RESUMO
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.
Assuntos
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
Preterm birth is the major cause of neonatal death and serious morbidity. Most preterm births are due to spontaneous onset of labor without a known cause or effective prevention. Both maternal and fetal genomes influence the predisposition to spontaneous preterm birth (SPTB), but the susceptibility loci remain to be defined. We utilized a combination of unique population structures, family-based linkage analysis, and subsequent case-control association to identify a susceptibility haplotype for SPTB. Clinically well-characterized SPTB families from northern Finland, a subisolate founded by a relatively small founder population that has subsequently experienced a number of bottlenecks, were selected for the initial discovery sample. Genome-wide linkage analysis using a high-density single-nucleotide polymorphism (SNP) array in seven large northern Finnish non-consanginous families identified a locus on 15q26.3 (HLOD 4.68). This region contains the IGF1R gene, which encodes the type 1 insulin-like growth factor receptor IGF-1R. Haplotype segregation analysis revealed that a 55 kb 12-SNP core segment within the IGF1R gene was shared identical-by-state (IBS) in five families. A follow-up case-control study in an independent sample representing the more general Finnish population showed an association of a 6-SNP IGF1R haplotype with SPTB in the fetuses, providing further evidence for IGF1R as a SPTB predisposition gene (frequency in cases versus controls 0.11 versus 0.05, P = 0.001, odds ratio 2.3). This study demonstrates the identification of a predisposing, low-frequency haplotype in a multifactorial trait using a well-characterized population and a combination of family and case-control designs. Our findings support the identification of the novel susceptibility gene IGF1R for predisposition by the fetal genome to being born preterm.
Assuntos
Predisposição Genética para Doença , Nascimento Prematuro/genética , Receptor IGF Tipo 1/genética , Estudos de Casos e Controles , Feminino , Finlândia , Ligação Genética , Estudo de Associação Genômica Ampla , Haplótipos/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , GravidezRESUMO
Coordination of fetal maturation with birth timing is essential for mammalian reproduction. In humans, preterm birth is a disorder of profound global health significance. The signals initiating parturition in humans have remained elusive, due to divergence in physiological mechanisms between humans and model organisms typically studied. Because of relatively large human head size and narrow birth canal cross-sectional area compared to other primates, we hypothesized that genes involved in parturition would display accelerated evolution along the human and/or higher primate phylogenetic lineages to decrease the length of gestation and promote delivery of a smaller fetus that transits the birth canal more readily. Further, we tested whether current variation in such accelerated genes contributes to preterm birth risk. Evidence from allometric scaling of gestational age suggests human gestation has been shortened relative to other primates. Consistent with our hypothesis, many genes involved in reproduction show human acceleration in their coding or adjacent noncoding regions. We screened >8,400 SNPs in 150 human accelerated genes in 165 Finnish preterm and 163 control mothers for association with preterm birth. In this cohort, the most significant association was in FSHR, and 8 of the 10 most significant SNPs were in this gene. Further evidence for association of a linkage disequilibrium block of SNPs in FSHR, rs11686474, rs11680730, rs12473870, and rs1247381 was found in African Americans. By considering human acceleration, we identified a novel gene that may be associated with preterm birth, FSHR. We anticipate other human accelerated genes will similarly be associated with preterm birth risk and elucidate essential pathways for human parturition.
Assuntos
Negro ou Afro-Americano/genética , Evolução Molecular , Parto/genética , Polimorfismo de Nucleotídeo Único , Nascimento Prematuro/genética , Adulto , Animais , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Finlândia , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação , Modelos Genéticos , Receptores do FSH/genética , Fatores de Risco , Adulto JovemRESUMO
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.
Assuntos
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
OBJECTIVE: While multiple lines of evidence suggest the importance of genetic contributors to risk of preterm birth, the nature of the genetic component has not been identified. We perform segregation analyses to identify the best fitting genetic model for gestational age, a quantitative proxy for preterm birth. METHODS: Because either mother or infant can be considered the proband from a preterm delivery and there is evidence to suggest that genetic factors in either one or both may influence the trait, we performed segregation analysis for gestational age either attributed to the infant (infant's gestational age), or the mother (by averaging the gestational ages at which her children were delivered), using 96 multiplex preterm families. RESULTS: These data lend further support to a genetic component contributing to birth timing since sporadic (i.e. no familial resemblance) and nontransmission (i.e. environmental factors alone contribute to gestational age) models are strongly rejected. Analyses of gestational age attributed to the infant support a model in which mother's genome and/or maternally-inherited genes acting in the fetus are largely responsible for birth timing, with a smaller contribution from the paternally-inherited alleles in the fetal genome. CONCLUSION: Our findings suggest that genetic influences on birth timing are important and likely complex.
Assuntos
Genoma/genética , Idade Gestacional , Mães , Nascimento Prematuro/genética , População Negra/genética , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Linhagem , Gravidez , População Branca/genéticaRESUMO
Respiratory distress syndrome (RDS) is a multifactorial developmental disease caused by lung immaturity and presenting as high-permeability lung edema ("hyaline membrane disease"). It is characterized by a transient deficiency of alveolar surfactant during the first week of life. During the first few days of life, the alveolar surfactant pool size increases up to that in the controls. The allelic variants of the genes encoding the surfactant proteins (SP) SP-A1, SP-A2, SP-B, and SP-C have been associated with RDS. The main SP-A haplotype, interactively with the SP-B Ile131Thr polymorphism and with constitutional and environmental factors, influence the risk. Case reports on mutations with partially functional SP-B have been published. The genetic susceptibility factors depend on the degree of prematurity at birth, consistent with sequential differentiation of the lung and gestation-dependent differences in clinical presentation. The preferentially type 2 cell expressed genes involved in critical functions (such as ATP-binding cassette transporter, ABCA3), those involved in susceptibility to acute lung damage, and those with known susceptibility to other severe lung diseases (such as G protein-coupled receptor for asthma susceptibility, GPR154 alias GPRA) will possibly serve as candidate genes in future studies. RDS associated with near-term and term births may have a different genetic predisposition and pathogenesis compared to RDS after very preterm birth. As we learn more about the molecular consequences of allelic variation, new therapies based on a new generation of surfactant diagnostics and individualized therapies may follow.
Assuntos
Predisposição Genética para Doença , Síndrome do Desconforto Respiratório do Recém-Nascido/genética , Transportadores de Cassetes de Ligação de ATP/genética , Feto/patologia , Feto/fisiopatologia , Humanos , Recém-Nascido , Pulmão/embriologia , Pulmão/patologia , Pulmão/fisiopatologia , Mutação , Proteínas Associadas a Surfactantes Pulmonares/genética , Receptores Acoplados a Proteínas G/genética , Síndrome do Desconforto Respiratório do Recém-Nascido/diagnóstico , Síndrome do Desconforto Respiratório do Recém-Nascido/epidemiologiaRESUMO
Here, we describe the approach of defining the genetic contribution to disease and discuss the polymorphisms of some genes that are associated with respiratory disease. The common allelic variants of SP-A1, SP-A2, SP-B, SP-C, and SP-D genes are associated with respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), or respiratory syncytial virus (RSV) bronchiolitis. The main SP-A haplotype, interactively with SP-B Ile131Thr polymorphism and with constitutional and environmental factors, influences the risk of RDS. The polymorphisms of SP-A2 and SP-D are associated with the risk of severe RSV. The polymorphism may turn out to be important in susceptibility to influenza virus. The SP-B intron 4 deletion variant is the risk factor of BPD. Understanding the molecular mechanisms behind the hereditary risk may lead to new focused treatment strategies.
Assuntos
Polimorfismo Genético , Proteínas Associadas a Surfactantes Pulmonares/genética , Síndrome do Desconforto Respiratório do Recém-Nascido/genética , Predisposição Genética para Doença , Humanos , Interações Hidrofóbicas e Hidrofílicas , Recém-Nascido , Modelos Biológicos , Proteínas Associadas a Surfactantes Pulmonares/química , Proteínas Associadas a Surfactantes Pulmonares/fisiologia , Síndrome do Desconforto Respiratório do Recém-Nascido/fisiopatologia , Fatores de RiscoRESUMO
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.
Assuntos
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
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
Respiratory distress syndrome (RDS) is caused by surfactant deficiency at birth. The risk of RDS decreases from the gestational age of 24 weeks to full-term. Genetic and acquired factors additionally influence the risk of RDS. Surfactant deficiency in RDS is mainly caused by immaturity and a lack of differentiation of the alveolar epithelial cells involved in surfactant synthesis and secretion. A network of hormones and growth factors regulate perinatal development. Host-related factors, including the levels of expression of surfactant proteins (SP), modulate the responsiveness of growth factors. SP-A has roles in surface activity and regulatory roles particularly in innate immunity; SP-B is essential for the processing of surfactant and for the surface activity; SP-C has roles in surfactant metabolism and function; the regulatory roles of SP-D mainly pertain to innate immunity. The genetic variation of SP-A and SP-B genes and the risk of RDS have been studied. Both SP-A and SP-B associate with susceptibility to RDS. The association between the SP-A allele and genotypes and the risk of RDS is dependent on the SP-B genotype and significantly influenced by the degree of prematurity, antenatal glucocorticoid therapy, multiple birth, and birth order. The alleles/genotypes of SP-A, SP-C, or SP-D also associate with several other inflammatory lung and airway diseases. Rare mutations in SP-B or SP-C cause serious, often fatal lung diseases. Genetic and post-genomic research is likely to eventually result in new diagnostic applications and specific therapies for the prevention of respiratory failure and inflammatory lung diseases.
Assuntos
Proteínas Associadas a Surfactantes Pulmonares/genética , Síndrome do Desconforto Respiratório do Recém-Nascido/genética , Desenvolvimento Embrionário e Fetal/genética , Desenvolvimento Embrionário e Fetal/fisiologia , Feminino , Predisposição Genética para Doença , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Polimorfismo Genético , Proteínas Associadas a Surfactantes Pulmonares/deficiência , Proteínas Associadas a Surfactantes Pulmonares/metabolismo , Síndrome do Desconforto Respiratório do Recém-Nascido/metabolismoRESUMO
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.
Assuntos
Cromossomos Humanos X/genética , Estudos de Associação Genética , Ligação Genética , Predisposição Genética para Doença , Nascimento Prematuro/genética , Receptores Androgênicos/genética , Estudos de Casos e Controles , Família , Feminino , Feto/patologia , Finlândia , Marcadores Genéticos , Haplótipos/genética , Humanos , Subunidade gama Comum de Receptores de Interleucina/genética , Escore Lod , Modelos Logísticos , Masculino , Modelos Genéticos , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos Testes , Expansão das Repetições de Trinucleotídeos/genéticaRESUMO
BACKGROUND: The onset of birth in humans, like other apes, differs from non-primate mammals in its endocrine physiology. We hypothesize that higher primate-specific gene evolution may lead to these differences and target genes involved in human preterm birth, an area of global health significance. METHODS: We performed a comparative genomics screen of highly conserved noncoding elements and identified PLA2G4C, a phospholipase A isoform involved in prostaglandin biosynthesis as human accelerated. To examine whether this gene demonstrating primate-specific evolution was associated with birth timing, we genotyped and analyzed 8 common single nucleotide polymorphisms (SNPs) in PLA2G4C in US Hispanic (n = 73 preterm, 292 control), US White (n = 147 preterm, 157 control) and US Black (n = 79 preterm, 166 control) mothers. RESULTS: Detailed structural and phylogenic analysis of PLA2G4C suggested a short genomic element within the gene duplicated from a paralogous highly conserved element on chromosome 1 specifically in primates. SNPs rs8110925 and rs2307276 in US Hispanics and rs11564620 in US Whites were significant after correcting for multiple tests (p < 0.006). Additionally, rs11564620 (Thr360Pro) was associated with increased metabolite levels of the prostaglandin thromboxane in healthy individuals (p = 0.02), suggesting this variant may affect PLA2G4C activity. CONCLUSIONS: Our findings suggest that variation in PLA2G4C may influence preterm birth risk by increasing levels of prostaglandins, which are known to regulate labor.
Assuntos
Evolução Molecular , Fosfolipases A2 do Grupo IV/genética , Mutagênese Insercional , Parto/genética , Nascimento Prematuro/genética , Primatas/genética , Animais , Vias Biossintéticas , Cromossomos Humanos Par 19 , Humanos , Íntrons , Filogenia , Nascimento Prematuro/etnologia , Primatas/fisiologia , Prostaglandinas/biossínteseRESUMO
BACKGROUND: Surfactant protein (SP) C has been shown to be expressed also outside pulmonary alveoli. Certain SP-C gene (SFTPC) polymorphisms associate with lung diseases and very preterm birth. AIMS: We investigated the association of SFTPC single nucleotide polymorphism (SNP) rs4715 with factors affecting spontaneous preterm birth and characterized the SP-C expression in human and mouse gestational tissues. METHODS: The SFTPC SNP rs4715 polymorphism was genotyped in a homogeneous northern European population of mothers and infants in spontaneous preterm birth and term controls. The expression and protein of SP-C in gestational tissues was analyzed. RESULTS: SFTPC SNP rs4715 did not associate with spontaneous preterm birth. However, fetuses with short interval (<72 hours) between preterm premature rupture of fetal membranes (PPROM) and preterm birth had significant over-representation of the minor allele A, whereas in fetuses with prolonged PPROM (>or=72 hours) the frequency was decreased. Maternal SFTPC did not associate with the duration of PPROM. SP-C mRNA and proprotein were detected in fetal membranes, placenta, and pregnant uterus. CONCLUSION: SFTPC SNP rs4715 associates with the duration of PPROM, and SP-C is expressed in gestational tissues. We propose that fetal SFTPC moderates the inflammatory activation within the fetal extra-embryonic compartment.
Assuntos
Ruptura Prematura de Membranas Fetais/genética , Expressão Gênica , Nascimento Prematuro/genética , Proteína C Associada a Surfactante Pulmonar/genética , Adolescente , Adulto , Alelos , Animais , Membranas Extraembrionárias/metabolismo , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Placenta/metabolismo , Polimorfismo de Nucleotídeo Único , Gravidez , Estudos Prospectivos , RNA Mensageiro/metabolismo , Estudos Retrospectivos , Fatores de Tempo , Útero/metabolismo , Adulto JovemRESUMO
BACKGROUND: Mannose-binding lectin (MBL) is a multifunctional protein involved in innate immunity. We tested whether MBL and elevated viral and bacterial antibodies were risk factors for acute coronary events. DESIGN: Controlled cohort study. METHODS: A total of 354 patients with unstable angina pectoris (UA) or acute myocardial infarction (AMI) were compared with 334 paired controls. RESULTS: Enterovirus titres were associated with increased risk of UA (odds ratio 10.04, P<0.001) and AMI (odds ratio 3.18, P=0.003), but titres did not correlate with either MBL concentration or genotype. Chlamydia pneumoniae heat shock protein 60 IgG concentrations were also associated with increased risk of UA (odds ratio 1.63, P=0.049). Compared to asymptomatic controls, patients had lower complement C3 serum concentrations (P<0.001), higher MBL serum concentration, and more frequently had MBL genotypes that determined high MBL levels (P<0.001). High MBL genotypes had odds ratios of 1.16 (P=0.010) for UA and 1.12 (P=0.007) for AMI. The elevation of MBL concentrations in the acute phase correlated with MBL concentrations after recovery (r=0.85, P<0.001). CONCLUSIONS: Elevated microbial titres, indicating an on-going inflammation, were associated with cardiovascular events. MBL might have a dual role both decreasing susceptibility to infections and increasing the risk of acute coronary syndromes.
Assuntos
Angina Instável/etiologia , Lectina de Ligação a Manose/sangue , Infarto do Miocárdio/etiologia , Angina Instável/genética , Angina Instável/microbiologia , Anticorpos Antibacterianos/análise , Anticorpos Antivirais/análise , Estudos de Casos e Controles , Chaperonina 60/imunologia , Chlamydophila pneumoniae/imunologia , Estudos de Coortes , Complemento C3/metabolismo , Enterovirus/imunologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Inflamação/etiologia , Inflamação/microbiologia , Masculino , Lectina de Ligação a Manose/genética , Pessoa de Meia-Idade , Infarto do Miocárdio/genética , Infarto do Miocárdio/microbiologia , Fatores de RiscoRESUMO
BACKGROUND: Adenosine triphosphate (ATP)-binding cassette transporter A3 (ABCA3) gene mutations cause fatal respiratory failure in term infants, but common ABCA3 polymorphisms have remained uncharacterized at the population level. AIM: To define a subset of tagging single-nucleotide polymorphisms (tSNPs) which capture most of the variation within the ABCA3 gene, and to assess ABCA3 as a novel candidate gene for susceptibility to respiratory distress syndrome (RDS) in preterm infants. METHODS: Based on an initial screen, nine tSNPs were selected. These 9 tSNPs and a length variation, representing > 90% of haplotypic variation of the gene, and 5 nonsynonymous coding SNPs were genotyped in 267 preterm infants. SNP rs13332514 was genotyped in an additional 48 infants. RESULTS: The fourth common haplotype was overrepresented in very premature infants with RDS, being accounted for by SNP rs13332514 (F353F), with an increased minor allele frequency in RDS. Furthermore, rs13332514 associated significantly with chronic lung disease defined as a requirement for supplemental O2 at 28 postnatal days in very premature infants. CONCLUSIONS: The results are suggestive of an association of a synonymous SNP in the ABCA3 gene with a prolonged course of respiratory distress syndrome in very premature infants and serve as a reference for further population-based studies of ABCA3.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Recém-Nascido Prematuro , Síndrome do Desconforto Respiratório do Recém-Nascido/genética , Displasia Broncopulmonar/genética , Feminino , Predisposição Genética para Doença , Humanos , Recém-Nascido , Masculino , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Síndrome do Desconforto Respiratório do Recém-Nascido/sangue , Estudos RetrospectivosRESUMO
Respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) are common, serious lung diseases in preterm infants. Polymorphism of the genes involved in basic lung function and alveolar stability, lung differentiation and pulmonary host defense may influence the risk. Natural selection has refined the genes responsible for cardiopulmonary adaptation and resistance against pneumonia in term and near-term infants. Before the era of antibiotics, however, virtually all very preterm infants died of asphyxia, respiratory failure or infections. Today, the degree of prematurity plays a dominant role in susceptibility to serious lung disease. In addition, genetic polymorphism and constitution modulate the risk of RDS and BPD that have different, partly overlapping predisposition. According to twin studies, the genetic impact on the risk of RDS and BPD among preterm and very preterm infants is 35-65%. Individual disease genes generally have low penetrance. Large-scale genetic studies are required as part of neonatal and perinatal research in order to learn about the risk factors and to investigate pharmacogenetics. The aim in the future is to individualize therapies.
Assuntos
Meio Ambiente , Doenças do Recém-Nascido/genética , Pneumopatias/genética , Aclimatação , Peso ao Nascer , Humanos , Recém-Nascido , Doenças do Recém-Nascido/etiologia , Recém-Nascido Prematuro , Pneumopatias/etiologia , Síndrome do Desconforto Respiratório do Recém-Nascido/etiologia , Síndrome do Desconforto Respiratório do Recém-Nascido/genéticaRESUMO
BACKGROUND: Respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) have some common features with asthma. AIM: To study whether G protein-coupled receptor for asthma susceptibility (GPRA) contributes to RDS or BPD. METHODS: A haplotype association study was performed in a case-control setting of 521 Finnish infants (including 176 preterm neonates with RDS and 37 with BPD). Immunoreactivity of GPRA isoforms A and B was determined in pulmonary samples of fetuses, term infants and preterm infants with RDS or BPD. GPRA mRNA expression was determined by quantitative real-time polymerase chain reaction (PCR) in samples from nasal respiratory epithelium of adults, term infants and preterm infants. RESULTS: In infants with RDS born at 32-35 weeks of gestation, GPRA haplotype H1 was significantly underrepresented in RDS, whereas haplotype H4/H5 was associated with an increased risk. As in asthma, GPRA B isoform was induced in bronchial smooth muscle cells in RDS and BPD. In nasal respiratory epithelium, relative GPRA mRNA expression was strong in adults, weak in preterm and slightly higher in term samples. CONCLUSIONS: The results suggest that near-term RDS and asthma share the same susceptibility and protective GPRA haplotypes. Altered GPRA expression may play a role in the pathogenesis of RDS and BPD in preterm infants.
Assuntos
Asma/etiologia , Receptores Acoplados a Proteínas G/genética , Síndrome do Desconforto Respiratório do Recém-Nascido/etiologia , Adulto , Asma/genética , Sequência de Bases , Displasia Broncopulmonar/etiologia , Displasia Broncopulmonar/genética , Displasia Broncopulmonar/patologia , Estudos de Casos e Controles , Haplótipos , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Polimorfismo Genético , Isoformas de Proteínas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Síndrome do Desconforto Respiratório do Recém-Nascido/genética , Síndrome do Desconforto Respiratório do Recém-Nascido/patologia , Fatores de RiscoRESUMO
Surfactant proteins, SP-A, SP-B, SP-C and SP-D, play important roles in pulmonary surfactant function and metabolism. SP-A and SP-D, being members of the collectin family of proteins, also interact with pathogens and are involved in pulmonary host defense. Respiratory diseases are among the most common causes of death worldwide. Several life-threatening lung diseases, such as neonatal respiratory distress syndrome (RDS) and acute ROS (ARDS), are associated with impaired surfactant function. Allelic variations of the SP-A and SP-B genes have been shown to be important genetic determinants in individual susceptibility to RDS, which is a good general model for a multifactorial pulmonary disease resulting from complex interactions between several environmental and genetic factors. Because SP-A and SP-D act directly in the clearance of common lung pathogens, the genes encoding these proteins have been implicated as candidates in a few infectious diseases, including respiratory syncytial virus (RSV) infections and tuberculosis.