Abstract
Background
To determine population-based prevalence and disease contribution of phosphatidylcholine synthetic pathway-associated gene variants in a native southern Chinese cohort.
Methods
We used bloodspots from 2010 that were obtained from the Guangxi Neonatal Screening Center in Nannning China and included the Han (n = 443) and Zhuang (n = 313) ethnic groups. We sequenced the exons of cholinephosphate cytidylyltransferase (PCYT1B) lysophospholipid acyltransferase 1 (LPCAT1), and cholinephosphotransferase (CHPT1) genes, and analyzed both rare and common exonic variants.
Results
We obtained five mutations (G199D, A299V, G434C, Y490C, L312S) with eight alleles in the three candidate genes. The collapsed minor allele frequency for candidate genes was not significantly different between the Han and Zhuang populations (0.0045 vs. 0.0064, respectively, P = 0.725). The combined Han and Zhuang pool collapsed carrier frequency of rare mutation allele was found to be 1.06%, which is much higher than previously reported for the Missouri population (0.1%). Further, we detected six exonic common variants (three in LPCAT1 and three in CHPT1), with three non-synonymous variants (F162S, F341L, M427K) among them. Two of the non-synonymous exonic variants (F341L, M427K) were not found in CHB; F341L was also not previously reported in exome sequencing project.
Conclusions
The population-based frequency of mutations in the phosphatidylcholine synthesis pathway-associated genes PCYT1B LPCAT1, CHPT1 is low in southern Chinese newborns and there is no evidence of contribution to population-based disease burden of respiratory distress syndrome. As a population-based study of rare mutations and common variants, this work is valuable in directing future research.
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References
Avery ME, Mead J. Surface properties in relation to atelectasis and hyaline membrane disease. AMA J Dis Child. 1959;97:517–23.
Veldhuizen R, Nag K, Orgeig S, Possmayer F. The role of lipids in pulmonary surfactant. Biochim Biophys Acta. 1998;1408:90–108.
Hamvas A. Evaluation and management of inherited disorders of surfactant metabolism. Chin Med J (Engl). 2010;123:2943–7.
Batenburg JJ. Surfactant phospholipids: synthesis and storage. Am J Physiol. 1992;262:L367–85.
Calkovska A, Linderholm B, Haegerstrand-Bjorkman M, Pioselli B, Pelizzi N, Johansson J, et al. Phospholipid composition in synthetic surfactants is important for tidal volumes and alveolar stability in surfactant-treated preterm newborn rabbits. Neonatology. 2016;109:177–85.
Goerke J. Pulmonary surfactant: functions and molecular composition. Biochim Biophys Acta. 1998;1408:79–89.
Goss V, Hunt AN, Postle AD. Regulation of lung surfactant phospholipid synthesis and metabolism. Biochim Biophys Acta. 2013;1831:448–58.
Wambach JA, Wegner DJ, Depass K, Heins H, Druley TE, Mitra RD, et al. Single ABCA3 mutations increase risk for neonatal respiratory distress syndrome. Pediatrics. 2012;130:e1575–82.
Bridges JP, Ikegami M, Brilli LL, Chen X, Mason RJ, Shannon JM. LPCAT1 regulates surfactant phospholipid synthesis and is required for transitioning to air breathing in mice. J Clin Invest. 2010;120:1736–48.
Nogee LM, Garnier G, Dietz HC, Singer L, Murphy AM, deMello DE, et al. A mutation in the surfactant protein B gene responsible for fatal neonatal respiratory disease in multiple kindreds. J Clin Invest. 1994;93:1860–3.
Shulenin S, Nogee LM, Annilo T, Wert SE, Whitsett JA, Dean M. ABCA3 gene mutations in newborns with fatal surfactant deficiency. N Engl J Med. 2004;350:1296–303.
Agrawal A, Hamvas A, Cole FS, Wambach JA, Wegner D, Coghill C, et al. An intronic ABCA3 mutation that is responsible for respiratory disease. Pediatr Res. 2012;71:633–7.
Wambach JA, Yang P, Wegner DJ, An P, Hackett BP, Cole FS, et al. Surfactant protein-C promoter variants associated with neonatal respiratory distress syndrome reduce transcription. Pediatr Res. 2010;68:216–20.
Cameron HS, Somaschini M, Carrera P, Hamvas A, Whitsett JA, Wert SE, et al. A common mutation in the surfactant protein C gene associated with lung disease. J Pediatr. 2005;146:370–5.
Li B, Leal SM. Methods for detecting associations with rare variants for common diseases: application to analysis of sequence data. Am J Hum Genet. 2008;83:311–21.
Qian L, Liu C, Zhuang W, Guo Y, Yu J, Chen H, et al. Neonatal respiratory failure: a 12-month clinical epidemiologic study from 2004 to 2005 in China. Pediatrics. 2008;121:e1115–24.
Ma XL, Xu XF, Chen C, Yan CY, Liu YM, Liu L, et al. Epidemiology of respiratory distress and the illness severity in late preterm or term infants: a prospective multi-center study. Chin Med J (Engl). 2010;123:2776–80.
Chen YJ, Wambach JA, DePass K, Wegner DJ, Chen SK, Zhang QY, et al. Population-based frequency of surfactant dysfunction mutations in a native Chinese cohort. World J Pediatr. 2016;12:190–5.
Zhao Q, Pan S, Qin Z, Cai X, Lu Y, Farina SE, et al. Gene flow between Zhuang and Han populations in the China–Vietnam borderland. J Hum Genet. 2010;55:774–6.
Acknowledgements
The authors would like to thank the NHLBI GO Exome Sequencing Project and its ongoing studies which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010).
Funding
This study was supported by the National Natural Science Foundation of China 81260094 (Chen YJ), National Institutes of Health R01 HL065174 (Cole FS, Hamvas A), R01 HL082747 (Cole FS, Hamvas A), K12 HL089968 (Wambach JA, Cole FS), K08 HL105891 (Wambach JA), Foundation of Health Department of Guangxi Zhuang Autonomous Region 2012059 (Chen YJ).
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Chen YJ contributed to the concept, design and drafting of the manuscript. Hamvas A contributed to the concept, design, drafting and revision of the manuscript. Wambach JA contributed to the concept and design. Wegner DJ and Zhang QY contributed to the analysis and interpretation of data. Meyer J drafted the article. All authors approved the final version.
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These studies were performed with a waiver of consent from the Washington University Human Research Protection Office and approved by the Ethics Committee of The First Affiliated Hospital of Guangxi Medical University.
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None of the authors has any financial, personal or professional interests that could be construed to have influenced the paper.
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Chen, YJ., Meyer, J., Wambach, J.A. et al. Gene variants of the phosphatidylcholine synthesis pathway do not contribute to RDS in the Chinese population. World J Pediatr 14, 52–56 (2018). https://doi.org/10.1007/s12519-017-0109-3
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DOI: https://doi.org/10.1007/s12519-017-0109-3