The SEPS1 G-105A Polymorphism Is Associated with Risk
of Spontaneous Preterm Birth in a Chinese Population
Yan Wang1., Xiao Yang1., Yong Zheng2., Zhi-Hao Wu3., Xiao-Ai Zhang4., Qiu-Ping Li1, Xi-Yu He1, Chun-
Zhi Wang1*, Zhi-Chun Feng1*
1BaYi Children’s Hospital, General Military Hospital of Beijing PLA, P. R. China, 2The 309 Hospital of PLA, Beijing, P. R. China, 3Department of Infectious Disease Control,
Beijing Institute of Disease Control and Prevention, Beijing, P. R. China, 4State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and
Epidemiology, Beijing, P. R. China
Inflammation plays an important role in the etiology and pathophysiology of spontaneous preterm birth (SPTB), and
selenoprotein S (SEPS1) is involved in regulating the inflammatory response. Recently the G-105A promoter polymorphism
in SEPS1 was shown to increase pro-inflammatory cytokine expression. We examined whether this functional polymorphism
was related to the risk of SPTB in a Chinese population. We also examined the impact of premature rupture of membranes
(PROM) on susceptibility to SPTB. The SEPS1 G-105A polymorphism was genotyped in 569 preterm singleton neonates and
673 term neonates by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. x2tests
and logistic regression analyses were used to calculate the odds ratios (ORs) and 95% confidence intervals (95% CIs). We
observed that, compared with the GG genotype, –105A positive genotypes (GA + AA genotypes) were associated with
significantly increased susceptibility to SPTB (adjusted OR, 1.87; 95% CI, 1.36–2.57; P,0.001). The –105A positive genotypes
were also significantly associated with increased susceptibility to SPTB, both in the patients with PROM (adjusted OR, 2.65;
95% CI, 1.73–4.03; P,0.001) and in those without PROM (adjusted OR, 1.56; 95% CI, 1.09–2.24; P=0.015). The –105A positive
genotypes were also significantly associated with increased susceptibility to SPTB between extremely preterm neonates and
controls (adjusted OR, 4.46; 95% CI, 1.86–10.73; P=0.002) and between moderately preterm neonates and controls
(adjusted OR, 1.76; 95% CI, 1.25–2.47; P=0.001). Our findings suggest that the SEPS1 G-105A polymorphism contributes to
the risk of developing SPTB in a Chinese population.
Citation: Wang Y, Yang X, Zheng Y, Wu Z-H, Zhang X-A, et al. (2013) The SEPS1 G-105A Polymorphism Is Associated with Risk of Spontaneous Preterm Birth in a
Chinese Population. PLoS ONE 8(6): e65657. doi:10.1371/journal.pone.0065657
Editor: Alberico Catapano, University of Milan, Italy
Received December 11, 2012; Accepted April 25, 2013; Published June 11, 2013
Copyright: ? 2013 Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by the National Natural Science Foundation of China (30973210 and 81170602). The funders had no role in study design, data
collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: firstname.lastname@example.org (ZCF); email@example.com (CZW)
. These authors contributed equally to this work.
Preterm birth (PTB), defined as birth before 37 complete weeks
of gestation, is the major cause of neonatal mortality and
morbidity. PTB is associated with over 75% of long-term
morbidity, including cerebral palsy, developmental delay, retinop-
athy of prematurity, and hearing and vision problems. PTB is a
global problem, with approximately 15 million premature births
occurring annually across the globe. This number is rising
according to the World Health Organization (http://www.who.
int/mediacentre/factsheets/fs363/en/). China contributes 7.8%
of these premature births, with nearly 1.1 million preterm infants
being born there every year, second only to India . PTB is an
important problem in obstetrics, and has become a major public
health concern in China.
Genetic factors are known contributors to spontaneous preterm
birth (SPTB) . Epidemiological studies suggest that SPTB
clusters in families . Moreover, there are significant racial/
ethnic disparities in the incidence of SPTB, with African
Americans running more than twice as great a risk of SPTB as
European-American women. In addition, association studies have
identified a number of genetic polymorphisms related to infection,
inflammation and innate immune systems that are risk factors for
SPTB [4,5,6,7,8,9]. Despite these advances, the alleles accounting
for the bulk of genetic susceptibility to SPTB remain undiscovered,
particularly in Chinese populations. Identifying susceptibility genes
conferring increased risks for SPTB would advance the develop-
ment of solutions to preventing SPTB and would help to clarify the
causes and mechanisms of this disease.
Evidence exists that inflammation plays a role in the patho-
physiology of SPTB [10,11,12]. Given that inflammation contrib-
utes to the initiation of SPTB, genes encoding proteins involved in
the regulation of inflammatory mediators are plausible candidate
genes. Selenoprotein S (SEPS1, gene aliases: SELS, VIMP,
TANIS) is a novel selenoprotein, and it impacts the immune
and inflammatory signal pathways . SEPS1 has been classified
as a new endoplasmic reticulum (ER) membrane protein that
moves misfolded proteins from the ER to the cytosol and prevents
stress responses that activate the inflammatory cascade . Thus,
it is expected that genetic polymorphisms affecting SEPS1 gene
transcription and subsequent SEPS1 expression levels might
PLOS ONE | www.plosone.org1June 2013 | Volume 8 | Issue 6 | e65657
polymorphism was significantly associated with SPTB in the
extremely preterm and moderately preterm groups, while we
observed only a borderline significant association in the very
preterm group. Interestingly, several other studies also suggested
differences of susceptibility between gestational age groupings
[26,27,28]. Thus, it is plausible to assume that the associations
between SEPS1 G-105A polymorphism and SPTB are different
based on the gestational age at delivery. However, considering the
limited sample size of extremely preterm neonates (n=26) in our
study, this assumption warrants further confirmation in future
In reviewing the results of this study, two potential limitations
should be kept in mind. Firstly, in our study, the influence of
maternal genomes on predispositions to SPTB was not considered.
SPTB is a function of both maternal and fetal risk factors and their
interactions at the genetic and biomarker levels. Additional well-
designed case-control studies that include both maternal and fetal
genomes are warranted to more fully understand the roles of the
SEPS1 polymorphism in the etiology of SPTB. Secondly, we
cannot rule out that the presence of polymorphisms in other genes,
especially other genes involved in the inflammation, could affect
the occurrence of the SPTB. We selected SEPS1 G-105A
polymorphism because it was strongly associated with circulating
levels of pro-inflammatory cytokines. However, the regulation of
inflammation is complex, with other genes warranting investiga-
tion. Recently, other investigators have used proteomics  and
microarray [30,31] to identify markers for SPTB in a more
comprehensive manner. Thus, further studies that cover more
genes involved in the inflammation are warranted to fully clarify
the etiology of SPTB.
In conclusion, we found that the SEPS1 G-105A polymorphism
was associated with the risk of SPTB in a Chinese population. If
confirmed by other studies, our findings of genetic factors
contributing to the pathogenesis of SPTB may have implications
for the screening and treatment of this disorder.
We thank all the tested individuals, their families, and collaborating
clinicians for their participation.
Conceived and designed the experiments: YW XY YZ ZHW XAZ CZW
ZCF. Performed the experiments: YW XY YZ ZHW XAZ. Analyzed the
data: YW XY YZ ZHW XAZ CZW ZCF. Contributed reagents/
materials/analysis tools: YW XY YZ QPL XYH. Wrote the paper: YW
XY YZ ZHW XAZ CZW ZCF.
1. Zhao X, Chen Y, Qiu G, Xiao M, Zhong N (2012) Reducing preterm births in
China. Lancet 380: 1144–1145; author reply 1145.
2. Varner MW, Esplin MS (2005) Current understanding of genetic factors in
preterm birth. BJOG 112 Suppl 1: 28–31.
3. Winkvist A, Mogren I, Hogberg U (1998) Familial patterns in birth
characteristics: impact on individual and population risks. Int J Epidemiol 27:
4. Pereyra S, Velazquez T, Bertoni B, Sapiro R (2012) Rapid multiplex high
resolution melting method to analyze inflammatory related SNPs in preterm
birth. BMC Res Notes 5: 69.
5. Yilmaz Y, Verdi H, Taneri A, Yazici AC, Ecevit AN, et al. (2012) Maternal-fetal
proinflammatory cytokine gene polymorphism and preterm birth. DNA Cell
Biol 31: 92–97.
6. Sata F, Toya S, Yamada H, Suzuki K, Saijo Y, et al. (2009) Proinflammatory
cytokine polymorphisms and the risk of preterm birth and low birthweight in a
Japanese population. Mol Hum Reprod 15: 121–130.
7. Engel SA, Erichsen HC, Savitz DA, Thorp J, Chanock SJ, et al. (2005) Risk of
spontaneous preterm birth is associated with common proinflammatory cytokine
polymorphisms. Epidemiology 16: 469–477.
8. Moura E, Mattar R, de Souza E, Torloni MR, Goncalves-Primo A, et al. (2009)
Inflammatory cytokine gene polymorphisms and spontaneous preterm birth.
J Reprod Immunol 80: 115–121.
9. Anum EA, Springel EH, Shriver MD, Strauss JF, 3rd (2009) Genetic
contributions to disparities in preterm birth. Pediatr Res 65: 1–9.
10. Ruiz RJ, Jallo N, Murphey C, Marti CN, Godbold E, et al. (2012) Second
trimester maternal plasma levels of cytokines IL-1Ra, Il-6 and IL-10 and
preterm birth. J Perinatol 32: 483–490.
11. Nold C, Anton L, Brown A, Elovitz M (2012) Inflammation promotes a cytokine
response and disrupts the cervical epithelial barrier: a possible mechanism of
premature cervical remodeling and preterm birth. Am J Obstet Gynecol 206:
12. Goepfert AR, Jeffcoat MK, Andrews WW, Faye-Petersen O, Cliver SP, et al.
(2004) Periodontal disease and upper genital tract inflammation in early
spontaneous preterm birth. Obstet Gynecol 104: 777–783.
13. Curran JE, Jowett JB, Elliott KS, Gao Y, Gluschenko K, et al. (2005) Genetic
variation in selenoprotein S influences inflammatory response. Nat Genet 37:
14. Yihong Y, Yoko S, Yun C, Ron D, Rapoport TA (2004) A membrane protein
complex mediates retro-translocation from the ER lumen into the cytosol.
NATURE 429: 841–847.
15. Olsson M, Olsson B, Jacobson P, Thelle DS, Bjorkegren J, et al. (2011)
Expression of the selenoprotein S (SELS) gene in subcutaneous adipose tissue
and SELS genotype are associated with metabolic risk factors. Metabolism 60:
16. Sutherland A, Kim DH, Relton C, Ahn YO, Hesketh J (2010) Polymorphisms in
the selenoprotein S and 15-kDa selenoprotein genes are associated with altered
susceptibility to colorectal cancer. Genes Nutr 5: 215–223.
17. Meplan C, Hughes DJ, Pardini B, Naccarati A, Soucek P, et al. (2010) Genetic
variants in selenoprotein genes increase risk of colorectal cancer. Carcinogenesis
18. Shibata T, Arisawa T, Tahara T, Ohkubo M, Yoshioka D, et al. (2009)
Selenoprotein S (SEPS1) gene -105G.A promoter polymorphism influences the
susceptibility to gastric cancer in the Japanese population. BMC Gastroenter-
ology 9: 2.
19. Moses EK, Johnson MP, Tømmerdal L, Forsmo S, Joanne E (2008) Genetic
association of preeclampsia to the inflammatory response gene SEPS1.
Am J Obstet 198: 336.
20. Alanne M, Kristiansson K, Auro K, Silander K, Kuulasmaa K, et al. (2007)
Variation in the selenoprotein S gene locus is associated with coronary heart
disease and ischemic stroke in two independent Finnish cohorts. Hum Genet
21. Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis.
Stat Med 21: 1539–1558.
22. Parry S, Strauss JF 3rd (1998) Premature rupture of the fetal membranes.
N Engl J Med 338: 663–670.
23. Kim KW, Romero R, Park HS, Park CW, Shim SS, et al. (2007) A rapid matrix
metalloproteinase-8 bedside test for the detection of intraamniotic inflammation
in women with preterm premature rupture of membranes. Am J Obstet Gynecol
197: 292 e291–295.
24. Lee SY, Buhimschi IA, Dulay AT, Ali UA, Zhao G, et al. (2011) IL-6 trans-
signaling system in intra-amniotic inflammation, preterm birth, and preterm
premature rupture of the membranes. J Immunol 186: 3226–3236.
25. Gulati S, Agrawal S, Raghunandan C, Bhattacharya J, Saili A, et al. (2012)
Maternal serum interleukin-6 and its association with clinicopathological
infectious morbidity in preterm premature rupture of membranes: a prospective
cohort study. J Matern Fetal Neonatal Med 25: 1428–1432.
26. Rey G, Skowronek F, Alciaturi J, Alonso J, Bertoni B, et al. (2008) Toll receptor
4 Asp299Gly polymorphism and its association with preterm birth and
premature rupture of membranes in a South American population. Mol Hum
Reprod 14: 555–559.
27. Krediet TG, Wiertsema SP, Vossers MJ, Hoeks SB, Fleer A, et al. (2007) Toll-
like receptor 2 polymorphism is associated with preterm birth. Pediatr Res 62:
28. Day LJ, Schaa KL, Ryckman KK, Cooper M, Dagle JM, et al. (2011) Single-
nucleotide polymorphisms in the KCNN3 gene associate with preterm birth.
Reprod Sci 18: 286–295.
29. Esplin MS, Merrell K, Goldenberg R, Lai Y, Iams JD, et al. (2011) Proteomic
identification of serum peptides predicting subsequent spontaneous preterm
birth. Am J Obstet Gynecol 204: 391 e391–398.
30. Weiner CP, Mason CW, Dong Y, Buhimschi IA, Swaan PW, et al. (2010)
Human effector/initiator gene sets that regulate myometrial contractility during
term and preterm labor. Am J Obstet Gynecol 202: 474 e471–420.
31. Chim SS, Lee WS, Ting YH, Chan OK, Lee SW, et al. (2012) Systematic
identification of spontaneous preterm birth-associated RNA transcripts in
maternal plasma. PLoS One 7: e34328.
SEPS1 Polymorphism and Spontaneous Preterm Birth
PLOS ONE | www.plosone.org7June 2013 | Volume 8 | Issue 6 | e65657