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1.
Environ Health Prev Med ; 24(1): 26, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31043174

RESUMO

BACKGROUND: Hypertension and atherosclerosis are bidirectionally related, while platelet count could serve as an indicator of endothelial repair. Therefore, high platelet counts could be associated with hypertension by indicating more intense endothelial repair activity. Furthermore, short stature has been shown to constitute a risk of atherosclerosis. Since inflammation-related single-nucleotide polymorphism (SNP (rs3782886)) is reportedly associated with myocardial infarction and short stature, rs3782886 could be associated with a high platelet count and thus more intense endothelial repair activity. METHODS: We conducted a cross-sectional study of 988 elderly Japanese who participated in a general health check-up. Short stature was defined as a height of at or under the 25th percentile of the study population, and high platelet count as the highest tertiles of the platelet levels. RESULTS: High platelet counts were found to be independently and positively associated with hypertension while rs3782886 was independently associated with high platelet levels and short stature. The classical cardiovascular risk factor-adjusted odds ratio (OR) and 95% confidence interval (CI) of high platelet count for hypertension was 1.34 (1.02, 1.77). With non-minor homo of the rs3782886 as the reference group, the adjusted OR and 95% CI for high platelet count and short stature of minor home were 2.40 (1.30, 4.42) and 2.21 (1.16, 4.21), respectively. CONCLUSION: SNP (rs3782886) was shown to be associated with high platelet count and short stature. This result partly explains how a genetic factor can influence the impact of height on endothelial repair.


Assuntos
Plaquetas/metabolismo , Estatura/genética , Endotélio Vascular/fisiologia , Predisposição Genética para Doença , Hipertensão/sangue , Polimorfismo de Nucleotídeo Único , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Hipertensão/epidemiologia , Hipertensão/genética , Masculino , Pessoa de Meia-Idade , Razão de Chances , Contagem de Plaquetas
2.
Nat Genet ; 51(5): 804-814, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31043758

RESUMO

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.


Assuntos
Peso ao Nascer/genética , Adulto , Pressão Sanguínea/genética , Estatura/genética , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Desenvolvimento Fetal/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Cardiopatias/etiologia , Cardiopatias/genética , Humanos , Recém-Nascido , Masculino , Herança Materna/genética , Troca Materno-Fetal/genética , Doenças Metabólicas/etiologia , Doenças Metabólicas/genética , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Gravidez , Fatores de Risco
3.
Nat Commun ; 10(1): 2054, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053729

RESUMO

Bone area is one measure of bone size that is easily derived from dual-energy X-ray absorptiometry (DXA) scans. In a GWA study of DXA bone area of the hip and lumbar spine (N ≥ 28,954), we find thirteen independent association signals at twelve loci that replicate in samples of European and East Asian descent (N = 13,608 - 21,277). Eight DXA area loci associate with osteoarthritis, including rs143384 in GDF5 and a missense variant in COL11A1 (rs3753841). The strongest DXA area association is with rs11614913[T] in the microRNA MIR196A2 gene that associates with lumbar spine area (P = 2.3 × 10-42, ß = -0.090) and confers risk of hip fracture (P = 1.0 × 10-8, OR = 1.11). We demonstrate that the risk allele is less efficient in repressing miR-196a-5p target genes. We also show that the DXA area measure contributes to the risk of hip fracture independent of bone density.


Assuntos
Densidade Óssea/genética , Fraturas do Quadril/genética , MicroRNAs/genética , Osteoartrite/genética , Absorciometria de Fóton , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estatura/genética , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/fisiologia , Estudos de Casos e Controles , Colágeno Tipo XI/genética , Feminino , Seguimentos , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Fator 5 de Diferenciação de Crescimento/genética , Fraturas do Quadril/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite/epidemiologia , Fatores de Risco
5.
J Pediatr Endocrinol Metab ; 32(4): 415-419, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-30893054

RESUMO

Background Monoallelic mutations of GHR have been described in idiopathic short stature (ISS), although the significance of these remain unclear. We report a case of ISS with novel monoallelic S219L mutation of GHR and discuss the possible significance of monoallelic GHR mutation in ISS. Case presentation The proband, a 13.9-year-old Japanese boy, had severe short stature (-3.8 standard deviation [SD]). Serum insulin-like growth factor (IGF)-I level and growth hormone (GH) secretion was normal. His parents were nonconsanguineous and had normal stature. Genetic analyses revealed a novel monoallelic missense variation in exon 7 of GHR (S219L). The proband's mother had the same variation. S219L might be the novel mutation judging from there being no registration of it as a single-nucleotide polymorphism (SNP) in any database, evolutional conservation of Ser219, in silico analyses, and computational molecular visualization analysis. Furthermore, a review of the literature showed that the median height of missense mutation carriers of GHR was relatively low. Conclusions We propose the possibility that monoallelic mutation of GHR increases the susceptibility to short stature.


Assuntos
Estatura/genética , Transtornos do Crescimento/genética , Transtornos do Crescimento/patologia , Hormônio do Crescimento Humano/genética , Mutação , Adolescente , Alelos , Humanos , Masculino , Prognóstico
6.
PLoS Genet ; 15(3): e1007530, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30875371

RESUMO

A common complementary strategy in Genome-Wide Association Studies (GWAS) is to perform Gene Set Analysis (GSA), which tests for the association between one phenotype of interest and an entire set of Single Nucleotide Polymorphisms (SNPs) residing in selected genes. While there exist many tools for performing GSA, popular methods often include a number of ad-hoc steps that are difficult to justify statistically, provide complicated interpretations based on permutation inference, and demonstrate poor operating characteristics. Additionally, the lack of gold standard gene set lists can produce misleading results and create difficulties in comparing analyses even across the same phenotype. We introduce the Generalized Berk-Jones (GBJ) statistic for GSA, a permutation-free parametric framework that offers asymptotic power guarantees in certain set-based testing settings. To adjust for confounding introduced by different gene set lists, we further develop a GBJ step-down inference technique that can discriminate between gene sets driven to significance by single genes and those demonstrating group-level effects. We compare GBJ to popular alternatives through simulation and re-analysis of summary statistics from a large breast cancer GWAS, and we show how GBJ can increase power by incorporating information from multiple signals in the same gene. In addition, we illustrate how breast cancer pathway analysis can be confounded by the frequency of FGFR2 in pathway lists. Our approach is further validated on two other datasets of summary statistics generated from GWAS of height and schizophrenia.


Assuntos
Estudo de Associação Genômica Ampla/estatística & dados numéricos , Estatura/genética , Neoplasias da Mama/genética , Mapeamento Cromossômico/estatística & dados numéricos , Biologia Computacional/métodos , Simulação por Computador , Bases de Dados Genéticas , Feminino , Redes Reguladoras de Genes , Humanos , Modelos Genéticos , Modelos Estatísticos , Polimorfismo de Nucleotídeo Único , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Esquizofrenia/genética
7.
Arch Endocrinol Metab ; 63(1): 70-78, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30864634

RESUMO

Short stature is a common feature, and frequently remains without a specific diagnosis after conventional clinical and laboratorial evaluation. Longitudinal growth is mainly determined by genetic factors, and hundreds of common variants have been associated to height variability among healthy individuals. Although isolated short stature may be caused by the combination of variants, with a deleterious impact on the growth of individuals with polygenic inheritance, recent studies have pointed out some monogenic defects as the cause of the growth disorder observed in nonsyndromic children. The majority of these defects are in genes related to the growth plate cartilage and in the growth hormone (GH) - insulin-like growth factor 1 (IGF-1) axis. Affected patients usually present the mildest spectrum of some forms of skeletal dysplasia, or subtle abnormalities of laboratory tests, suggesting hormonal resistance or insensibility. The lack of specific characteristics, however, does not allow formulation of a definitive diagnosis without the use of broad genetic studies. Thus, molecular genetic studies including panels of genes or exome analysis will become essential in investigating and identifying the causes of isolated short stature in children, with a crucial impact on treatment and follow-up.


Assuntos
Estatura/genética , Variação Genética/genética , Transtornos do Crescimento/genética , Hormônio do Crescimento Humano/genética , Fator de Crescimento Insulin-Like I/genética , Humanos
8.
Leg Med (Tokyo) ; 37: 83-85, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30776764

RESUMO

Recently it has been recognized that a considerable number of copy number variations (CNVs) are associated with diseases and other complex human traits. In our previous study, we developed a simple quantitative real-time PCR (Q-PCR) method for analysis of CNV copy number, which had the advantage of obviating the need for reference DNA with a known copy number. Using DNA samples obtained from 231 Japanese individuals, we applied this method for analyzing the copy number of a candidate CNV associated with body height, located in the neural precursor cell expressed, developmentally down-regulated 4-like, E3 ubiquitin protein ligase (NEDD4L) gene. In addition, the appropriateness of the results was evaluated and confirmed by quantification of amplicons with an Agilent 2100 Bioanalyzer. The NEDD4L gene encodes a member of the Nedd4 family of HECT domain E3 ubiquitin ligases. The target CNV located in the intron has been found to be significantly associated with height variation in Chinese. However, it remains unknown whether such an association exists in other populations, including Japanese. Analysis of the correlations between copy number and body height using ANOVA revealed no statistically significant correlations in Japanese.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Estatura/genética , Variações do Número de Cópias de DNA/genética , Estudos de Associação Genética , Ubiquitina-Proteína Ligases Nedd4/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Íntrons/genética , Masculino , Pessoa de Meia-Idade , Ubiquitina-Proteína Ligases Nedd4/metabolismo , Células-Tronco Neurais/metabolismo , Reação em Cadeia da Polimerase em Tempo Real/métodos , Ubiquitina-Proteína Ligases/genética
9.
Fetal Pediatr Pathol ; 37(6): 404-410, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30592236

RESUMO

BACKGROUND: Short stature with optic atrophy and Pelger-Huet anomaly (SOPH; MIM 614800) syndrome is a genetic disease caused by mutation in the neuroblastoma amplified sequence (NBAS) gene. CASE REPORT: We present a 11-year-old Chinese boy with SOPH syndrome, growth hormone deficiency with a normal bone age. Gene sequencing in the patient revealed a novel compound heterozygous mutation of c.5752A > C (Thr1918Pro) and c.500_501delTT (Phe167Cysfs*7) in the NBAS gene. CONCLUSIONS: To our best knowledge, these novel mutations in the NBAS gene have not been reported. Normal bone age with growth hormone deficiency in this patient is different from the patients with SOPH syndrome that have been previously reported. These findings enrich the mutant spectrum of the NBAS gene and add our understanding of SOPH syndrome.


Assuntos
Hormônio do Crescimento Humano/deficiência , Proteínas de Neoplasias/genética , Anomalia de Pelger-Huët/genética , Estatura/genética , Desenvolvimento Ósseo/genética , Criança , Humanos , Masculino
10.
Science ; 361(6401): 511-516, 2018 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-30072539

RESUMO

Flores Island, Indonesia, was inhabited by the small-bodied hominin species Homo floresiensis, which has an unknown evolutionary relationship to modern humans. This island is also home to an extant human pygmy population. Here we describe genome-scale single-nucleotide polymorphism data and whole-genome sequences from a contemporary human pygmy population living on Flores near the cave where H. floresiensis was found. The genomes of Flores pygmies reveal a complex history of admixture with Denisovans and Neanderthals but no evidence for gene flow with other archaic hominins. Modern individuals bear the signatures of recent positive selection encompassing the FADS (fatty acid desaturase) gene cluster, likely related to diet, and polygenic selection acting on standing variation that contributed to their short-stature phenotype. Thus, multiple independent instances of hominin insular dwarfism occurred on Flores.


Assuntos
Adaptação Biológica/genética , Evolução Biológica , Estatura/genética , Nanismo/genética , Ilhas , População/genética , Seleção Genética , Animais , Fluxo Gênico , Genoma Humano , Humanos , Indonésia , Homem de Neandertal/genética
11.
Lipids Health Dis ; 17(1): 181, 2018 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-30064420

RESUMO

BACKGROUND: Observational studies have illustrated that maternal central obesity is associated with birth size, including of birth weight, birth length and head circumference, but the causal nature of these associations remains unclear. Our study aimed to test the causal effect of maternal central obesity on birth size and puberty height growth using a Mendelian randomization (MR) analysis. METHODS: We performed two-sample MR using summary-level genome-wide public data. Thirty-five single nucleotide polymorphisms (SNPs), 25 SNPs and 41 SNPs were selected as instrumental variables for waist-to-hip ratio adjusted for BMI, waist circumference adjusted for BMI and hip circumference adjusted for BMI, respectively to test the causal effects of maternal central obesity on birth size and puberty height using an inverse-variance-weighted approach. RESULTS: In this MR analysis, we found no evidence of a causal association between waist circumference or waist-to-hip ratio and the outcomes. However, we observed that one standard deviation (SD) increase in hip circumference (HIP) was associated with a 0.392 SD increase in birth length (p = 1.1 × 10- 6) and a 0.168 SD increase in birth weight (p = 7.1 × 10- 5), respectively at the Bonferroni-adjusted level of significance. In addition, higher genetically predicted maternal HIP was strongly associated with the puberty heights (0.835 SD, p = 8.4 × 10- 10). However, HIP was not associated with head circumference (p = 0.172). CONCLUSIONS: A genetic predisposition to higher maternal HIP was causally associated with larger offspring birth size independent of maternal BMI. However, we found no evidence of a causal association between maternal waist circumference, waist-to-hip ratio and birth size.


Assuntos
Peso ao Nascer/genética , Estatura/genética , Obesidade Abdominal/genética , Circunferência da Cintura/genética , Índice de Massa Corporal , Feminino , Humanos , Recém-Nascido , Estudos Longitudinais , Masculino , Análise da Randomização Mendeliana , Obesidade Abdominal/patologia , Polimorfismo de Nucleotídeo Único , Gravidez , Puberdade/genética , Relação Cintura-Quadril
12.
Genet Epidemiol ; 42(7): 608-620, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29971821

RESUMO

Mendelian randomization (MR) has been increasingly used to strengthen causal inference in observational epidemiology. Methodological developments in the field allow detecting and/or adjusting for different potential sources of bias, mainly bias due to horizontal pleiotropy (or "off-target" genetic effects). Another potential source of bias is nonrandom matching between spouses (i.e., assortative mating). In this study, we performed simulations to investigate the bias caused in MR by assortative mating. We found that bias can arise due to either cross-trait assortative mating (i.e., assortment on two phenotypes, such as highly educated women selecting taller men) or single-trait assortative mating (i.e., assortment on a single phenotype), even if the exposure and outcome phenotypes are not the phenotypes under assortment. The simulations also indicate that bias due to assortative mating accumulates over generations and that MR methods robust to horizontal pleiotropy are also affected by this bias. Finally, we show that genetic data from mother-father-offspring trios can be used to detect and correct for this bias.


Assuntos
Viés , Análise da Randomização Mendeliana , Reprodução/genética , Estatura/genética , Criança , Simulação por Computador , Pai , Feminino , Genótipo , Humanos , Análise dos Mínimos Quadrados , Masculino , Modelos Genéticos , Mães , Fenótipo , Análise de Regressão
13.
Theriogenology ; 118: 27-33, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-29883841

RESUMO

The size and body condition of cows can affect their reproductive efficiency. However, few studies reported genetic correlations between these traits in beef cattle. Thus, we estimated the genetic parameters and correlations between weight (MW), height (MH) and body condition score (BCS) of cows and reproductive traits (SC: scrotal circumference, AFC: age at first calving, GL: gestation length, DC: days to calving, and CI: calving interval) in Nelore animals. In addition, it has also obtained direct and correlated responses aiming at determining whether changes in cow size and body condition may affect the herd reproductive performance. A series of two-trait Bayesian analyzes were performed including MW, MH or BCS with each of the reproductive traits. The heritability estimated for MW, MH and BCS were 0.46 ±â€¯0.02, 0.35 ±â€¯0.01 and 0.17 ±â€¯0.02, indicating an involvement of additive gene action mainly in cows' size determination. For the reproductive traits of females, heritability ranged from 0.05 ±â€¯0.00 for CI to 0.18 ±â€¯0.01 for GL, and was 0.37 ±â€¯0.01 for SC. Low repeatability were estimates for GL (0.19 ±â€¯0.00), DC (0.19 ±â€¯0.00) and CI (0.05 ±â€¯0.00). The MW was positive correlated with AFC (0.23 ±â€¯0.08), CI (0.25 ±â€¯0.15) and, with lower magnitude, of GL (0.14 ±â€¯0.03). Null genetic correlations were obtained between MW with SC (0.03 ±â€¯0.03) and DC (-0.01 ±â€¯0.04). The MH showed positive and low genetic association with all female reproductive traits, but negative with SC (-0.08 ±â€¯0.03). Negative and favorable genetic correlations were estimated between BCS and females reproductive traits, but unfavorable with SC (-0.13 ±â€¯0.06). In summary, the negative impact of increase the size of Nelore females on their reproductive performance is expected to be small in tropical regions. The use of sires with high genetic breeding values for SC should result in slight reduction of BCS of cows, but no effective genetic response in female size is expected. Selection based on BCS should promote little improvement in reproductive efficiency of cows.


Assuntos
Composição Corporal/fisiologia , Tamanho Corporal/fisiologia , Bovinos/genética , Reprodução/genética , Reprodução/fisiologia , Animais , Estatura/genética , Peso Corporal/genética , Cruzamento , Bovinos/fisiologia , Feminino , Idade Gestacional , Humanos , Masculino , Característica Quantitativa Herdável , Escroto/anatomia & histologia
15.
BMC Evol Biol ; 18(1): 63, 2018 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-29747567

RESUMO

BACKGROUND: One explanation for the persistence of schizophrenia despite the reduced fertility of patients is that it is a by-product of recent human evolution. This hypothesis is supported by evidence suggesting that recently-evolved genomic regions in humans are involved in the genetic risk for schizophrenia. Using summary statistics from genome-wide association studies (GWAS) of schizophrenia and 11 other phenotypes, we tested for enrichment of association with GWAS traits in regions that have undergone methylation changes in the human lineage compared to Neanderthals and Denisovans, i.e. human-specific differentially methylated regions (DMRs). We used analytical tools that evaluate polygenic enrichment of a subset of genomic variants against all variants. RESULTS: Schizophrenia was the only trait in which DMR SNPs showed clear enrichment of association that passed the genome-wide significance threshold. The enrichment was not observed for Neanderthal or Denisovan DMRs. The enrichment seen in human DMRs is comparable to that for genomic regions tagged by Neanderthal Selective Sweep markers, and stronger than that for Human Accelerated Regions. The enrichment survives multiple testing performed through permutation (n = 10,000) and bootstrapping (n = 5000) in INRICH (p < 0.01). Some enrichment of association with height was observed at the gene level. CONCLUSIONS: Regions where DNA methylation modifications have changed during recent human evolution show enrichment of association with schizophrenia and possibly with height. Our study further supports the hypothesis that genetic variants conferring risk of schizophrenia co-occur in genomic regions that have changed as the human species evolved. Since methylation is an epigenetic mark, potentially mediated by environmental changes, our results also suggest that interaction with the environment might have contributed to that association.


Assuntos
Metilação de DNA/genética , Evolução Molecular , Esquizofrenia/genética , Adulto , Transtorno Bipolar/genética , Estatura/genética , Índice de Massa Corporal , Feminino , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Complexo Principal de Histocompatibilidade/genética , Masculino , Anotação de Sequência Molecular , Herança Multifatorial , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
16.
Genet Med ; 20(6): 630-638, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29758562

RESUMO

PurposeShort stature is a common condition of great concern to patients and their families. Mostly genetic in origin, the underlying cause often remains elusive due to clinical and genetic heterogeneity.MethodsWe systematically phenotyped 565 patients where common nongenetic causes of short stature were excluded, selected 200 representative patients for whole-exome sequencing, and analyzed the identified variants for pathogenicity and the affected genes regarding their functional relevance for growth.ResultsBy standard targeted diagnostic and phenotype assessment, we identified a known disease cause in only 13.6% of the 565 patients. Whole-exome sequencing in 200 patients identified additional mutations in known short-stature genes in 16.5% of these patients who manifested only part of the symptomatology. In 15.5% of the 200 patients our findings were of significant clinical relevance. Heterozygous carriers of recessive skeletal dysplasia alleles represented 3.5% of the cases.ConclusionA combined approach of systematic phenotyping, targeted genetic testing, and whole-exome sequencing allows the identification of the underlying cause of short stature in at least 33% of cases, enabling physicians to improve diagnosis, treatment, and genetic counseling. Exome sequencing significantly increases the diagnostic yield and consequently care in patients with short stature.


Assuntos
Estatura/genética , Feminino , Testes Genéticos , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Mutação , Linhagem , Fenótipo , Análise de Sequência de DNA/métodos , Sequenciamento Completo do Exoma/métodos
17.
Biomed Res Int ; 2018: 7431050, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29687007

RESUMO

Objective: This study was designed to analyze the association between the growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis gene polymorphisms and short stature in Chinese children. Methods: 181 growth hormone deficiency (GHD) patients and 206 normal stature controls were enrolled to attend this study. Five single-nucleotide polymorphisms in the GH receptor (GHR) and 5 SNPs within the GH-signaling pathway were genotyped by matrix-assisted laser desorption/ionization time of flight mass spectrometry. We conducted an association study between these SNPs and the risk of developing short stature. Linkage disequilibrium analysis was performed using Haploview software and the associations of the SNPs frequencies with short stature were analyzed using X2 tests. Results: No significant difference was found in gender, weight, height, and BMI between the GHD and control groups, except that the age of GHD group was older than the control one. Allele and genotype frequencies were consistent with those expected from Hardy-Weinberg equilibrium. Compared with the controls, heterozygous genotype frequencies (CT) of rs12515480 and rs6873545 of GHR gene were significantly lower. Genotype frequencies of the other 8 SNPs did not show significant difference between these two groups. Considering a dominant model, an OR < 1 was observed for genotypes rs12515480 (OR = 0.532, P = 0.019) and rs6873545 (OR = 0.587, P = 0.017). Conclusions: The heterozygous genotypes of rs12515480 and rs6873545 of GHR gene were associated with decreased risk of GHD in Chinese children.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Estatura/genética , Nanismo/genética , Predisposição Genética para Doença/genética , Hormônio do Crescimento Humano/genética , Fator de Crescimento Insulin-Like I/genética , Polimorfismo de Nucleotídeo Único/genética , Alelos , Criança , Feminino , Genótipo , Transtornos do Crescimento/genética , Humanos , Masculino
18.
PLoS One ; 13(4): e0194541, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29617452

RESUMO

The propensity of a trait to vary within a population may have evolutionary, ecological, or clinical significance. In the present study we deploy sibling models to offer a novel and unbiased way to ascertain loci associated with the extent to which phenotypes vary (variance-controlling quantitative trait loci, or vQTLs). Previous methods for vQTL-mapping either exclude genetically related individuals or treat genetic relatedness among individuals as a complicating factor addressed by adjusting estimates for non-independence in phenotypes. The present method uses genetic relatedness as a tool to obtain unbiased estimates of variance effects rather than as a nuisance. The family-based approach, which utilizes random variation between siblings in minor allele counts at a locus, also allows controls for parental genotype, mean effects, and non-linear (dominance) effects that may spuriously appear to generate variation. Simulations show that the approach performs equally well as two existing methods (squared Z-score and DGLM) in controlling type I error rates when there is no unobserved confounding, and performs significantly better than these methods in the presence of small degrees of confounding. Using height and BMI as empirical applications, we investigate SNPs that alter within-family variation in height and BMI, as well as pathways that appear to be enriched. One significant SNP for BMI variability, in the MAST4 gene, replicated. Pathway analysis revealed one gene set, encoding members of several signaling pathways related to gap junction function, which appears significantly enriched for associations with within-family height variation in both datasets (while not enriched in analysis of mean levels). We recommend approximating laboratory random assignment of genotype using family data and more careful attention to the possible conflation of mean and variance effects.


Assuntos
Modelos Genéticos , Locos de Características Quantitativas , Irmãos , Estatura/genética , Índice de Massa Corporal , Mapeamento Cromossômico/métodos , Simulação por Computador , Genótipo , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único
19.
J Pediatr Endocrinol Metab ; 31(1): 25-31, 2018 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-29197219

RESUMO

Background Growth hormone (GH) treatment in children with short stature homeobox-containing gene (SHOX) deficiency is recognized to increase height velocity (HV) and adult height. Prediction of growth response continues to be a challenge. A comparatively accurate method is the Cologne prediction model developed in children with GH deficiency. The aim was to investigate whether this model also applies to patients with SHOX deficiency. Methods Included were 48 patients with SHOX deficiency confirmed by DNA analysis and treated with 0.05 mg/kg/day of somatropin. Prediction by the Cologne model uses the following variables: relative bone age (BA) retardation, baseline insulin-like growth factor-I (IGF-I), urinary deoxypyridinoline (DPD) cross-links at 4 weeks and HV at 3 months. Results HV and height standard deviation scores (SDS) increased significantly during the first year of treatment. Predicted and observed HV (cm/year) showed a Pearson correlation coefficient of 0.50 (p<0.001; root-mean-square error=1.63) and for first-year change in height SDS a Pearson correlation coefficient of 0.751 (p<0.001; root-mean-square error=0.32). Poor response could be adequately predicted using SDS change, with sensitivity and specificity both above 70% for certain thresholds. CONCLUSIONS: The results demonstrate that the Cologne model can be used to predict growth response in patients with SHOX deficiency with reasonable precision in the first treatment year, comparable to prediction in patients with GH deficiency.


Assuntos
Estatura/genética , Transtornos do Crescimento/genética , Hormônio do Crescimento Humano/administração & dosagem , Modelos Estatísticos , Mutação , Proteína de Homoeobox de Baixa Estatura/genética , Estatura/efeitos dos fármacos , Feminino , Transtornos do Crescimento/tratamento farmacológico , Humanos , Masculino , Valor Preditivo dos Testes , Estudos Prospectivos , Proteína de Homoeobox de Baixa Estatura/deficiência
20.
J Formos Med Assoc ; 117(10): 909-914, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29254682

RESUMO

BACKGROUND: SHOX deficiency is a common cause of idiopathic short stature. The aim of this study was to describe the clinical characteristics and molecular findings of patients with SHOX deficiency in Taiwan. METHODS: A phenotype scoring system was used to evaluate several anthropometric measures in patients with idiopathic short stature. Twenty-three patients with a phenotype score >7 were enrolled for SHOX gene analysis by MLPA and sequencing. Another patient with a deletion/insertion of the short arm of the X chromosome containing the SHOX gene was enrolled for the assessment. RESULTS: SHOX deficiency was detected in 26% of short children with a phenotype score >7. The arm-span-to-height ratio was significantly lower in SHOX-D patients than in non-SHOX-D patients. In patients with SHOX deficiency, an arm-span-to-height ratio <96.5% and short forearm were the most common characteristics. Three patients also exhibited typical radiological findings. A molecular analysis of the SHOX gene revealed five patients with intragenic deletions, one with a deletion in the regulatory region, and one with a missense mutation at exon 5. CONCLUSION: The phenotype scoring system is useful to select children with SHOX deficiency in Taiwan. Family history and radiological image of the radius are also of value for the diagnosis. This study may aid physicians in the early diagnosis of children with SHOX deficiency.


Assuntos
Transtornos do Crescimento/genética , Fenótipo , Proteína de Homoeobox de Baixa Estatura/genética , Adolescente , Estatura/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Deleção de Genes , Transtornos do Crescimento/diagnóstico por imagem , Humanos , Masculino , Proteína de Homoeobox de Baixa Estatura/deficiência , Taiwan
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