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BACKGROUND: Preterm birth is defined as live birth before 37 completed weeks of pregnancy, and it is a major problem worldwide. The molecular mechanisms that lead to onset of spontaneous preterm birth are incompletely understood. Prediction and evaluation of the risk of preterm birth is challenging as there is a lack of accurate biomarkers. In this study, our aim was to identify placental proteins that associate with spontaneous preterm birth. METHODS: We analyzed the proteomes from placentas to identify proteins that associate with both gestational age and spontaneous labor. Next, rare and potentially damaging gene variants of the identified protein candidates were sought for from our whole exome sequencing data. Further experiments we performed on placental samples and placenta-associated cells to explore the location and function of the spontaneous preterm labor-associated proteins in placentas. RESULTS: Exome sequencing data revealed rare damaging variants in SERPINA1 in families with recurrent spontaneous preterm deliveries. Protein and mRNA levels of alpha-1 antitrypsin/SERPINA1 from the maternal side of the placenta were downregulated in spontaneous preterm births. Alpha-1 antitrypsin was expressed by villous trophoblasts in the placenta, and immunoelectron microscopy showed localization in decidual fibrinoid deposits in association with specific extracellular proteins. siRNA knockdown in trophoblast-derived HTR8/SVneo cells revealed that SERPINA1 had a marked effect on regulation of the actin cytoskeleton pathway, Slit-Robo signaling, and extracellular matrix organization. CONCLUSIONS: Alpha-1 antitrypsin is a protease inhibitor. We propose that loss of the protease inhibition effects of alpha-1 antitrypsin renders structures critical to maintaining pregnancy susceptible to proteases and inflammatory activation. This may lead to spontaneous premature birth.
Assuntos
Trabalho de Parto Prematuro , Nascimento Prematuro , Éxons , Feminino , Humanos , Recém-Nascido , Trabalho de Parto Prematuro/genética , Placenta/metabolismo , Gravidez , Nascimento Prematuro/genética , Proteômica , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/metabolismoRESUMO
Spontaneous preterm birth (SPTB) is the leading cause of neonatal death and morbidity worldwide. Both maternal and fetal genetic factors likely contribute to SPTB. We performed a genome-wide association study (GWAS) on a population of Finnish origin that included 247 infants with SPTB (gestational age [GA] < 36 weeks) and 419 term controls (GA 38-41 weeks). The strongest signal came within the gene encoding slit guidance ligand 2 (SLIT2; rs116461311, minor allele frequency 0.05, p = 1.6×10-6). Pathway analysis revealed the top-ranking pathway was axon guidance, which includes SLIT2. In 172 very preterm-born infants (GA <32 weeks), rs116461311 was clearly overrepresented (odds ratio 4.06, p = 1.55×10-7). SLIT2 variants were associated with SPTB in another European population that comprised 260 very preterm infants and 9,630 controls. To gain functional insight, we used immunohistochemistry to visualize SLIT2 and its receptor ROBO1 in placentas from spontaneous preterm and term births. Both SLIT2 and ROBO1 were located in villous and decidual trophoblasts of embryonic origin. Based on qRT-PCR, the mRNA levels of SLIT2 and ROBO1 were higher in the basal plate of SPTB placentas compared to those from term or elective preterm deliveries. In addition, in spontaneous term and preterm births, placental SLIT2 expression was correlated with variations in fetal growth. Knockdown of ROBO1 in trophoblast-derived HTR8/SVneo cells by siRNA indicated that it regulate expression of several pregnancy-specific beta-1-glycoprotein (PSG) genes and genes involved in inflammation. Our results show that the fetal SLIT2 variant and both SLIT2 and ROBO1 expression in placenta and trophoblast cells may be correlated with susceptibility to SPTB. SLIT2-ROBO1 signaling was linked with regulation of genes involved in inflammation, PSG genes, decidualization and fetal growth. We propose that this receptor-ligand couple is a component of the signaling network that promotes SPTB.
Assuntos
Desenvolvimento Fetal/genética , Predisposição Genética para Doença , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas do Tecido Nervoso/genética , Nascimento Prematuro/genética , Receptores Imunológicos/genética , Feminino , Feto , Finlândia , Regulação da Expressão Gênica/genética , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Placenta/patologia , Polimorfismo de Nucleotídeo Único , Gravidez , Glicoproteínas beta 1 Específicas da Gravidez/genética , Nascimento Prematuro/patologia , Transdução de Sinais , Trofoblastos/patologia , Proteínas RoundaboutRESUMO
[This corrects the article DOI: 10.1371/journal.pgen.1007394.].
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Preterm birth is a leading cause of morbidity and mortality in infants. Genetic and environmental factors play a role in the susceptibility to preterm birth, but despite many investigations, the genetic basis for preterm birth remain largely unknown. Our objective was to identify rare, possibly damaging, nucleotide variants in mothers from families with recurrent spontaneous preterm births (SPTB). DNA samples from 17 Finnish mothers who delivered at least one infant preterm were subjected to whole exome sequencing. All mothers were of northern Finnish origin and were from seven multiplex families. Additional replication samples of European origin consisted of 93 Danish sister pairs (and two sister triads), all with a history of a preterm delivery. Rare exonic variants (frequency <1%) were analyzed to identify genes and pathways likely to affect SPTB susceptibility. We identified rare, possibly damaging, variants in genes that were common to multiple affected individuals. The glucocorticoid receptor signaling pathway was the most significant (p<1.7e-8) with genes containing these variants in a subgroup of ten Finnish mothers, each having had 2-4 SPTBs. This pathway was replicated among the Danish sister pairs. A gene in this pathway, heat shock protein family A (Hsp70) member 1 like (HSPA1L), contains two likely damaging missense alleles that were found in four different Finnish families. One of the variants (rs34620296) had a higher frequency in cases compared to controls (0.0025 vs. 0.0010, p = 0.002) in a large preterm birth genome-wide association study (GWAS) consisting of mothers of general European ancestry. Sister pairs in replication samples also shared rare, likely damaging HSPA1L variants. Furthermore, in silico analysis predicted an additional phosphorylation site generated by rs34620296 that could potentially affect chaperone activity or HSPA1L protein stability. Finally, in vitro functional experiment showed a link between HSPA1L activity and decidualization. In conclusion, rare, likely damaging, variants in HSPA1L were observed in multiple families with recurrent SPTB.
Assuntos
Predisposição Genética para Doença , Proteínas de Choque Térmico HSP70/genética , Nascimento Prematuro/genética , Difosfato de Adenosina/química , Difosfato de Adenosina/metabolismo , Estudos de Casos e Controles , Linhagem Celular , Exoma/genética , Feminino , Fibroblastos , Finlândia , Estudo de Associação Genômica Ampla , Proteínas de Choque Térmico HSP70/química , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Recém-Nascido , Masculino , Modelos Moleculares , Fosforilação/genética , Polimorfismo de Nucleotídeo Único , Gravidez , Receptores de Glucocorticoides/metabolismo , Recidiva , Fatores de Risco , Transdução de Sinais/genética , Sequenciamento do ExomaRESUMO
BACKGROUND: Despite evidence that genetic factors contribute to the duration of gestation and the risk of preterm birth, robust associations with genetic variants have not been identified. We used large data sets that included the gestational duration to determine possible genetic associations. METHODS: We performed a genomewide association study in a discovery set of samples obtained from 43,568 women of European ancestry using gestational duration as a continuous trait and term or preterm (<37 weeks) birth as a dichotomous outcome. We used samples from three Nordic data sets (involving a total of 8643 women) to test for replication of genomic loci that had significant genomewide association (P<5.0×10-8) or an association with suggestive significance (P<1.0×10-6) in the discovery set. RESULTS: In the discovery and replication data sets, four loci (EBF1, EEFSEC, AGTR2, and WNT4) were significantly associated with gestational duration. Functional analysis showed that an implicated variant in WNT4 alters the binding of the estrogen receptor. The association between variants in ADCY5 and RAP2C and gestational duration had suggestive significance in the discovery set and significant evidence of association in the replication sets; these variants also showed genomewide significance in a joint analysis. Common variants in EBF1, EEFSEC, and AGTR2 showed association with preterm birth with genomewide significance. An analysis of mother-infant dyads suggested that these variants act at the level of the maternal genome. CONCLUSIONS: In this genomewide association study, we found that variants at the EBF1, EEFSEC, AGTR2, WNT4, ADCY5, and RAP2C loci were associated with gestational duration and variants at the EBF1, EEFSEC, and AGTR2 loci with preterm birth. Previously established roles of these genes in uterine development, maternal nutrition, and vascular control support their mechanistic involvement. (Funded by the March of Dimes and others.).
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Predisposição Genética para Doença , Variação Genética , Idade Gestacional , Fatores de Alongamento de Peptídeos/genética , Nascimento Prematuro/genética , Receptor Tipo 2 de Angiotensina/genética , Transativadores/genética , Adenilil Ciclases/genética , Conjuntos de Dados como Assunto , Feminino , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Gravidez , Análise de Regressão , Proteína Wnt4/genética , Proteínas ras/genéticaRESUMO
Spontaneous preterm birth is a serious and common pregnancy complication associated with hormonal dysregulation, infection, inflammation, immunity, rupture of fetal membranes, stress, bleeding, and uterine distention. Heredity is 25-40% and mostly involves the maternal genome, with contribution of the fetal genome. Significant discoveries of candidate genes by genome-wide studies and confirmation in independent replicate populations serve as signposts for further research. The main task is to define the candidate genes, their roles, localization, regulation, and the associated pathways that influence the onset of human labor. Genomic research has identified some candidate genes that involve growth, differentiation, endocrine function, immunity, and other defense functions. For example, selenocysteine-specific elongation factor (EEFSEC) influences synthesis of selenoproteins. WNT4 regulates decidualization, while a heat-shock protein family A (HSP70) member 1 like, HSPAIL, influences expression of glucocorticoid receptor and WNT4. Programming of pregnancy duration starts before pregnancy and during placentation. Future goals are to understand the interactive regulation of the pathways in order to define the clocks that influence the risk of prematurity and the duration of pregnancy. Premature birth has a great impact on the duration and the quality of life. Intensification of focused research on causes, prediction and prevention of prematurity is justified.
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Genoma Humano , Nascimento Prematuro/genética , Feminino , Humanos , Recém-Nascido , Masculino , Trabalho de Parto Prematuro/prevenção & controle , Gravidez , Fatores de RiscoRESUMO
Spontaneous preterm birth (SPTB) is a major factor associating with deaths and with lowered quality of life in humans. Environmental and genetic factors influence the susceptibility. Previously, by analyzing families with recurrent SPTB in linkage analysis, we identified a linkage peak close to the gene encoding CXCR3. Present objectives were to investigate the association of CXCR3 with SPTB in Finnish mothers (n = 443) and infants (n = 747), to analyze CXCR3 expression levels in human placenta and levels of its ligands in umbilical cord blood, and to verify the influence of Cxcr3 on SPTB-associating cytokines in mice. We detected an association between an intronic CXCR3 polymorphism, rs2280964, and SPTB in infants from families with recurrent preterm births (p = 0.009 versus term controls, odds ratio 0.52, 95% confidence interval 0.32-0.86). The minor allele was protective and undertransmitted to SPTB infants (p = 0.007). In the placenta and fetal membranes, the rs2280964 major allele homozygotes had higher expression levels than minor allele homozygotes; decidual trophoblasts showed strong CXCR3 immunoreactivity. Expression was higher in SPTB placentas compared with those from elective deliveries. Concentration of a CXCR3 ligand, CXCL9, was increased in cord blood from SPTB, and the protective rs2280964 allele was associated with low CXCL9. In CXCR3-deficient mice (Mus musculus), SPTB-associating cytokines were not acutely increased in amniotic fluid after preterm birth-inducing dose of maternal LPS. Our results indicate that CXCR3 contributes to SPTB. Activation of CXCR3 signaling may disturb the maternal-fetal tolerance, and this may promote labor.
Assuntos
Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Nascimento Prematuro/genética , Receptores CXCR3/genética , Alelos , Animais , Western Blotting , Estudos de Casos e Controles , Citocinas/sangue , Feminino , Sangue Fetal/metabolismo , Expressão Gênica , Frequência do Gene , Humanos , Imuno-Histoquímica , Recém-Nascido , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Placenta/metabolismo , Gravidez , Receptores CXCR3/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: Bronchopulmonary dysplasia (BPD) is a common chronic lung disease associated with very preterm birth. The major risk factors include lung inflammation and lung immaturity. In addition, genetic factors play an important role in susceptibility to moderate-to-severe BPD. In this study, the aim was to investigate whether common polymorphisms of specific genes that are involved in inflammation or differentiation of the lung have influence on BPD susceptibility. METHODS: Genes encoding interleukin-6 (IL6) and its receptors (IL6R and IL6ST), IL-10 (IL10), tumor necrosis factor (TNF), and glucocorticoid receptor (NR3C1) were assessed for associations with moderate-to-severe BPD susceptibility. Five IL6, nine IL6R, four IL6ST, one IL10, two TNF, and 23 NR3C1 single nucleotide polymorphisms (SNPs) were analyzed in very preterm infants born in northern Finland (56 cases and 197 controls) and Canada (58 cases and 68 controls). IL-6, TNF and gp130 contents in umbilical cord blood, collected from very preterm infants, were studied for associations with the polymorphisms. Epistasis (i.e., interactions between SNPs in BPD susceptibility) was also examined. SNPs showing suggestive associations were analyzed in additional replication populations from Finland (39 cases and 188 controls) and Hungary (29 cases and 40 controls). RESULTS: None of the studied SNPs were associated with BPD nor were the IL6, TNF or IL6ST SNPs associated with cord blood IL-6, TNF and gp130, respectively. However, epistasis analysis suggested that SNPs in IL6ST and IL10 were associated interactively with risk of BPD in the northern Finnish population; however, this finding did not remain significant after correction for multiple testing and the finding was not replicated in the other populations. CONCLUSIONS: We conclude that the analyzed SNPs within IL6, IL6R, IL6ST, IL10, TNF, and NR3C1 were not associated with BPD. Furthermore, there was no evidence that the studied SNPs directly contribute to the cord blood protein contents.
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Displasia Broncopulmonar/genética , Citocinas/genética , Receptores de Citocinas/genética , Receptores de Glucocorticoides/genética , Displasia Broncopulmonar/patologia , Estudos de Casos e Controles , Receptor gp130 de Citocina/genética , Suscetibilidade a Doenças , Epistasia Genética , Genótipo , Idade Gestacional , Humanos , Recém-Nascido , Interleucina-10/genética , Interleucina-6/genética , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina-6/genética , Fator de Necrose Tumoral alfa/genéticaRESUMO
BACKGROUND: Surfactant protein B (SP-B) is essential for normal lung function, and decreased concentrations of SP-B have a deleterious effect on pulmonary outcome. SP-B levels may correlate with variations in the encoding gene (SFTPB). SFTPB single-nucleotide polymorphism Ile131Thr affects proSP-B N-glycosylation in humans and the glycosylated Thr variant associates with pulmonary diseases. METHODS: We analyzed SP-B levels in amniotic fluid samples for associations with SFTPB polymorphisms and generated cell lines expressing either proSP-B/131Ile or proSP-B/131Thr for examining the effect of glycosylation on proSP-B secretion kinetics. To determine any transcription preference between Ile131Thr allelic variants, we used heterozygous human lungs for allelic expression imbalance assays. RESULTS: Protein levels correlated with Ile131Thr genotype and the lowest SP-B levels were observed in Thr/Thr homozygotes. Our results suggest that Ile131Thr variation-dependent N-glycosylation associates with decreased levels of SP-B, which is secreted from fetal lung to amniotic fluid. Glycosylated proSP-B/131Thr was secreted from transfected cells at a lower rate than nonglycosylated proSP-B/131Ile. Expression levels of the mRNA variants were equal. Secretion of the glycosylated variant was thus delayed in vitro by a posttranscriptional mechanism. CONCLUSION: These data support the hypothesis that proSP-B glycosylation due to Ile131Thr variation may have a causal role in genetic susceptibility to acute respiratory distress.
Assuntos
Alelos , Proteína B Associada a Surfactante Pulmonar/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Glicosilação , Humanos , Isoleucina/metabolismo , Polimorfismo de Nucleotídeo Único , Proteína B Associada a Surfactante Pulmonar/genética , Treonina/metabolismoRESUMO
INTRODUCTION: Preterm birth is the major cause of mortality and morbidity in neonates. Intrauterine infection and/or inflammatory response are evident in 60-70% of spontaneous preterm births (SPTBs). Genetic factors significantly increase this risk. However, the genetic background associated with SPTB is poorly understood. Surfactant protein (SP) A, SP-D, and mannose-binding lectin (MBL) are structurally and functionally related collectins that bind pathogen-associated molecular patterns, and mostly suppress innate immune responses. RESULTS: We detected an overrepresentation of the methionine allele of the SFTPD gene (encoding SP-D) Met31Thr polymorphism in preterm infants as compared to term infants. This association was highly significant in infants of families with recurrent SPTBs (P = 0.001, odds ratio = 1.65, 95% confidence interval = 1.22-2.22); however, there was no such association with SFTPD in the mothers of these infants. Polymorphism of the genes encoding SP-A and MBL did not influence the risk of SPTB. DISCUSSION: Our results suggest that the fetal SFTPD Met31Thr polymorphism plays a significant role in genetic predisposition to SPTB. We propose that fetal immune responses influence sensitivity to preterm labor-inducing signals. METHODS: Genes encoding SP-A, SP-D, and MBL were investigated as potential candidates for association with SPTB in a population of preterm singleton infants (n = 406) and their mothers (n = 308), and in mothers with term deliveries (n = 201) and their infants (n = 201), all originating from northern Finland.
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Colectinas/genética , Predisposição Genética para Doença , Recém-Nascido Prematuro , Polimorfismo Genético , Nascimento Prematuro/genética , Proteína D Associada a Surfactante Pulmonar/genética , Adolescente , Adulto , Feminino , Idade Gestacional , Haplótipos , Humanos , Recém-Nascido , Doenças do Prematuro/genética , Desequilíbrio de Ligação , Lectina de Ligação a Manose/genética , Metionina/genética , Pessoa de Meia-Idade , Gravidez , Proteína A Associada a Surfactante Pulmonar/genética , Treonina/genética , Adulto JovemRESUMO
BACKGROUND: Skeletal dysplasia is typically diagnosed using a combination of radiographic imaging, clinical examinations, and molecular testing. Identifying a molecular diagnosis for an individual with a skeletal dysplasia can lead to improved clinical care, guide future medical management and treatment, and inform assessment of risk for familial recurrence. The molecular diagnostic utility of multi-gene panel testing using next-generation sequencing (NGS) has not yet been characterized for an unselected population of individuals with suspected skeletal dysplasia. In this study, we retrospectively reviewed patient reports to assess the diagnostic yield, reported variant characteristics, impact of copy number variation, and performance in prenatal diagnostics of panel tests for variants in genes associated with skeletal dysplasia and growth disorders. RESULTS: Clinical reportsâ¯ofâ¯consecutiveâ¯patientsâ¯with a clinical indication ofâ¯suspectedâ¯skeletal dysplasiaâ¯who underwentâ¯panel testingâ¯were examined. The 543 patients included in the study submitted samples for diagnostic genetic testing with an indication of suspected skeletal dysplasia or growth disorder and received one of three nested panel tests. A molecular diagnosis was established in 42.0% of patients (n = 228/543). Diagnostic variants were identified in 71 genes, nearly half of which (n = 35, 49.3%) contributed uniquely to a molecular diagnosis for a single patient in this cohort. Diagnostic yield was significantly higher among fetal samples (58.0%, n = 51/88) than postnatal samples (38.9%, n = 177/455; z = 3.32, p < 0.0009). Diagnostic variants in fetal cases were identified across 18 genes. Thirteen diagnosticâ¯CNVs were reported, representing 5.7%â¯of diagnostic findings and ranging in size from 241-bpâ¯toâ¯whole chromosome aneuploidy. Additionally, 11.4% (36/315) of non-diagnostic patient reports had suspicious variants of unknown significance (VUS), in which additional family studies that provide segregation data and/or functional characterization may result in reclassification to likely pathogenic. CONCLUSIONS: These findings demonstrate the utility of panel testing for individuals with a suspected skeletal dysplasia or growth disorder, with a particularly high diagnostic yield seen in prenatal cases. Pursuing comprehensive panel testing with high-resolution CNV analysis can provide a diagnostic benefit, given the considerable phenotype overlap amongst skeletal dysplasia conditions.
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Variações do Número de Cópias de DNA , Osteocondrodisplasias , Variações do Número de Cópias de DNA/genética , Feminino , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Gravidez , Estudos RetrospectivosRESUMO
Heat shock proteins are involved in the response to stress including activation of the immune response. Elevated circulating heat shock proteins are associated with spontaneous preterm birth (SPTB). Intracellular heat shock proteins act as multifunctional molecular chaperones that regulate activity of nuclear hormone receptors. Since SPTB has a significant genetic predisposition, our objective was to identify genetic and transcriptomic evidence of heat shock proteins and nuclear hormone receptors that may affect risk for SPTB. We investigated all 97 genes encoding members of the heat shock protein families and all 49 genes encoding nuclear hormone receptors for their potential role in SPTB susceptibility. We used multiple genetic and genomic datasets including genome-wide association studies (GWASs), whole-exome sequencing (WES), and placental transcriptomics to identify SPTB predisposing factors from the mother, infant, and placenta. There were multiple associations of heat shock protein and nuclear hormone receptor genes with SPTB. Several orthogonal datasets supported roles for SEC63, HSPA1L, SACS, RORA, and AR in susceptibility to SPTB. We propose that suppression of specific heat shock proteins promotes maintenance of pregnancy, whereas activation of specific heat shock protein mediated signaling may disturb maternal-fetal tolerance and promote labor.
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Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico/genética , Chaperonas Moleculares/genética , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Nascimento Prematuro/genética , Proteínas de Ligação a RNA/genética , Receptores Androgênicos/genética , Adulto , Feminino , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico/metabolismo , Humanos , Recém-Nascido Prematuro , Masculino , Chaperonas Moleculares/metabolismo , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Placenta/metabolismo , Gravidez , Proteínas de Ligação a RNA/metabolismo , Receptores Androgênicos/metabolismo , TranscriptomaRESUMO
Circulating immature surfactant protein B (proSP-B) forms emerged as the most reliable lung-specific circulating marker for alveolar-capillary membrane (ACM) dysfunction and for the overall clinical status of heart failure (HF). Notably, in terms of HF hospitalization, immature SP-B overwhelms the prognostic role of other most frequently used clinical parameters such as those related to lung dysfunction. The strong prognostic value of circulating proSP-B in HF suggests more widespread and possible systemic effects. Thus, we assessed the plasma distribution of proSP-B evaluating whether it exists in a lipoprotein-bound form and its impact on lipoprotein structure and function. ProSP-B forms were detectable in high-density lipoprotein (HDL) only. To assess the impact of proSP-B on HDL, HDL from healthy subjects were enriched with proSP-B produced by a stably transfected CHO cell line that specifically expresses and releases the human proSP-B. After enrichment, HDL size and lipoprotein electrophoretic mobility, and protein composition did not show apparent differences. HDL antioxidant capacity (HOI), assessed as their ability to inhibit air-induced LDL oxidation, was impaired after proSP-B enrichment. HOI was also higher in HF patients with respect to age-matched control healthy subjects (pâ¯=â¯0.013). Circulating proSP-B, besides its potential role as a specific marker for ACM dysfunction in HF patients with diagnostic and prognostic value, binds to human HDL impairing their antioxidant capacity. These findings shed light on proSP-B as a molecule that contributes to the reduction of the defense against oxidative stress, a key mediator in the pathogenesis of HF.
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Antioxidantes/metabolismo , Insuficiência Cardíaca/metabolismo , Lipoproteínas HDL/sangue , Estresse Oxidativo , Proteína B Associada a Surfactante Pulmonar/metabolismo , Biomarcadores/metabolismo , Células Cultivadas , Feminino , Insuficiência Cardíaca/patologia , Humanos , Immunoblotting , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Bronchopulmonary dysplasia (BPD), the main consequence of prematurity, has a significant heritability, but little is known about predisposing genes. The aim of this study was to identify gene loci predisposing infants to BPD. The initial genome-wide association study (GWAS) included 174 Finnish preterm infants of gestational age 24-30 weeks. Thereafter, the most promising single-nucleotide polymorphisms (SNPs) associated with BPD were genotyped in both Finnish (n = 555) and non-Finnish (n = 388) replication cohorts. Finally, plasma CRP levels from the first week of life and the risk of BPD were assessed. SNP rs11265269, flanking the CRP gene, showed the strongest signal in GWAS (odds ratio [OR] 3.2, p = 3.4 × 10-6). This association was nominally replicated in Finnish and French African populations. A number of other SNPs in the CRP region, including rs3093059, had nominal associations with BPD. During the first week of life the elevated plasma levels of CRP predicted the risk of BPD (OR 3.4, p = 2.9 × 10-4) and the SNP rs3093059 associated nominally with plasma CRP levels. Finally, SNP rs11265269 was identified as a risk factor of BPD (OR 1.8, p = 5.3 × 10-5), independently of the robust antenatal risk factors. As such, in BPD, a potential role for variants near CRP gene is proposed.
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Displasia Broncopulmonar/diagnóstico , Displasia Broncopulmonar/genética , Estudo de Associação Genômica Ampla , Alelos , Displasia Broncopulmonar/sangue , Proteína C-Reativa/genética , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Projetos de Pesquisa , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Bronchopulmonary dysplasia (BPD) is one of the main consequences of prematurity, with notably high heritability. Vascular endothelial growth factor A (VEGF-A) and its main receptor, vascular endothelial growth factor receptor 2 (VEGFR-2), have been implicated in the pathogenesis of BPD. OBJECTIVE: To study whether common polymorphisms of the genes encoding VEGF-A and VEGFR-2 are associated with BPD. METHODS: In this association study, six tagging single nucleotide polymorphism (tSNPs) for VEGFA and 25 tSNPs for VEGFR2 were genotyped in a prospectively collected, genetically homogeneous discovery population of 160 infants (44 infants with grade 2-3 BPD) born before 30 completed gestational weeks. The replication population of 328 infants included 120 cases of BPD. RESULTS: VEGFR2 SNP rs4576072 was associated with BPD grade 2-3 with a minor allele frequency in 23.9% of the cases compared to 9.1% in controls (p = 0.0005, odds ratio 3.15, 95% CI: 1.62-6.12) in the discovery population. This association was not observed in the more heterogeneous replication population. CONCLUSIONS: In line with the results of recent large-scale genetic studies, our findings indicate that common polymorphisms of the genes encoding VEGF-A and VEGFR-2 are not consistently associated with BPD. This finding does not rule out the involvement of VEGFA and VEGFR2 in BPD pathogenesis since, in addition to common variations within the gene region, other mechanisms also play important roles in the regulation of gene function.
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Displasia Broncopulmonar/genética , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Lactente Extremamente Prematuro , Polimorfismo de Nucleotídeo Único/genética , Fator A de Crescimento do Endotélio Vascular/genética , Feminino , Frequência do Gene , Variação Genética , Genótipo , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Estudos Prospectivos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
BACKGROUND: Prematurity and hereditary factors predispose to cerebral palsy (CP). Previously, low cord blood levels of the anti-inflammatory chemokine CCL18 have been found to be associated with risk of CP in preterm children. OBJECTIVES: To investigate the association between single nucleotide polymorphisms (SNPs) in CCL18 and susceptibility to CP, as well as the association between the SNPs and cord blood levels of CCL18. METHODS: The original population comprised very-low-gestational-age (VLGA; <32 weeks) children from northern and central Finland (25 cases, 195 controls). Five CCL18 SNPs were genotyped and examined for associations with CP and cord blood CCL18. The replication population comprised Caucasian VLGA children from southern Finland and Canada (23 cases, 248 controls). RESULTS: In the original population, SNP rs2735835 was associated with CP; the minor allele A was underrepresented in cases compared to controls (OR = 0.42, 95% CI: 0.21-0.83, p = 0.01). This association remained significant after adjustment for multiple testing and risk factors of CP, and after combining the original and replication populations (OR = 0.52, 95% CI: 0.33-0.83, p = 0.005). Intraventricular hemorrhage (IVH) additively predicted CP. The Rs2015086 genotype was modestly associated with CCL18 concentration. CONCLUSIONS: A common CCL18 polymorphism together with IVH had an additive influence on CP susceptibility. Developmentally regulated CCL18, confined to primates, may be involved in the complex sequence of events leading to brain injury and predisposition to CP phenotype.
Assuntos
Hemorragia Cerebral/complicações , Paralisia Cerebral/genética , Quimiocinas CC/genética , Lactente Extremamente Prematuro/sangue , Polimorfismo de Nucleotídeo Único , Canadá , Estudos de Casos e Controles , Feminino , Sangue Fetal , Finlândia , Predisposição Genética para Doença , Genótipo , Idade Gestacional , Humanos , Recém-Nascido , Modelos Logísticos , Masculino , FenótipoRESUMO
Bronchopulmonary dysplasia (BPD) is a chronic inflammatory lung disease that affects infants born preterm. Family studies indicate that BPD has a significant genetic component. RATIONALE: We assessed the gene encoding Kit ligand (KITLG) as a candidate for genetic predisposition to moderate-to-severe BPD (controls were infants with no or mild BPD). STUDY DESIGN: Eight KITLG-tagging single nucleotide polymorphisms (SNPs) were analyzed in cohorts of very preterm infants originating from northern Finland (56 cases and 197 controls), southern Finland (n = 59 + 52), and Canada (n = 58 + 68). Additional replication populations included infants born in Finland (n = 41 + 241) and Hungary (n = 29 + 40). All infants were of European origin. Results were controlled for risk factors of BPD. Kit ligand concentration in umbilical cord blood, collected from very preterm infants (n = 120), was studied. RESULTS: Six SNPs of KITLG and a haplotype including all eight genotyped SNPs were associated with moderate-to-severe BPD in the northern Finnish population. When all the populations were combined, SNP rs11104948 was significantly associated with BPD. Kit ligand concentration in umbilical cord blood of infants born very preterm was an independent risk factor of BPD. CONCLUSIONS: We show that KITLG polymorphisms are associated with susceptibility to moderate-to-severe BPD. In addition, higher Kit ligand concentrations were observed in infants that subsequently developed BPD. These results support the possibility that KITLG gene is involved in predisposition to BPD. Pediatr Pulmonol. 2015; 50:260-270. © 2014 Wiley Periodicals, Inc.
RESUMO
Preterm birth is the major cause of neonatal mortality and morbidity. In many cases, it has severe life-long consequences for the health and neurological development of the newborn child. More than 50% of all preterm births are spontaneous, and currently there is no effective prevention. Several studies suggest that genetic factors play a role in spontaneous preterm birth (SPTB). However, its genetic background is insufficiently characterized. The aim of the present study was to perform a linkage analysis of X chromosomal markers in SPTB in large northern Finnish families with recurrent SPTBs. We found a significant linkage signal (HLOD = 3.72) on chromosome locus Xq13.1 when the studied phenotype was being born preterm. There were no significant linkage signals when the studied phenotype was giving preterm deliveries. Two functional candidate genes, those encoding the androgen receptor (AR) and the interleukin-2 receptor gamma subunit (IL2RG), located near this locus were analyzed as candidates for SPTB in subsequent case-control association analyses. Nine single-nucleotide polymorphisms (SNPs) within these genes and an AR exon-1 CAG repeat, which was previously demonstrated to be functionally significant, were analyzed in mothers with preterm delivery (n = 272) and their offspring (n = 269), and in mothers with exclusively term deliveries (n = 201) and their offspring (n = 199), all originating from northern Finland. A replication study population consisting of individuals born preterm (n = 111) and term (n = 197) from southern Finland was also analyzed. Long AR CAG repeats (≥ 26) were overrepresented and short repeats (≤ 19) underrepresented in individuals born preterm compared to those born at term. Thus, our linkage and association results emphasize the role of the fetal genome in genetic predisposition to SPTB and implicate AR as a potential novel fetal susceptibility gene for SPTB.