Genetic variant associations of human SP-A and SP-D with acute and chronic lung injury

Abstract

Pulmonary surfactant, a lipoprotein complex, maintains alveolar integrity and plays an important role in lung host defense, and control of inflammation. Altered inflammatory processes and surfactant dysfunction are well described events that occur in patients with acute or chronic lung disease that can develop secondary to a variety of insults. Genetic variants of surfactant proteins, including single nucleotide polymorphisms, haplotypes, and other genetic variations have been associated with acute and chronic lung disease throughout life in several populations and study groups. The hydrophilic surfactant proteins SP-A and SP-D, also known as collectins, in addition to their surfactant-related functions, are important innate immunity molecules as these, among others, exhibit the ability to bind and enhance clearance of a wide range of pathogens and allergens. This review focuses on published association studies of human surfactant proteins A and D genetic polymorphisms with respiratory, and non-respiratory diseases in adults, children, and newborns. The potential role of genetic variations in pulmonary disease or pathogenesis is discussed following an evaluation, and comparison of the available literature.

An 11-nt sequence polymorphism at the 3′UTR of human SFTPA1 and SFTPA2 gene variants differentially affect gene expression levels and miRNA regulation in cell culture

“…Studies of the genetics of SP-A have revealed correlations of SFTPA1 and SFTPA2 variants with lung disease susceptibility (16,58), and polymorphisms of SP-A variants have been associated with variable gene expression levels (6). variants 6A, 6A 2 , 6A 3 , and 6A 4 , as well as mutants of the 11-nt element 6Ains, 6A 2 del, 6A 3 ins, and 6A 4 ins were cotransfected in NCI-H441 cells with miRNA mimics and a Renilla luciferase control plasmid.…”

“…Recently, certain SP-A2 variants were associated with low levels of SP-A, and low SP-A levels were associated with poor outcome in patients with lung transplants (6). We have previously hypothesized that the SP-A functional activity depends on the relative amount of SP-A1 and SP-A2, as alterations in both total SP-A content and the SP-A1/SP-A ratio have been observed in lung secretions of patients suffering from asthma and cystic fibrosis (58,61,74). Thus it is likely that independent regulatory mechanisms control the expression of variants of SFTPA1 and SFTPA2.…”

“…These are found in the population with variable frequency, and some of them have been found to be risk factors for lung disease, including tuberculosis, idiopathic pulmonary fibrosis, lung cancer, bronchopulmonary dysplasia, respiratory distress syndrome, and various alveolar and airway infections (15,24,51,55,58). The most commonly found variants (Ͼ1% in the general population) are 6A, 6A 2 , 6A 3 , and 6A 4 for SFTPA1, and 1A, 1A 0 , 1A 1 , 1A 2 , 1A 3 , and 1A 5 for SFTPA2 (Fig.…”

Human Surfactant Proteins (SP-) A1 and SP-A2: to Include or Not in Surfactant Replacement Therapy, and If Yes, Both or Which One?

“…These variants have been associated with many lung diseases including neonatal diseases, such as Respiratory Distress Syndrome (RDS) and Bronchopulmonary Dysplasia (BPD) [11]. The SP-A1 and SP-A2 gene products have been shown to differ in several functions related to innate immunity [12] and in surfactantrelated functions [13,14].…”

“…Because low levels of SP-A have been associated with neonatal disease (RDS, BPD) risk, as well as with risk in adult disease (IPF) or condition (lung trauma) [11], enhancing the expression of SP-A1, SP-A2, or both depending on the particular functional need may be another way to increase their levels in neonatal life. Although individuals with lung disease have been shown to have altered levels of SP-A, it is not known whether these reflect change in both gene products, or just one, and if the latter, which one.…”