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SNP-SNP Interactions of Surfactant Protein Genes in Persistent Respiratory Morbidity Susceptibility in Previously Healthy Children.

ABSTRACT: We studied associations of persistent respiratory morbidity (PRM) at 6 and 12 months after acute respiratory failure (ARF) in previously healthy children with single-nucleotide polymorphisms (SNPs) of surfactant protein (SP) genes. Of the 250 enrolled subjects, 155 and 127 were followed at 6 and 12 months after an ARF episode, respectively. Logistic regression analysis and SNP-SNP interaction models were used. We found that 1) in the multivariate analysis, an increased risk at 6 and 12 months was associated with rs1124_A and rs4715_A of SFTPC, respectively; 2) in a single SNP model, increased and decreased risks of PRM at both timepoints were associated with rs1124 of SFTPC and rs721917 of SFTPD, respectively; an increased risk at 6 months was associated with rs1130866 of SFTPB and rs4715 of SFTPC, and increased and decreased risks at 12 months were associated with rs17886395 of SFTPA2 and rs2243639 of SFTPD, respectively; 3) in a two-SNP model, PRM susceptibility at both timepoints was associated with a number of intergenic interactions between SNPs of the studied SP genes. An increased risk at 12 months was associated with one intragenic (rs1965708 and rs113645 of SFTPA2) interaction; 4) in a three-SNP model, decreased and increased risks at 6 and 12 months, respectively, were associated with an interaction among rs1130866 of SFTPB, rs721917 of SFTPD, and rs1059046 of SFTPA2. A decreased risk at 6 months was associated with an interaction among the same SNPs of SFTPB and SFTPD and the rs1136450 of SFTPA1. The findings revealed that SNPs of all SFTPs appear to play a role in long-term outcomes of ARF survivors and may serve as markers for disease susceptibility.

SUBMITTER: Gandhi CK

PROVIDER: S-EPMC8989419 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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SNP-SNP Interactions of Surfactant Protein Genes in Persistent Respiratory Morbidity Susceptibility in Previously Healthy Children.

Gandhi Chintan K CK Thomas Neal J NJ Meixia Ye Y Spear Debbie D Fu Chenqi C Zhou Shouhao S Wu Rongling R Keim Garrett G Yehya Nadir N Floros Joanna J

Frontiers in genetics 20220324

We studied associations of persistent respiratory morbidity (PRM) at 6 and 12 months after acute respiratory failure (ARF) in previously healthy children with single-nucleotide polymorphisms (SNPs) of surfactant protein (SP) genes. Of the 250 enrolled subjects, 155 and 127 were followed at 6 and 12 months after an ARF episode, respectively. Logistic regression analysis and SNP-SNP interaction models were used. We found that 1) in the multivariate analysis, an increased risk at 6 and 12 months wa ...[more]

PMID: 35401703

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Project description:ObjectivesAcute respiratory failure is a common reason for admission to PICUs. Short- and long-term effects on pulmonary health in previously healthy children after acute respiratory failure requiring mechanical ventilation are unknown. The aim was to determine if clinical course or characteristics of mechanical ventilation predict persistent respiratory morbidity at follow-up.DesignProspective cohort study with follow-up questionnaires at 6 and 12 months.SettingTen U.S. PICUs.PatientsTwo-hundred fifty-five children were included in analysis after exclusion for underlying chronic disease or incomplete data. One-hundred fifty-eight and 130 children had follow-up data at 6 and 12 months, respectively.InterventionsNone.Measurements and main resultsPulmonary dysfunction at discharge a priori defined as one of: mechanical ventilation, supplemental oxygen, bronchodilators or steroids at 28 days or discharge. Persistent respiratory morbidity a priori defined as a respiratory PedsQL, a pediatric quality of life measure, greater than or equal to 5 or asthma diagnosis, bronchodilator or inhaled steroids, or unscheduled clinical evaluation for respiratory symptoms. Multivariate backward stepwise regression using Akaike information criterion minimization determined independent predictors of these outcomes. Pulmonary dysfunction at discharge was present in 34% of patients. Positive bacterial respiratory culture predicted pulmonary dysfunction at discharge (odds ratio, 4.38; 95% CI, 1.66-11.56). At 6- and 12-month follow-up 42% and 44% of responders, respectively, had persistent respiratory morbidity. Pulmonary dysfunction at discharge was associated with persistent respiratory morbidity at 6 months, and persistent respiratory morbidity at 6 months was strongly predictive of 12-month persistent respiratory morbidity (odds ratio, 18.58; 95% CI, 6.68-52.67). Positive bacterial respiratory culture remained predictive of persistent respiratory morbidity in patients at both follow-up points.ConclusionsPersistent respiratory morbidity develops in up to potentially 44% of previously healthy children less than or equal to 24 months old at follow-up after acute respiratory failure requiring mechanical ventilation. This is the first study, to our knowledge, to suggest a prevalence of persistent respiratory morbidity and the association between positive bacterial respiratory culture and pulmonary morbidity in a population of only previously healthy children with acute respiratory failure.

Project description:BackgroundBreast cancer predisposition genes identified to date (e.g., BRCA1 and BRCA2) are responsible for less than 5% of all breast cancer cases. Many studies have shown that the cancer risks associated with individual commonly occurring single nucleotide polymorphisms (SNPs) are incremental. However, polygenic models suggest that multiple commonly occurring low to modestly penetrant SNPs of cancer related genes might have a greater effect on a disease when considered in combination.MethodsIn an attempt to identify the breast cancer risk conferred by SNP interactions, we have studied 19 SNPs from genes involved in major cancer related pathways. All SNPs were genotyped by TaqMan 5'nuclease assay. The association between the case-control status and each individual SNP, measured by the odds ratio and its corresponding 95% confidence interval, was estimated using unconditional logistic regression models. At the second stage, two-way interactions were investigated using multivariate logistic models. The robustness of the interactions, which were observed among SNPs with stronger functional evidence, was assessed using a bootstrap approach, and correction for multiple testing based on the false discovery rate (FDR) principle.ResultsNone of these SNPs contributed to breast cancer risk individually. However, we have demonstrated evidence for gene-gene (SNP-SNP) interaction among these SNPs, which were associated with increased breast cancer risk. Our study suggests cross talk between the SNPs of the DNA repair and immune system (XPD-[Lys751Gln] and IL10-[G(-1082)A]), cell cycle and estrogen metabolism (CCND1-[Pro241Pro] and COMT-[Met108/158Val]), cell cycle and DNA repair (BARD1-[Pro24Ser] and XPD-[Lys751Gln]), and within carcinogen metabolism (GSTP1-[Ile105Val] and COMT-[Met108/158Val]) pathways.ConclusionThe importance of these pathways and their communication in breast cancer predisposition has been emphasized previously, but their biological interactions through SNPs have not been described. The strategy used here has the potential to identify complex biological links among breast cancer genes and processes. This will provide novel biological information, which will ultimately improve breast cancer risk management.

Project description:Abstract Background Differential expression of selected immunity genes may have a role in susceptibility to Respiratory Syncytial Virus (RSV). There are few data about some candidate gene single nucleotide polymorphisms (SNPs) associated with the severity of respiratory infections (e.g., Toll-like receptor 4 [TLR4], Toll-like receptor 8 [TLR8], macrophage receptor with colagenous structure [MARCO], myxovirus resistance 1 [MX1]). The aims of this study were to detect the presence of SNPs in selected genes of previously healthy infants infected with RSV, to assess viral load (VL) and to analyze their relationship with life-threatening disease (LTD) Methods Prospective cohort study including previously healthy full-term infants < 12 months, hospitalized with a first RSV infection during 2017–2018. RSV diagnosis, virus quantification and genotyping for SNPs (TLR4 rs4986790, TLR4 rs4986791, MARCO rs1318645, MX1 rs469390, TLR8 rs3761624) were performed by qRT–PCR in nasopharyngeal aspirates obtained on admission. Patients with LTD were those admitted to the intensive care unit needing mechanical or non invasive ventilation Results 75 patients, mean age 3.9 months (±2.8), 41 (54.7%) male. Fifteen developed LTD. Infants who were homozygous (−/−) or heterozygous (+/−) for MX1rs469390 and TLR8rs3761624 or MARCOrs1318645 and TLR8rs3761624 had significantly more risk of developing LTD (OR 3.45, P = 0.042; OR 3.63, P = 0.048, respectively). Multivariable logistic regression analysis showed that concurrent MARCOrs1318645, MX1rs469390 and TLR8rs3761624 SNPs increased the risk of LTD (aOR 4.7, P = 0.018), fig 1. These SNPs also associated with prolonged length of stay (LOS) (P = 0.026) and > 7 days of hypoxemia (P = 0.031). No differences were seen in VL of patients with LTD compared with those with better outcome (P = 0.737). No differences in VL were seen in patients with SNPs. VL did not correlate with LOS or days of hypoxemia. No other socioeconomic, pregnancy or infant variables associated with LTD Conclusion To the best of our knowledge, this is the first study assessing the presence of concurrent SNPs and their association with life-threatening disease in previously healthy infants with RSV infection. These findings provide evidence on the importance of the host and its immune response for the severity of RSV infection. Disclosures All authors: No reported disclosures.

Dataset Information

SNP-SNP Interactions of Surfactant Protein Genes in Persistent Respiratory Morbidity Susceptibility in Previously Healthy Children.

Publications

SNP-SNP Interactions of Surfactant Protein Genes in Persistent Respiratory Morbidity Susceptibility in Previously Healthy Children.

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