Polymorphisms of human SP‐A, SP‐B, and SP‐D genes: association of SP‐B Thr131Ile with ARDS

Lin, Zhenwu; Pearson, Christopher E.; Chinchilli, V. M.; Pietschmann, S.; Luo, Jiang; Pison, U.; Floros, Joanna

doi:10.1034/j.1399-0004.2000.580305.x

Cited by 188 publications

(155 citation statements)

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“…Genetic variation in intron 4 of the surfactant protein B gene has been statistically associated with pulmonary pathology in both newborn infants and adults Haataja, et al, 2000;Lin, et al, 2000;Makri, et al, 2002;Seifart, et al, 2002a). Reliable assessment of allelic variation in this region is critical to ensure valid comparisons between cohorts of patients studied by different investigators.…”

Section: Discussionmentioning

confidence: 99%

Genetic variant characterization in intron 4 of the surfactant protein B gene

et al. 2005

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Genetic variants in intron 4 of the surfactant protein B gene SFTPB have been associated with pulmonary morbidity in newborn infants and adults. Genetic variant discovery in intron 4 requires high fidelity polymerase amplification due to a variable number of intermotif dinucleotide repeats and reliable characterization of alleles genetically distinct due to insertion, deletion, or both of 11 conserved sequence motifs. To optimize genetic variant discovery, we selected a high fidelity polymerase enzyme by replicate amplification and compared automated sequencing with agarose gel electrophoresis for all variant alleles (N=68) in a cohort of Missouri infants with (N=187) and without (N=53) respiratory distress. We identified and characterized six new alleles based on sequence motifs and two pairs of variant alleles with similar mobilities by agarose gel electrophoresis but distinct motif sequences. We confirmed uniformity of invariant alleles by sequencing (N=77). Logistic regression using race and intron 4 genotype for infants > 35 weeks gestation suggested that the invariant allele was independently associated with increased risk of respiratory distress (OR for the invariant allele 2.7, 95% CI 1.0-7.2). Reliable characterization of genetic variants in intron 4 requires both a high fidelity polymerase and sequencing of variant alleles.

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Section: Discussionmentioning

confidence: 99%

Genetic variant characterization in intron 4 of the surfactant protein B gene

et al. 2005

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“…Despite the evidence from association-based studies suggesting that genetic variation contributes to ALI susceptibility and severity (5)(6)(7)(8)(9)(10)(11)(12)(13), the genetic basis of ALI remains incompletely understood. Multiple factors contribute to the difficulty in defining the exact nature of genetic factors relevant to ALI.…”

Section: Studies Implicating a Genetic Basis For Ali Susceptibility Amentioning

confidence: 99%

Functional Genomic Insights into Acute Lung Injury: Role of Ventilators and Mechanical Stress

Nonas

Finigan

Gao

et al. 2005

Proceedings of the American Thoracic Society

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Acute lung injury (ALI) is a complex and devastating illness, often occurring in the setting of sepsis and trauma. Despite recent advances in the understanding and treatment of ALI, pathogenic mechanisms and genetic modifiers in ALI remain incompletely understood. Furthermore, there has been increasing interest in the identification of genetic variations that contribute to ALI susceptibility and severity in order to gain unique insights into ALI pathogenesis and to design novel treatment strategies. However, the sporadic nature of ALI and the lack of family-based cohort studies preclude conventional genomic approaches such as linkage mapping (or "positional cloning"). We have used a "candidate gene approach" with extensive gene expression profiling studies in animal (rat, murine, canine) and human models of ALI to identify potential ALI candidate genes associated with sepsis and ventilator-associated lung injury. These studies, when combined with innovative in silico bioinformatics approaches, revealed both novel (pre-B-cell colony enhancing factor, myosin light chain kinase) and previously identified (interleukin 6, macrophage migration inhibitory factor) gene candidates. Subsequent single nucleotide polymorphism discovery and genotyping studies revealed polymorphisms that demonstrate an influence on ALI susceptibility in patients. These studies indicate that the candidate gene approach is a robust strategy to provide novel insights into the genetic basis of ALI, and the identification of potentially novel therapeutic targets.Keywords: single nucleotide polymorphism; interleukin 6; pre-B-cell colony enhancing factor Acute lung injury (ALI) is a common and devastating illness in patients with sepsis, pneumonia, or trauma, and carries an annual mortality rate of 30 to 50% (1). Marked by profound inflammation, increased vascular permeability, and alveolar flooding, the acute respiratory failure that is associated with ALI invariably requires mechanically assisted ventilation. Despite advances in care for patients with ALI, the development of sophisticated hemodynamic monitoring technologies, and new insights into the pathogenesis underlying sepsis and ALI, there remains a significant gap in the full translation of this progress into increased ALI survival (2). Furthermore, improved understanding of ALI at both the molecular and population level has not reconciled the heterogeneity in patient susceptibility to ALI or ALI outcomes. Until recently, studies focused on understanding the molecular basis of complex disorders such as ALI were limited to a gene-by-gene approach. However, the capacity for high-throughput sequencing coupled with the mapping of the human genome heralded additional revolutionary technologic breakthroughs with tools for a large-scale analysis of the genome, including rapid, high-throughput gene expression profiling and genotyping (3, 4). Access to the complete genome sequences of prokaryotes, eukaryotic model organisms, as well as the mouse, rat, and dog has sparked efforts to identify specific...

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“…The T allele of the polymorphism 1580 (C/T) does not have the N-linked glycosylation site at the N-terminal fragment, and it is considered a protector factor regarding RDS, whereas the allelic variant C, which contains the recognition N glycosylation site of the fragment N-terminal, is a risk factor for chronic obstructive pulmonary disease (COPD) and ARDS. 39,58 Martilla et al 59 analyzed pairs of preterm twins of the same sex of white race, where at least one of them presented RDS, and showed that genotypes specific for SP-A and SP-B could influence the susceptibility to RDS. Regarding the protection against the development of the disease, it was evident both in the heterozygous C/T and homozygous T/T genotype.…”

Section: Genetic Factors Of Respiratory Distress Syndromementioning

confidence: 99%

“…The authors concluded that the determination of polymorphisms on genes that codify the surfactant proteins could be useful for the study of pulmonary diseases, and that the polymorphism C/T1580 could serve to differentiate subgroups of patients with ARDS. 39 Some studies suggest that allelic variations of SP-A and SP-D could be associated with bronchiolitis caused by the respiratory syncytial virus. The amino acids at position 223 of the SPA2 gene and 11 of SP-D gene could be involved in the susceptibility to infections by the respiratory syncytial virus, and they could be potential targets for prophylaxis and treatment with specific surfactant preparations.…”

Section: Sp-b Polymorphisms and Other Pathologiesmentioning

confidence: 99%

“…32,33 Some descriptions about the presence of polymorphisms and mutations in genes from the surfactant components are reported in the literature, particularly regarding the SP-B gene, which seems to be associated with RDS, ARDS, and CAP. [34][35][36][37][38][39][40] The inability to produce SP-B is the result of an autosomic recessive disease that leads to a fatal respiratory insufficiency, congenital alveolar proteinosis (CAP), indicating the fundamental role this protein plays in normal pulmonary function. 41 In 1994, Nogee et al 42 demonstrated the existence of a mutation-type frameshift, consisting of the substitution of a nucleotide sequence, GAA, with a single nucleotide, C, on codon 121 of the gene responsible for the production of SP-B.…”

Section: Surfactant Proteins: Genetic Determinants and Pulmonary Disementioning

confidence: 99%

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