Association of LPCAT1*rs9728 Variant with Reduced Susceptibility to Neonatal Respiratory Distress Syndrome

Abstract

Background/Objectives: Neonatal respiratory distress syndrome (NRDS) is a heterogenous respiratory illness that mainly affects preterm neonates. It is characterized by insufficient production of pulmonary surfactant and impaired lung compliance. The lysophosphatidylcholine acyltransferase 1 (LPCAT1) enzyme has a crucial function in lipid remodeling through the conversion of lysophosphatidylcholine to phosphatidylcholine, the major component of pulmonary surfactant. In this research, we aimed to investigate the association of the LPCAT1*rs9728 variant with NRDS susceptibility using hereditary analysis and bioinformatic approaches. Methods: The LPCAT1 (rs9728; c.*1668T>C) variant was characterized among 100 preterm neonates with RDS and 100 non-RDS neonates utilizing the TaqMan SNP genotyping assay. Logistic regression analysis was performed to identify the risk factors of respiratory distress syndrome. The functional mechanism of the LPCAT1 gene was elucidated using bioinformatic approaches. Results: The LPCAT1*rs9728 C/C genotype was significantly associated with a 78% reduced risk of NRDS (OR = 0.22, p = 0.027), although the minor C allele did not attain a significant finding (OR = 0.83, p = 0.416). Apgar score and Silverman-Andersen respiratory severity score (RSS) were statistically significant with prematurity classes (p < 0.05). Additionally, gestational age and birth weight were considered independent risk factors in the progression of RDS among preterm neonates. Conclusions: This research exhibited a significant difference between the LPCAT1 (rs9728; c.*1668T>C) variant and reduced risk against the development of RDS among preterm neonates. The rs9728*C/C genotype revealed a significant association with decreased risk of NRDS compared to non-RDS neonates.

Keywords: LPCAT1*rs9728; NRDS; genetic polymorphism; preterm neonates.

Figure 1

Biosynthetic pathway of phosphatidylcholine (PC) in mammalian tissues. Two metabolic processes were involved in the synthesis of phosphatidylcholine, including the de novo mechanism (Kennedy pathway) and the remodeling pathway (Lands’ cycle). In the de novo pathway, the production of lysophosphatidic acid (LPA) is achieved from the combination of glycerol-3-phosphate and acyl-CoA by the action of glycerol-3-phosphate acyltransferases (GPAT). Then, LPA is converted to phosphatidic acid using acylglycerol phosphate acyltransferases (AGPAT). The phosphatidic acid phosphatase (PAP) catalyzes the dephosphorylation reaction of phosphatidic acid, yielding diacylglycerol (DAG). The CDP-choline branch of the Kennedy pathway generates phosphatidylcholine using three enzymatic reactions. The LPCAT1 enzyme was expressed within the alveolar type II pneumocytes and executed a crucial function in the conversion of lysophosphatidylcholine to phosphatidylcholine using the remodeling pathway of Lands’ cycle. In this cyclic pathway, the lysophosphatidylcholine generated by the action of phospholipase A2 and lecithin–cholesterol acyltransferase (LCAT) was subjected to a re-acylation reaction via the incorporation of a definite fatty acid into the sn-2-position to produce new phosphatidylcholine by the action of the LPCAT1 enzyme. Abbreviations: PAF, platelet-activating factor; CTP, cytidine triphosphate; CDP, cytidine diphosphate; ATP, adenosine triphosphate, and LPCAT1, lysophosphatidylcholine acyltransferase 1.

Figure 2

Genetic association models for LPCAT1 (rs9728; c.*1668T>C) variant among RDS preterm neonates compared to healthy controls. Bold values indicate the p < 0.05.

Figure 3

Kaplan–Meier curve of overall survival of RDS preterm neonates clustered based on (A) prematurity groups, (B) birth weight categories, and (C) LPCAT1*rs9726 genotypes. The log-rank p-value test was employed to compare the survival probability (%) of RDS preterm neonates based on the length of hospital stay.

Figure 4

Computational bioinformatic frameworks of the LPCAT1 gene. (A) The chromosomal localization of the LPCAT1 gene. It is positioned directly on the chromosome number 5p15.33 that spanned about 67,843 bases (Chr.5:1,456,480–1,523,962) and is oriented along the reverse strand. (B) The genomic structure of the LPCAT1 gene identified that it consisted of six splice transcript variants, with the main one which referred to LPCAT1-201 (ENST00000283415) and included 14 exons and 13 introns. (C) Amino acid residues of the LPCAT1 protein and its domains. (D) The predicted structure of human LPCAT1 protein designed using the AlphaFold Protein Structure database. (E) The subcellular localization of LPCAT1 protein. Darker color represents more abundance. (F) Gene–gene interaction networks of the LPCAT1 gene. (G) Functional protein network analysis of the LPCAT1 protein using STRING database v12.0. [Data source: Ensembl.org, NCBI database, Protter database, Compartment database, GeneMania, and STRING database].

Figure 4

Computational bioinformatic frameworks of the LPCAT1 gene. (A) The chromosomal localization of the LPCAT1 gene. It is positioned directly on the chromosome number 5p15.33 that spanned about 67,843 bases (Chr.5:1,456,480–1,523,962) and is oriented along the reverse strand. (B) The genomic structure of the LPCAT1 gene identified that it consisted of six splice transcript variants, with the main one which referred to LPCAT1-201 (ENST00000283415) and included 14 exons and 13 introns. (C) Amino acid residues of the LPCAT1 protein and its domains. (D) The predicted structure of human LPCAT1 protein designed using the AlphaFold Protein Structure database. (E) The subcellular localization of LPCAT1 protein. Darker color represents more abundance. (F) Gene–gene interaction networks of the LPCAT1 gene. (G) Functional protein network analysis of the LPCAT1 protein using STRING database v12.0. [Data source: Ensembl.org, NCBI database, Protter database, Compartment database, GeneMania, and STRING database].