARDIA, JHS, MESA, WFSM; n=2,725 cases, 4,167 controls) with T2D as the outcome. In single variant analyses, suggestively significant (Pinteraction < 5×10-6) interactions were observed at several loci including DGKB (rs978989), CDK18 (rs12126276), CXCL12 (rs7921850), HCN1 (rs6895191), FAM98A (rs1900780), and MGMT (rs568530). Notable beta-cell GRS interactions included two SNPs at the DGKB locus (rs6976381; rs6962498). These data support the hypothesis that additional genetic factors contributing to T2D risk can be identified by interactions with insulin secretion loci.


Assuntos
Afro-Americanos/genética , Diabetes Mellitus Tipo 2/genética , Estudos de Casos e Controles , Biologia Computacional , Diabetes Mellitus Tipo 2/fisiopatologia , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Resistência à Insulina/genética , Células Secretoras de Insulina/fisiologia , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal , Fatores de Risco
9.
PLoS One ; 11(7): e0159977, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27448167

RESUMO

Type 2 diabetes (T2D) is the result of metabolic defects in insulin secretion and insulin sensitivity, yet most T2D loci identified to date influence insulin secretion. We hypothesized that T2D loci, particularly those affecting insulin sensitivity, can be identified through interaction with insulin secretion loci. To test this hypothesis, single nucleotide polymorphisms (SNPs) associated with acute insulin response to glucose (AIRg), a dynamic measure of first-phase insulin secretion, were identified in African Americans from the Insulin Resistance Atherosclerosis Family Study (IRASFS; n = 492 subjects). These SNPs were tested for interaction, individually and jointly as a genetic risk score (GRS), using genome-wide association study (GWAS) data from five cohorts (ARIC, CARDIA, JHS, MESA, WFSM; n = 2,725 cases, 4,167 controls) with T2D as the outcome. In single variant analyses, suggestively significant (Pinteraction<5×10-6) interactions were observed at several loci including LYPLAL1 (rs10746381), CHN2 (rs7796525), and EXOC1 (rs4289500). Notable AIRg GRS interactions were observed with SAMD4A (rs11627203) and UTRN (rs17074194). These data support the hypothesis that additional genetic factors contributing to T2D risk can be identified by interactions with insulin secretion loci.


Assuntos
Afro-Americanos/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Insulina/metabolismo , Locos de Características Quantitativas , Adulto , Glicemia , Epistasia Genética , Feminino , Genótipo , Humanos , Resistência à Insulina/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Adulto Jovem
10.
Hum Genet ; 135(11): 1251-1262, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27461219

RESUMO

African Americans (AAs) are at higher risk for developing end-stage kidney disease (ESKD) compared to European Americans. Genome-wide association studies have identified variants associated with diabetic and non-diabetic kidney diseases. Nephropathy loci, including SLC7A9, UMOD, and SHROOM3, have been implicated in the maintenance of normal glomerular and renal tubular structure and function. Herein, 47 genes important in podocyte, glomerular basement membrane, mesangial cell, mesangial matrix, renal tubular cell, and renal interstitium structure were examined for association with type 2 diabetes (T2D)-attributed ESKD in AAs. Single-variant association analysis was performed in the discovery stage, including 2041 T2D-ESKD cases and 1140 controls (non-diabetic, non-nephropathy). Discrimination analyses in 667 T2D cases-lacking nephropathy excluded T2D-associated SNPs. Nominal associations were tested in an additional 483 T2D-ESKD cases and 554 controls in the replication stage. Meta-analysis of 4218 discovery and replication samples revealed three significant associations with T2D-ESKD at CD2AP and MMP2 (P corr < 0.05 corrected for effective number of SNPs in each locus). Removal of APOL1 renal-risk genotype carriers revealed additional association at five loci, TTC21B, COL4A3, NPHP3-ACAD11, CLDN8, and ARHGAP24 (P corr < 0.05). Genetic variants at COL4A3, CLDN8, and ARHGAP24 were potentially pathogenic. Gene-based associations revealed suggestive significant aggregate effects of coding variants at four genes. Our findings suggest that genetic variation in kidney structure-related genes may contribute to T2D-attributed ESKD in the AA population.


Assuntos
Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Falência Renal Crônica/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Proteínas do Citoesqueleto/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Nefropatias Diabéticas/patologia , Grupo com Ancestrais do Continente Europeu , Feminino , Genótipo , Membrana Basal Glomerular/metabolismo , Membrana Basal Glomerular/ultraestrutura , Haplótipos , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/patologia , Túbulos Renais Distais/metabolismo , Túbulos Renais Distais/ultraestrutura , Masculino , Metaloproteinase 2 da Matriz/genética , Células Mesangiais/metabolismo , Células Mesangiais/ultraestrutura , Pessoa de Meia-Idade , Podócitos/metabolismo , Podócitos/ultraestrutura , Polimorfismo de Nucleotídeo Único
11.
Hum Genet ; 133(12): 1487-95, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25273842

RESUMO

The prevalence of type 2 diabetes (T2D) is greater in populations of African descent compared to European-descent populations. Genetic risk factors may underlie the disparity in disease prevalence. Genome-wide association studies (GWAS) have identified >60 common genetic variants that contribute to T2D risk in populations of European, Asian, African and Hispanic descent. These studies have not comprehensively examined population differences in cumulative risk allele load. To investigate the relationship between risk allele load and T2D risk, 46 T2D single nucleotide polymorphisms (SNPs) in 43 loci from GWAS in European, Asian, and African-derived populations were genotyped in 1,990 African Americans (n = 963 T2D cases, n = 1,027 controls) and 1,644 European Americans (n = 719 T2D cases, n = 925 controls) ascertained and recruited using a common protocol in the southeast United States. A genetic risk score (GRS) was constructed from the cumulative risk alleles for each individual. In African American subjects, risk allele frequencies ranged from 0.024 to 0.964. Risk alleles from 26 SNPs demonstrated directional consistency with previous studies, and 3 SNPs from ADAMTS9, TCF7L2, and ZFAND6 showed nominal evidence of association (p < 0.05). African American individuals carried 38-67 (53.7 ± 4.0, mean ± SD) risk alleles. In European American subjects, risk allele frequencies ranged from 0.084 to 0.996. Risk alleles from 36 SNPs demonstrated directional consistency, and 10 SNPs from BCL11A, PSMD6, ADAMTS9, ZFAND3, ANK1, CDKN2A/B, TCF7L2, PRC1, FTO, and BCAR1 showed evidence of association (p < 0.05). European American individuals carried 38-65 (50.9 ± 4.4) risk alleles. African Americans have a significantly greater burden of 2.8 risk alleles (p = 3.97 × 10(-89)) compared to European Americans. However, GRS modeling showed that cumulative risk allele load was associated with risk of T2D in European Americans, but only marginally in African Americans. This result suggests that there are ethnic-specific differences in genetic architecture underlying T2D, and that these differences complicate our understanding of how risk allele load impacts disease susceptibility.


Assuntos
Diabetes Mellitus Tipo 2/genética , Polimorfismo de Nucleotídeo Único , Adulto , Afro-Americanos/genética , Idoso , Diabetes Mellitus Tipo 2/etnologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Estudos de Associação Genética , Humanos , Falência Renal Crônica/genética , Masculino , Pessoa de Meia-Idade , Risco
12.
Hum Mol Genet ; 23(24): 6441-7, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25027322

RESUMO

Familial clustering and presumed genetic risk for type 2 diabetic (T2D) and non-diabetic end-stage kidney disease (ESKD) appear strong in African Americans. Examination of exome sequencing data in African American T2D-ESKD cases and non-diabetic non-nephropathy controls identified two low-frequency variants in the RREB1 gene, a repressor of the angiotensinogen (AGT) gene previously associated with kidney function, as being associated with T2D-ESKD: rs9379084 (P = 0.00087, OR = 0.26; D1171N) and rs41302867 (P = 0.00078, OR = 0.21; splice site variant). Rs41302867 replicated association in an independent sample of African Americans with T2D-ESKD [rs41302867 P = 0.033 (OR = 0.50)], and a trend towards rs9379084 association was observed (P = 0.070). In European Americans with T2D-ESKD compared with European American population based controls, both RREB1 variants replicated association [rs9379084 P = 1.67 × 10(-4) (OR = 0.54) and rs41302867 P = 0.013 (OR = 0.69)]. Rs9379084 was not associated with non-T2D-ESKD or T2D in African Americans (P = 0.55 and P = 0.37, respectively), but was associated with T2D in European Americans (P = 0.014, OR = 0.65). In African Americans, rs41302867 was associated with non-T2D-ESKD [P = 0.036 (OR = 0.54)] and hypertension attributed ESKD [H-ESKD, P = 0.029 (OR = 0.50)]. A meta-analysis combining African American and European American T2D-ESKD data revealed P = 3.52 × 10(-7) and 3.70 × 10(-5) for rs9379084 and rs41302867 association, respectfully. A locus-wide analysis evaluating putatively functional SNPs revealed several nominal associations with T2D-ESKD, non-T2D-ESKD and T2D in African and European Americans. RREB1 is a large, complex gene which codes a multidomain zinc finger binding protein and transcription factor. We posit that variants in RREB1 modulate seemingly disparate phenotypes (i.e. T2D, T2D-ESKD and non-T2D-ESKD) through altered activity resulting from splice site and missense variants.


Assuntos
Proteínas de Ligação a DNA/genética , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Falência Renal Crônica/genética , Mutação de Sentido Incorreto , Fatores de Transcrição/genética , Afro-Americanos , Idoso , Processamento Alternativo , Angiotensinogênio/genética , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/patologia , Grupo com Ancestrais do Continente Europeu , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/etnologia , Falência Renal Crônica/patologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único
13.
Clin J Am Soc Nephrol ; 9(8): 1434-40, 2014 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-24948143

RESUMO

BACKGROUND AND OBJECTIVES: Presumed genetic risk for diabetic and nondiabetic end stage renal disease is strong in African Americans. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Exome sequencing data from African Americans with type 2 diabetic end stage renal disease and nondiabetic, non-nephropathy controls in the T2D-GENES study (Discovery, n=529 patients and n=535 controls) were evaluated, focusing on missense variants in NPHS1. Associated variants were then evaluated in independent type 2 diabetic end stage renal disease (Replication, n=1305 patients and n=760 controls), nondiabetic end stage renal disease (n=1705), and type 2 diabetes-only, non-nephropathy samples (n=503). All participants were recruited from dialysis facilities and internal medicine clinics across the southeastern United States from 1991 to present. Additional NPHS1 missense variants were identified from exome sequencing resources, genotyped, and sequence kernel association testing was then performed. RESULTS: Initial analysis identified rs35238405 (T233A; minor allele frequency=0.0096) as associated with type 2 diabetic end stage renal disease (adjustment for admixture P=0.042; adjustment for admixture+APOL1 P=0.080; odds ratio, 2.89 and 2.36, respectively); with replication in independent type 2 diabetic end stage renal disease samples (P=0.018; odds ratio, 4.30) and nondiabetic end stage renal disease samples (P=0.016; odds ratio, 4.48). In a combined analysis (all patients with end stage renal disease versus all controls), T233A was associated with all-cause end stage renal disease (P=0.0038; odds ratio, 2.82; n=3270 patients and n=1187 controls). A P-value of <0.001 was obtained after adjustment for admixture and APOL1 in sequence kernel association testing. Two additional variants (H800R and Y1174H) were nominally associated with protection from end stage renal disease (P=0.036; odds ratio, 0.44; P=0.0084; odds ratio, 0.040, respectively) in the locus-wide single-variant association tests. CONCLUSIONS: Coding variants in NPHS1 are associated with both risk for and protection from common forms of nephropathy in African Americans.


Assuntos
Afro-Americanos/genética , Nefropatias Diabéticas/genética , Falência Renal Crônica/genética , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Idoso , Apolipoproteína L1 , Apolipoproteínas/genética , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etnologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Falência Renal Crônica/etnologia , Lipoproteínas HDL/genética , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Fatores de Proteção , Medição de Risco , Fatores de Risco
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