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1.
Sci Rep ; 9(1): 14360, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31591475

RESUMO

Differentiating between inherited renal hypouricemia and transient hypouricemic status is challenging. Here, we aimed to describe the genetic background of hypouricemia patients using whole-exome sequencing (WES) and assess the feasibility for genetic diagnosis using two founder variants in primary screening. We selected all cases (N = 31) with extreme hypouricemia (<1.3 mg/dl) from a Korean urban cohort of 179,381 subjects without underlying conditions. WES and corresponding downstream analyses were performed for the discovery of rare causal variants for hypouricemia. Two known recessive variants within SLC22A12 (p.Trp258*, pArg90His) were identified in 24 out of 31 subjects (77.4%). In an independent cohort, we identified 50 individuals with hypouricemia and genotyped the p.Trp258* and p.Arg90His variants; 47 of the 50 (94%) hypouricemia cases were explained by only two mutations. Four novel coding variants in SLC22A12, p.Asn136Lys, p.Thr225Lys, p.Arg284Gln, and p.Glu429Lys, were additionally identified. In silico studies predict these as pathogenic variants. This is the first study to show the value of genetic diagnostic screening for hypouricemia in the clinical setting. Screening of just two ethnic-specific variants (p.Trp258* and p.Arg90His) identified 87.7% (71/81) of Korean patients with monogenic hypouricemia. Early genetic identification of constitutive hypouricemia may prevent acute kidney injury by avoidance of dehydration and excessive exercise.

2.
Transl Stroke Res ; 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31650369

RESUMO

Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by progressive stenosis of large intracranial arteries and a hazy network of basal collaterals called moyamoya vessels. A polymorphism (R4810K) in the Ring Finger Protein 213 (RNF213) gene, at chromosome 17q25.3, is the strongest genetic susceptibility factor for MMD in East Asian populations. MMD was regarded prevalent in childhood and in East Asian populations. However, the so-called MMD could represent only the tip of the iceberg. MMD is increasingly reported in adult patients and in Western populations. Moreover, the RNF213 variant was recently reported to be associated with non-MMD disorders, such as intracranial atherosclerosis and systemic vasculopathy (e.g., peripheral pulmonary artery stenosis and renal artery stenosis). In this review, we summarize the spectrums of RNF213 vasculopathy in terms of clinical and genetic phenotypes. Continuous efforts are required for pathophysiology-based diagnoses and treatment, which will benefit from collaboration between clinicians and researchers, and between stroke and vascular physicians.

3.
Neurobiol Aging ; 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31217084

RESUMO

There is a genetic overlap among various neurodegenerative diseases that cause dementia. We analyzed dementia-related gene variants in 60 apolipoprotein E ε4 non-carrying Korean patients with early-onset Alzheimer's disease. Thirty-one dementia-related genes were screened by exome sequencing. Among the 60 patients, three likely pathogenic variants (LPVs) and 1 variant of uncertain significance (VUS) were identified in PSEN1. In addition, two LPVs in TYROBP (c.141del) and PINK1 (c.1220G>A) and 17 VUS were found in other dementia-causing genes. Two variants in SORL1 and TREM2 were identified that were associated with Alzheimer's disease. In this study, we identified 5 (8.3%) LPVs and 18 (30%) VUSs in known dementia-related genes in apolipoprotein E ε4 noncarrying Korean patients with early-onset Alzheimer's disease.

4.
Circ Genom Precis Med ; 12(5): e002376, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30939045

RESUMO

Background Familial hypobetalipoproteinemia is a genetic disorder caused by rare protein-truncating variants (PTV) in the gene encoding APOB (apolipoprotein B), the major protein component of LDL (low-density lipoprotein) and triglyceride-rich lipoprotein particles. Whether heterozygous APOB deficiency is associated with decreased risk for coronary heart disease (CHD) is uncertain. We combined family-based and large scale gene-sequencing to characterize the association of rare PTVs in APOB with circulating LDL-C (LDL cholesterol), triglycerides, and risk for CHD. Methods We sequenced the APOB gene in 29 Japanese hypobetalipoproteinemia families, as well as 57 973 individuals derived from 12 CHD case-control studies-18 442 with early-onset CHD and 39 531 controls. We defined PTVs as variants that lead to a premature stop, disrupt canonical splice-sites, or lead to insertions/deletions that shift reading frame. We tested the association of rare APOB PTV carrier status with blood lipid levels and CHD. Results Among 29 familial hypobetalipoproteinemia families, 8 families harbored APOB PTVs. Carrying 1 APOB PTV was associated with 55 mg/dL lower LDL-C ( P=3×10-5) and 53% lower triglyceride level ( P=2×10-4). Among 12 case-control studies, an APOB PTV was present in 0.038% of CHD cases as compared to 0.092% of controls. APOB PTV carrier status was associated with a 43 mg/dL lower LDL-C ( P=2×10-7), a 30% decrease in triglycerides ( P=5×10-4), and a 72% lower risk for CHD (odds ratio, 0.28; 95% CI, 0.12-0.64; P=0.002). Conclusions Rare PTV mutations in APOB which are associated with lower LDL-C and reduced triglycerides also confer protection against CHD.

5.
J Affect Disord ; 252: 413-420, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31003110

RESUMO

BACKGROUND: Psychological distress symptoms are associated with an increased risk of psychiatric disorders and medical illness. Although psychological distress is influenced by environmental factors, such as socioeconomic status, lifetime events, or interpersonal relationships, substantial interindividual variation also exists. However, heritability and genetic determinants of distress are poorly understood. METHODS: In the Korean Genome and Epidemiology Study sample (n = 12,680), we estimated the heritability of individual psychological distress symptoms using the GCTA-REML method and carried out a genome-wide association study of individual psychological distress symptoms showing significant heritability. RESULTS: We found three psychological distress items showing significant heritability: subjective well-being (9%), fatigue and appetite (11%), and enjoying daily life (8%). Additionally, we found genome-wide significant associations of rs6735649 located between STEAP3 and C1QL2 on chromosome 2 with subjective well-being (P = 1.32 × 10-8, odds ratio [OR] = 1.18, 95% confidence interval [CI]: 1.12-1.25) and rs35543418 located between SYT16 and KCNH5 on chromosome 14 with enjoying daily life (P = 1.33 × 10-8, OR = 1.59, 95% CI: 1.35-1.86). LIMITATIONS: The lack of replication in independent cohorts and longitudinal assessment of distress may limit generalizability. CONCLUSIONS: Our results indicate that distress symptoms are partly heritable. Further analysis in larger cohorts investigating gene-environment interactions is required to identify genetic variants that explain the proportion of variation in distress.

6.
PLoS Med ; 16(1): e1002725, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30645594

RESUMO

BACKGROUND: Studies have shown strong positive associations between serum urate (SU) levels and chronic kidney disease (CKD) risk; however, whether the relation is causal remains uncertain. We evaluate whether genetic data are consistent with a causal impact of SU level on the risk of CKD and estimated glomerular filtration rate (eGFR). METHODS AND FINDINGS: We used Mendelian randomization (MR) methods to evaluate the presence of a causal effect. We used aggregated genome-wide association data (N = 110,347 for SU, N = 69,374 for gout, N = 133,413 for eGFR, N = 117,165 for CKD), electronic-medical-record-linked UK Biobank data (N = 335,212), and population-based cohorts (N = 13,425), all in individuals of European ancestry, for SU levels and CKD. Our MR analysis showed that SU has a causal effect on neither eGFR level nor CKD risk across all MR analyses (all P > 0.05). These null associations contrasted with our epidemiological association findings from the 4 population-based cohorts (change in eGFR level per 1-mg/dl [59.48 µmol/l] increase in SU: -1.99 ml/min/1.73 m2; 95% CI -2.86 to -1.11; P = 8.08 × 10(-6); odds ratio [OR] for CKD: 1.48; 95% CI 1.32 to 1.65; P = 1.52 × 10(-11)). In contrast, the same MR approaches showed that SU has a causal effect on the risk of gout (OR estimates ranging from 3.41 to 6.04 per 1-mg/dl increase in SU, all P < 10-3), which served as a positive control of our approach. Overall, our MR analysis had >99% power to detect a causal effect of SU level on the risk of CKD of the same magnitude as the observed epidemiological association between SU and CKD. Limitations of this study include the lifelong effect of a genetic perturbation not being the same as an acute perturbation, the inability to study non-European populations, and some sample overlap between the datasets used in the study. CONCLUSIONS: Evidence from our series of causal inference approaches using genetics does not support a causal effect of SU level on eGFR level or CKD risk. Reducing SU levels is unlikely to reduce the risk of CKD development.


Assuntos
Insuficiência Renal Crônica/etiologia , Ácido Úrico/sangue , Adulto , Fatores Etários , Feminino , Estudo de Associação Genômica Ampla , Taxa de Filtração Glomerular/genética , Humanos , Masculino , Análise da Randomização Mendeliana , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/genética , Fatores Sexuais , Adulto Jovem
7.
Leukemia ; 33(6): 1439-1450, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30555164

RESUMO

Achieving a deep molecular response (DMR) to tyrosine kinase inhibitor (TKI) therapy for chronic myeloid leukemia (CML) remains challenging and at present, there is no biomarker to predict DMR in this setting. Herein, we report that an HMGCLL1 genetic variant located in 6p12.1 can be used as a predictive genetic biomarker for intrinsic sensitivity to imatinib (IM) therapy. We measured DMR rate according to HMGCLL1 variant in a discovery set of CML patients (n = 201) and successfully replicated it in a validation set (n = 270). We also investigated the functional relevance of HMGCLL1 blockade with respect to response to TKI therapy and showed that small interfering RNA mediated blockade of HMGCLL1 isoform 3 results in significant decrease in viability of BCR-ABL1-positive cells including K562, CML-T1 or BaF3 cell lines with or without ABL1 kinase domain mutations such as T315I mutation. Decreased cell viability was also demonstrated in murine CML stem cells and human hematopoietic progenitor cells. RNA sequencing showed that blockade of HMGCLL1 was associated with G0/G1 arrest and the cell cycle. In summary, the HMGCLL1 gene polymorphism is a novel genetic biomarker for intrinsic sensitivity to IM therapy in CML patients that predicts DMR in this setting.


Assuntos
Biomarcadores Tumorais/genética , Resistencia a Medicamentos Antineoplásicos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Mutação , Oxo-Ácido-Liases/genética , Inibidores de Proteínas Quinases/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Estudos de Casos e Controles , Sobrevivência Celular , Estudos de Coortes , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas , Adulto Jovem
8.
Curr Eye Res ; 43(4): 534-538, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29199866

RESUMO

PURPOSE: To evaluate the association of matrix metalloproteinases (MMP)-9 gene polymorphisms with normal tension glaucoma (NTG) and primary open-angle glaucoma (POAG) in the South Korean population. MATERIALS AND METHODS: A total of 700 South Korean subjects were recruited: 146 patients with NTG, 174 patients with POAG, and 380 healthy adults. Five single-nucleotide polymorphisms (SNPs; rs3918429, rs2274755, rs3787268, rs3918261, and rs3918270) of MMP-9 were analyzed in all subjects. The association with each disease was tested using an allelic χ2 test and p values were corrected by permutation tests with 100 000 permutations. RESULTS: Among the five SNPs, rs2274755 showed a significant association with NTG (p = 0.021). The T allele of rs2274755 had an allelic odds ratio of 1.67 (95% confidence interval, 1.12-2.50). The association remained significant after correction using permutation tests (p = 0.039). It was also significant in an association analysis for genotype frequency (p = 0.011). The SNP was predicted to be found within a splicing site and a conserved region. No SNPs analyzed were significantly associated with POAG (p > 0.05). CONCLUSIONS: The rs2274755 SNP in the MMP-9 gene was significantly associated with NTG. This supports a possible role of the MMP-9 gene in NTG pathogenesis.

9.
Stroke ; 48(10): 2819-2826, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28798260

RESUMO

BACKGROUND AND PURPOSE: Ischemic stroke patients often have intracranial atherosclerosis (ICAS), despite heterogeneity in the cause of stroke. We tested the hypothesis that ICAS burden can independently reflect the risk of long-term vascular outcome. METHODS: This was a retrospective cohort study analyzing data from a prospective stroke registry enrolling consecutive patients with acute ischemic stroke or transient ischemic attack. A total of 1081 patients were categorized into no ICAS, single ICAS, and advanced ICAS (ICAS ≥2 different intracranial arteries) groups. Primary and secondary end points were time to occurrence of recurrent ischemic stroke and composite vascular outcome, respectively. Study end points by ICAS burden were compared using Cox proportional hazards models in overall and propensity-matched patients. RESULTS: ICAS was present in 405 patients (37.3%). During a median 5-year follow-up, recurrent stroke and composite vascular outcome occurred in 6.8% and 16.8% of patients, respectively. As the number of ICAS increased, the risk for study end points increased after adjustment of potential covariates (hazard ratio per 1 increase in ICAS, 1.19; 95% confidence interval, 1.01-1.42 for recurrent ischemic stroke and hazard ratio, 1.18; 95% confidence interval, 1.05-1.33 for composite vascular outcome). The hazard ratios (95% confidence interval) for recurrent stroke and composite vascular outcome in patients with advanced ICAS compared with those without ICAS were 1.56 (0.88-2.74) and 1.72 (1.17-2.53), respectively, in the overall patients. The corresponding values in the propensity-matched patients were 1.28 (0.71-2.30) and 1.95 (1.27-2.99), respectively. CONCLUSIONS: ICAS burden was independently associated with the risk of subsequent composite vascular outcome in patients with ischemic stroke. These findings suggest that ICAS burden can reflect the risk of long-term vascular outcome.


Assuntos
Isquemia Encefálica/diagnóstico por imagem , Efeitos Psicossociais da Doença , Arteriosclerose Intracraniana/diagnóstico por imagem , Acidente Vascular Cerebral/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/epidemiologia , Estudos de Coortes , Feminino , Humanos , Arteriosclerose Intracraniana/epidemiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sistema de Registros , Estudos Retrospectivos , Acidente Vascular Cerebral/epidemiologia , Fatores de Tempo , Resultado do Tratamento
10.
Circ Res ; 121(1): 81-88, 2017 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-28506971

RESUMO

RATIONALE: Therapies that inhibit CETP (cholesteryl ester transfer protein) have failed to demonstrate a reduction in risk for coronary heart disease (CHD). Human DNA sequence variants that truncate the CETP gene may provide insight into the efficacy of CETP inhibition. OBJECTIVE: To test whether protein-truncating variants (PTVs) at the CETP gene were associated with plasma lipid levels and CHD. METHODS AND RESULTS: We sequenced the exons of the CETP gene in 58 469 participants from 12 case-control studies (18 817 CHD cases, 39 652 CHD-free controls). We defined PTV as those that lead to a premature stop, disrupt canonical splice sites, or lead to insertions/deletions that shift frame. We also genotyped 1 Japanese-specific PTV in 27561 participants from 3 case-control studies (14 286 CHD cases, 13 275 CHD-free controls). We tested association of CETP PTV carrier status with both plasma lipids and CHD. Among 58 469 participants with CETP gene-sequencing data available, average age was 51.5 years and 43% were women; 1 in 975 participants carried a PTV at the CETP gene. Compared with noncarriers, carriers of PTV at CETP had higher high-density lipoprotein cholesterol (effect size, 22.6 mg/dL; 95% confidence interval, 18-27; P<1.0×10-4), lower low-density lipoprotein cholesterol (-12.2 mg/dL; 95% confidence interval, -23 to -0.98; P=0.033), and lower triglycerides (-6.3%; 95% confidence interval, -12 to -0.22; P=0.043). CETP PTV carrier status was associated with reduced risk for CHD (summary odds ratio, 0.70; 95% confidence interval, 0.54-0.90; P=5.1×10-3). CONCLUSIONS: Compared with noncarriers, carriers of PTV at CETP displayed higher high-density lipoprotein cholesterol, lower low-density lipoprotein cholesterol, lower triglycerides, and lower risk for CHD.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/genética , Doença das Coronárias/diagnóstico , Doença das Coronárias/genética , Variação Genética/genética , Adulto , Idoso , Estudos de Casos e Controles , Proteínas de Transferência de Ésteres de Colesterol/sangue , Doença das Coronárias/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
11.
Nature ; 544(7649): 235-239, 2017 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-28406212

RESUMO

A major goal of biomedicine is to understand the function of every gene in the human genome. Loss-of-function mutations can disrupt both copies of a given gene in humans and phenotypic analysis of such 'human knockouts' can provide insight into gene function. Consanguineous unions are more likely to result in offspring carrying homozygous loss-of-function mutations. In Pakistan, consanguinity rates are notably high. Here we sequence the protein-coding regions of 10,503 adult participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS), designed to understand the determinants of cardiometabolic diseases in individuals from South Asia. We identified individuals carrying homozygous predicted loss-of-function (pLoF) mutations, and performed phenotypic analysis involving more than 200 biochemical and disease traits. We enumerated 49,138 rare (<1% minor allele frequency) pLoF mutations. These pLoF mutations are estimated to knock out 1,317 genes, each in at least one participant. Homozygosity for pLoF mutations at PLA2G7 was associated with absent enzymatic activity of soluble lipoprotein-associated phospholipase A2; at CYP2F1, with higher plasma interleukin-8 concentrations; at TREH, with lower concentrations of apoB-containing lipoprotein subfractions; at either A3GALT2 or NRG4, with markedly reduced plasma insulin C-peptide concentrations; and at SLC9A3R1, with mediators of calcium and phosphate signalling. Heterozygous deficiency of APOC3 has been shown to protect against coronary heart disease; we identified APOC3 homozygous pLoF carriers in our cohort. We recruited these human knockouts and challenged them with an oral fat load. Compared with family members lacking the mutation, individuals with APOC3 knocked out displayed marked blunting of the usual post-prandial rise in plasma triglycerides. Overall, these observations provide a roadmap for a 'human knockout project', a systematic effort to understand the phenotypic consequences of complete disruption of genes in humans.


Assuntos
Consanguinidade , Análise Mutacional de DNA , Deleção de Genes , Genes/genética , Estudos de Associação Genética/métodos , Homozigoto , Fenótipo , 1-Alquil-2-acetilglicerofosfocolina Esterase/deficiência , 1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Apolipoproteína C-III/deficiência , Apolipoproteína C-III/genética , Estudos de Coortes , Doença das Coronárias/sangue , Doença das Coronárias/genética , Família 2 do Citocromo P450/genética , Gorduras na Dieta/farmacologia , Exoma/genética , Jejum/sangue , Feminino , Frequência do Gene , Humanos , Interleucina-8/sangue , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/genética , Neurregulinas/genética , Paquistão , Linhagem , Fosfoproteínas/genética , Período Pós-Prandial , Sítios de Splice de RNA/genética , Genética Reversa/métodos , Trocadores de Sódio-Hidrogênio/genética , Triglicerídeos/sangue
12.
Pharmacogenet Genomics ; 27(5): 197-200, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28277331

RESUMO

Thiopurines have a narrow therapeutic range because of frequent toxicity (i.e. marrow suppression), which is only partly explained by TPMT genetic polymorphisms, especially within Asian populations. Recent studies have identified NUDT15 variation as another important factor affecting thiopurine metabolism. In this study, a total of four NUDT15 coding variants (p.Arg139Cys, p.Arg139His, p.Val18Ile, and p.Val18_Val19insGlyVal) were genotyped in 920 Korean individuals using direct sequencing of NUDT15 for the first time in a Korean population. The allele frequencies were 86.7% for NUDT15*1, and 4.4, 6.9, 0.4, 1.1, and 0.50% for *2, *3, *4, *5, and *6, respectively. The NUDT15 phenotypes based on diplotypes included normal activity (n=692), intermediate activity (n=209), and low activity (n=19), occurring in 75.2, 22.7, and 2.1% of the population, respectively. This study was the first to report NUDT15 variants other than NUDT15*3 in the Korean population and more individuals who were categorized as having intermediate or low NUDT15 activity in our study than in previously reported studies in the Korean population (24.8 vs. 19.4%, P<0.05). This study is useful for future clinical studies on thiopurine pharmacogenetics and dosage adjustment in the Korean population.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Variantes Farmacogenômicos , Pirofosfatases/genética , Pirofosfatases/metabolismo , Adolescente , Adulto , Criança , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , República da Coreia , Adulto Jovem
13.
JAMA ; 317(9): 937-946, 2017 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-28267856

RESUMO

Importance: The activity of lipoprotein lipase (LPL) is the rate-determining step in clearing triglyceride-rich lipoproteins from the circulation. Mutations that damage the LPL gene (LPL) lead to lifelong deficiency in enzymatic activity and can provide insight into the relationship of LPL to human disease. Objective: To determine whether rare and/or common variants in LPL are associated with early-onset coronary artery disease (CAD). Design, Setting, and Participants: In a cross-sectional study, LPL was sequenced in 10 CAD case-control cohorts of the multinational Myocardial Infarction Genetics Consortium and a nested CAD case-control cohort of the Geisinger Health System DiscovEHR cohort between 2010 and 2015. Common variants were genotyped in up to 305 699 individuals of the Global Lipids Genetics Consortium and up to 120 600 individuals of the CARDIoGRAM Exome Consortium between 2012 and 2014. Study-specific estimates were pooled via meta-analysis. Exposures: Rare damaging mutations in LPL included loss-of-function variants and missense variants annotated as pathogenic in a human genetics database or predicted to be damaging by computer prediction algorithms trained to identify mutations that impair protein function. Common variants in the LPL gene region included those independently associated with circulating triglyceride levels. Main Outcomes and Measures: Circulating lipid levels and CAD. Results: Among 46 891 individuals with LPL gene sequencing data available, the mean (SD) age was 50 (12.6) years and 51% were female. A total of 188 participants (0.40%; 95% CI, 0.35%-0.46%) carried a damaging mutation in LPL, including 105 of 32 646 control participants (0.32%) and 83 of 14 245 participants with early-onset CAD (0.58%). Compared with 46 703 noncarriers, the 188 heterozygous carriers of an LPL damaging mutation displayed higher plasma triglyceride levels (19.6 mg/dL; 95% CI, 4.6-34.6 mg/dL) and higher odds of CAD (odds ratio = 1.84; 95% CI, 1.35-2.51; P < .001). An analysis of 6 common LPL variants resulted in an odds ratio for CAD of 1.51 (95% CI, 1.39-1.64; P = 1.1 × 10-22) per 1-SD increase in triglycerides. Conclusions and Relevance: The presence of rare damaging mutations in LPL was significantly associated with higher triglyceride levels and presence of coronary artery disease. However, further research is needed to assess whether there are causal mechanisms by which heterozygous lipoprotein lipase deficiency could lead to coronary artery disease.


Assuntos
Doença da Artéria Coronariana/genética , Lipase Lipoproteica/genética , Mutação , Adulto , Idade de Início , Estudos de Casos e Controles , Estudos Transversais , Feminino , Genótipo , Heterozigoto , Humanos , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Razão de Chances , Triglicerídeos/sangue
14.
J Am Coll Cardiol ; 69(7): 823-836, 2017 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-28209224

RESUMO

BACKGROUND: Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. OBJECTIVES: This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. METHODS: In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. RESULTS: We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10-4 with a range of other diseases/traits. CONCLUSIONS: We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.


Assuntos
Doença da Artéria Coronariana/genética , Loci Gênicos , Pleiotropia Genética , Estudos de Casos e Controles , Doença da Artéria Coronariana/epidemiologia , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único
15.
J Am Coll Cardiol ; 68(25): 2761-2772, 2016 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-28007139

RESUMO

BACKGROUND: Genomic analyses have suggested that the LPA gene and its associated plasma biomarker, lipoprotein(a) (Lp[a]), represent a causal risk factor for coronary heart disease (CHD). As such, lowering Lp(a) levels has emerged as a therapeutic strategy. Beyond target identification, human genetics may contribute to the development of new therapies by defining the full spectrum of beneficial and adverse consequences and by developing a dose-response curve of target perturbation. OBJECTIVES: The goal of this study was to establish the full phenotypic impact of LPA gene variation and to estimate a dose-response curve between genetically altered plasma Lp(a) and risk for CHD. METHODS: We leveraged genetic variants at the LPA gene from 3 data sources: individual-level data from 112,338 participants in the U.K. Biobank; summary association results from large-scale genome-wide association studies; and LPA gene sequencing results from case subjects with CHD and control subjects free of CHD. RESULTS: One SD genetically lowered Lp(a) level was associated with a 29% lower risk of CHD (odds ratio [OR]: 0.71; 95% confidence interval [CI]: 0.69 to 0.73), a 31% lower risk of peripheral vascular disease (OR: 0.69; 95% CI: 0.59 to 0.80), a 13% lower risk of stroke (OR: 0.87; 95% CI: 0.79 to 0.96), a 17% lower risk of heart failure (OR: 0.83; 95% CI: 0.73 to 0.94), and a 37% lower risk of aortic stenosis (OR: 0.63; 95% CI: 0.47 to 0.83). We observed no association with 31 other disorders, including type 2 diabetes and cancer. Variants that led to gain of LPA gene function increased the risk for CHD, whereas those that led to loss of gene function reduced the CHD risk. CONCLUSIONS: Beyond CHD, genetically lowered Lp(a) levels are associated with a lower risk of peripheral vascular disease, stroke, heart failure, and aortic stenosis. As such, pharmacological lowering of plasma Lp(a) may influence a range of atherosclerosis-related diseases.


Assuntos
Doença das Coronárias/genética , Terapia Genética/métodos , Estudo de Associação Genômica Ampla/métodos , Lipoproteína(a)/sangue , Biomarcadores , Doença das Coronárias/sangue , Doença das Coronárias/terapia , DNA/genética , Feminino , Humanos , Lipoproteína(a)/genética , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , Prognóstico , Fatores de Risco
16.
Sci Rep ; 6: 35278, 2016 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-27731410

RESUMO

In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD.


Assuntos
Cromossomos Humanos X , Doença da Artéria Coronariana/genética , Estudos de Coortes , Feminino , Humanos , Internacionalidade , Masculino
17.
Nature ; 536(7616): 285-91, 2016 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-27535533

RESUMO

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes.


Assuntos
Exoma/genética , Variação Genética/genética , Análise Mutacional de DNA , Conjuntos de Dados como Assunto , Humanos , Fenótipo , Proteoma/genética , Doenças Raras/genética , Tamanho da Amostra
18.
J Clin Lab Anal ; 30(6): 1061-1070, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27132877

RESUMO

BACKGROUND: Despite recent advances in the investigation of myeloproliferative neoplasms (MPN), the impact of genetic heterogeneity on its molecular pathogenesis has not been fully elucidated. Thus, in this study, we aim to characterize the genetic complexity in Korean patients with polycythemia vera (PV) and essential thrombocythemia (ET). METHODS: We conducted association studies using 84 single-nucleotide polymorphisms (SNPs) in 229 patients (96 with PV and 133 with ET) and 170 controls. Further, whole-genome sequencing was performed in six patients (two with JAK2 V617F and four with wild-type JAK2), and putative somatic mutations were validated in a further 69 ET patients. Clinical and laboratory characteristics were also analyzed. RESULTS: Several germline SNPs and the 46 haplotype were significantly associated with PV and ET. Three somatic mutations in MPDZ, IQCH, and CALR genes were selected and validated. The frequency of the CALR mutation was 58.0% (40/69) in ET patients, who did not carry JAK2/MPL mutations. Moreover, compared with JAK2 V617F-positive patients, those with CALR mutations showed lower hemoglobin and hematocrit levels (P = 0.004 and P = 0.002, respectively), higher platelet counts (P =0.008), and a lower frequency of cytoreductive therapy (P = 0.014). CONCLUSION: This study was the first comprehensive investigation of the genetic characteristics of Korean patients with PV and ET. We found that somatic mutations and the 46 haplotype contribute to PV and ET pathogenesis in Korean patients.


Assuntos
Predisposição Genética para Doença/genética , Janus Quinase 2/genética , Policitemia Vera/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Trombopoetina/genética , Trombocitemia Essencial/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas de Transporte/genética , Análise Mutacional de DNA , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Policitemia Vera/epidemiologia , República da Coreia/epidemiologia , Estatísticas não Paramétricas , Trombocitemia Essencial/epidemiologia , Adulto Jovem
19.
J Am Coll Cardiol ; 67(22): 2578-89, 2016 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-27050191

RESUMO

BACKGROUND: Approximately 7% of American adults have severe hypercholesterolemia (untreated low-density lipoprotein [LDL] cholesterol ≥190 mg/dl), which may be due to familial hypercholesterolemia (FH). Lifelong LDL cholesterol elevations in FH mutation carriers may confer coronary artery disease (CAD) risk beyond that captured by a single LDL cholesterol measurement. OBJECTIVES: This study assessed the prevalence of an FH mutation among those with severe hypercholesterolemia and determined whether CAD risk varies according to mutation status beyond the observed LDL cholesterol level. METHODS: Three genes causative for FH (LDLR, APOB, and PCSK9) were sequenced in 26,025 participants from 7 case-control studies (5,540 CAD case subjects, 8,577 CAD-free control subjects) and 5 prospective cohort studies (11,908 participants). FH mutations included loss-of-function variants in LDLR, missense mutations in LDLR predicted to be damaging, and variants linked to FH in ClinVar, a clinical genetics database. RESULTS: Among 20,485 CAD-free control and prospective cohort participants, 1,386 (6.7%) had LDL cholesterol ≥190 mg/dl; of these, only 24 (1.7%) carried an FH mutation. Within any stratum of observed LDL cholesterol, risk of CAD was higher among FH mutation carriers than noncarriers. Compared with a reference group with LDL cholesterol <130 mg/dl and no mutation, participants with LDL cholesterol ≥190 mg/dl and no FH mutation had a 6-fold higher risk for CAD (odds ratio: 6.0; 95% confidence interval: 5.2 to 6.9), whereas those with both LDL cholesterol ≥190 mg/dl and an FH mutation demonstrated a 22-fold increased risk (odds ratio: 22.3; 95% confidence interval: 10.7 to 53.2). In an analysis of participants with serial lipid measurements over many years, FH mutation carriers had higher cumulative exposure to LDL cholesterol than noncarriers. CONCLUSIONS: Among participants with LDL cholesterol ≥190 mg/dl, gene sequencing identified an FH mutation in <2%. However, for any observed LDL cholesterol, FH mutation carriers had substantially increased risk for CAD.


Assuntos
Apolipoproteína B-100/genética , Variação Genética , Heterozigoto , Hipercolesterolemia/epidemiologia , Hiperlipoproteinemia Tipo II/diagnóstico , Pró-Proteína Convertase 9/genética , Receptores de LDL/genética , Estudos de Casos e Controles , LDL-Colesterol/sangue , Estudos de Coortes , Doença da Artéria Coronariana/epidemiologia , Feminino , Humanos , Hiperlipoproteinemia Tipo II/genética , Masculino , Pessoa de Meia-Idade , Análise de Sequência
20.
N Engl J Med ; 374(12): 1134-44, 2016 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-26934567

RESUMO

BACKGROUND: The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets. METHODS: Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes. RESULTS: We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P=4.2×10(-10)) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P=4.0×10(-8)), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P=0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P=0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P=2.0×10(-4)) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P=2.5×10(-7)). CONCLUSIONS: We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease. (Funded by the National Institutes of Health and others.).


Assuntos
Angiopoietinas/genética , Moléculas de Adesão Celular/genética , Doença da Artéria Coronariana/genética , Lipase Lipoproteica/genética , Mutação , Triglicerídeos/sangue , Idoso , Proteína 4 Semelhante a Angiopoietina , Feminino , Técnicas de Genotipagem , Humanos , Lipase Lipoproteica/antagonistas & inibidores , Lipase Lipoproteica/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Fatores de Risco , Análise de Sequência de DNA , Triglicerídeos/genética
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