Original Article

Optimal Function Prediction of Key Aberrant Genes in Early-onset Preeclampsia Using a Modified Network-based Guilt by Association Method


Background: To predict the optimal functions of key aberrant genes in early-onset preeclampsia (EOPE) by using a modified network-based gene function inference method.

Methods: First, differentially expressed genes (DEGs) were extracted using linear models for microarray data (LIMMA) package. Then the Spearman's rank correlation coefficient was calculated to assess co-expressed strength of each interaction between DEGs, based on which the co-expressed genes network was constructed to vividly exhibit their interlinking relationship. Subsequently, Gene ontology (GO) annotations for EOPE were collected according to known confirmed database and DEGs. Ultimately, the multifunctionality algorithm was used to extend the “guilt by association” method based on the co-expressed network, and a 3-fold cross validation was operated to evaluate the accuracy of the algorithm.

Results: During the process, the GO terms, of which the area under the curve (AUC) over 0.7 were screened as the optimal gene functions for EOPE. Six functions including the ion binding and cellular response to stimulus were determined as the optimal gene functions.

Conclusion: Such findings should help to better understand the pathogenesis of EOPE, so as to provide some references for clinical diagnosis and treatment in the future.


1. Ghulmiyyah L, Sibai B (2012). Maternal mortality from preeclampsia/eclampsia. Semin Perinatol, 36: 56-59.
2. Eiland E, Nzerue C, Faulkner M (2012). Preeclampsia 2012. J Pregnancy, 2012: 586578.
3. Roberts CL, Ford JB, Algert CS, et al (2011). Population-based trends in pregnancy hypertension and pre-eclampsia: an international comparative study. BMJ Open, 1(1): e000101.
4. Lisonkova S, Sabr Y, Mayer C, Young C, Skoll A, Joseph KS (2014). Maternal morbidity associated with early-onset and late-onset preeclampsia. Obstet Gynecol, 124: 771-781.
5. Chelbi ST, Mondon F, Jammes H et al (2007). Expressional and epigenetic alterations of placental serine protease inhibitors: SERPINA3 is a potential marker of preeclampsia. Hypertension, 49(1): 76-83.
6. Song L, Zhong M (2015). Association between Interleukin-10 gene polymorphisms and risk of early-onset preeclampsia. Int J Clin Exp Pathol, 8(9): 11659-11664.
7. Weedon-Fekjaer MS, Sheng Y, Sugulle M et al (2014). Placental miR-1301 is dysregulated in early-onset preeclampsia and inversely correlated with maternal circulating leptin. Placenta, 35(9): 709-717.
8. Rahmatallah Y, Emmert-Streib F, Glazko G (2014). Gene Sets Net Correlations Analysis (GSNCA): a multivariate differential coexpression test for gene sets. Bioinformatics, 30(3): 360-368.
9. Smyth GK, Ritchie M, Thorne N, Wettenhall J (2005). In: Gentleman R, Carey VJ, Huber W, Irizarry RA, Dudoit S. (eds) Bioinformatics and Computational Biology Solutions Using R and Bioconductor. Statistics for Biology and Health. Springer, New York, NY.
10. Verleyen W, Ballouz S, Gillis J (2015). Measuring the wisdom of the crowds in network-based gene function inference. Bioinformatics, 31(5): 745-752.
11. Hecker M, Lambeck S, Toepfer S, van Someren E, Guthke R (2009). Gene regulatory network inference: data integration in dynamic models-a review. Biosystems, 96(1): 86-103.
12. Bonow RO (2014). Left atrial function in mitral regurgitation: guilt by association. JACC Cardiovascular imaging, 7(3): 233-235.
13. Demokan S, Chuang A, Suoglu Y et al (2012). Promoter methylation and loss of p16(INK4a) gene expression in head and neck cancer. Head Neck, 34(10): 1470-1475.
14. Cirillo A, Di Salle A, Petillo O et al (2014). High grade glioblastoma is associated with aberrant expression of ZFP57, a protein involved in gene imprinting, and of CPT1A and CPT1C that regulate fatty acid metabolism. Cancer Biol Ther, 15(6): 735-741.
15. Riquelme G (2009). Placental chloride channels: a review. Placenta, 30(8): 659-669.
16. Vallejos C, Riquelme G (2007). The maxi-chloride channel in human syncytiotrophoblast: a pathway for taurine efflux in placental volume regulation? Placenta, 28(11): 1182-1191.
17. Marino GI, Kotsias BA (2013). Expression of the epithelial sodium channel sensitive to amiloride (ENaC) in normal and preeclamptic human placenta. Placenta, 34(2): 197-200.
18. Moon SY, Lee JH, Choi HY, Cho IJ, Kim SC, Kim YW (2014). Tryptanthrin protects hepatocytes against oxidative stress via activation of the extracellular signal-regulated kinase/NF-E2-related factor 2 pathway. Biol Pharm Bull, 37(10): 1633-1640.
19. Hilali N, Kocyigit A, Demir M et al (2013). DNA damage and oxidative stress in patients with mild preeclampsia and offspring. Eur J Obstet Gynecol Reprod Biol, 170: 377-380.
20. Karacay Ö, Sepici-Dincel A, Karcaaltincaba D et al (2010). A quantitative evaluation of total antioxidant status and oxidative stress markers in preeclampsia and gestational diabetic patients in 24–36 weeks of gestation. Diabetes Res Clin Pract, 89(3): 231-238.
IssueVol 47 No 11 (2018) QRcode
SectionOriginal Article(s)
Early-onset preeclampsia Optional function Co-expressed genes network Multifunctionality algorithm

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
WANG J, BI Y, LI J, TIAN Y, YANG X, SUN Z. Optimal Function Prediction of Key Aberrant Genes in Early-onset Preeclampsia Using a Modified Network-based Guilt by Association Method. Iran J Public Health. 2018;47(11):1688-1693.