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Genetics and Genomics of Preterm Birth

Genetics and Genomics of Preterm Birth

Lubna Nadeem; Stephen J. Lye; Oksana Shynlova
2018

Synopsis

A review of the literature on preterm birth (PTB).
In a group of women with prior spontaneous PTB, the incidence of recurrent PTB is higher in black women compared to white women. It was reported that for mothers who consumed more than three alcoholic drinks per day, the risk of having a preterm born child increased by 23%. No therapies have been shown to be effective across populations in preventing PTB and improving infant outcomes. Two distinct yet integrated pathways play a key role in labor initiation by inducing molecular changes within the uterine muscle. Identification of women at risk for delivering preterm based on their genetic predisposition will potentially assist the development and implementation of preventive measures to improve the clinical management of PTB. The Norwegian Mother and Child Cohort Study mitochondrial genome mitochondrially encoded tRNA leucine 1 National Center for Health Statistics nuclear factor kappa-light-chain-enhancer of activated B cells.

Key points

● Two distinct yet integrated pathways–an endocrine cascade comprising the fetal hypothalamic-pituitary-adrenal-placental axis and a mechanical pathway in which fetal growth imposes tension on the uterine wall–both play a key role in labor initiation by inducing molecular changes within the uterine muscle. These changes include the expression of a cassette of contraction-associated proteins (CAPs), that is, the gap junction protein connexin43 (Cx43/GJA1); receptors for oxytocin and prostaglandins (OTR, EP1-4 and prostaglandin F receptor (FP)); and Na+ and Ca2+ ion channels that control the excitability of the myometrium [58]; as well as extracellular matrix (ECM) proteins [59], cellmatrix adhesion complexes [60], COX2, and proinflammatory genes (NF-κB2, CCL2, interleukins (IL)-1, CXCL8, etc.)
● While the analysis of genetic polymorphisms linked to disease is a powerful tool, it has so far provided limited actionable information with respect to the etiology of preterm birth (PTB)
● Identification of women at risk for delivering preterm based on their genetic predisposition will potentially assist the development and implementation of preventive measures to improve the clinical management of PTB
● Fully resolve this critical public health problem until we develop a better understanding of how genotype is influenced by environmental factors
● The search for a genetic contribution to PTB has been complicated by methodologic challenges such as variations in inclusion/exclusion criteria, population size, and racial differences, which can significantly influence the interpretation of the results

Summary

15. GENETICS AND GENOMICS OF PRETERM BIRTH BMI BV C19MC CAPs CCL2 CDX2 COX2 CpG CRH CRHR1 Cx43 CXCL CYP2E1 dbGaP DHCR7 DHFR DNBC DRD2 ECM ENPP1 EP1 EVs FokI FP GENEVA GPN GWAS HDL HPC IGF1R IGFBP3 IL IL2RG IVF LDL MELAS miRNA MMPs MnSOD MoBa mtDNA MT-TL1 NCHS NF-κB OHD OS OTR P4 PGE2 PGF2α PGI2 PGs pPROM PREs PRKCA body mass index bacterial vaginosis chromosome 19 microRNA cluster contraction-associated proteins C-C motif chemokine ligand 2 caudal type homeobox 2 cyclooxygenase 2 cytosine-phosphate-Guanine corticotropin releasing hormone corticotropin-releasing-hormone receptor 1 connexin 43 C-X-C motif chemokine ligand cytochrome P450, family 2, subfamily E, poly-peptide 1 database of genotypes and phenotypes 7-dehyrocholesterol reductase dihydrofolate reductase Danish National Birth Cohort dopamine receptor D2 extracellular matrix ectonucleotide pyrophosphatase prostaglandin E2 receptor 1 extracellular vesicles flavobacterium okeanokoites prostaglandin F receptor Gene Environment Association Studies Initiative genomic and proteomic network genome wide association high-density lipoproteins hydroxyprogesterone caproate insulin-like growth factor 1 receptor insulin-like growth factor binding protein 3 interleukins IL-2 receptor γ subunit in vitro fertilization low-density lipoproteins mitochondrial encephalomyopathy, lactic acidosis, and stroke-like micro RNA matrix metalloproteinases manganese superoxide dismutase The Norwegian Mother and Child Cohort Study mitochondrial genome mitochondrially encoded tRNA leucine 1 National Center for Health Statistics nuclear factor kappa-light-chain-enhancer of activated B cells hydroxyvitamin D oxidative stress oxytocin receptor progesterone prostaglandin E2 prostaglandin F2α prostacyclin prostaglandins preterm premature rupture of membranes progesterone response elements protein kinase C-α episodes
EMBRYO IMPLANTATION, PLACENTA DEVELOPMENT AND PREGNANCY Preterm birth (PTB, birth at <37 completed weeks of gestation) is a significant worldwide problem of clinical obstetrics.
Two distinct yet integrated pathways–an endocrine cascade comprising the fetal hypothalamic-pituitary-adrenal-placental axis and a mechanical pathway in which fetal growth imposes tension on the uterine wall–both play a key role in labor initiation by inducing molecular changes within the uterine muscle
These changes include the expression of a cassette of contraction-associated proteins (CAPs), that is, the gap junction protein connexin (Cx43/GJA1); receptors for oxytocin and prostaglandins (OTR, EP1-4 and FP); and Na+ and Ca2+ ion channels that control the excitability of the myometrium [58]; as well as extracellular matrix (ECM) proteins [59], cellmatrix adhesion complexes [60], COX2, and proinflammatory genes (NF-κB2, CCL2, IL-1, CXCL8, etc.).
Findings In a group of women with prior spontaneous PTB, the incidence of recurrent PTB is higher in black women compared to white women (8.2% vs. 13.4% for very preterm and moderate preterm delivery) [17].
It was reported that for mothers who consumed more than three alcoholic drinks per day, the risk of having a preterm born child increased by 23% [41]
CONCLUSION No therapies have been shown to be effective across populations in preventing PTB and improving infant outcomes; clearly, new approaches are required [145].
Identification of women at risk for delivering preterm based on their genetic predisposition will potentially assist the development and implementation of preventive measures to improve the clinical management of PTB.
It will not, fully resolve this critical public health problem until the authors develop a better understanding of how genotype is influenced by environmental factors.
Risk factors for spontaneous preterm birth among Aboriginal and non-Aboriginal women in Manitoba.
The vaginal microbiome, vaginal anti-microbial defence mechanisms and the clinical challenge of reducing infection-related preterm birth.
Fidel P, Ghezzi F, Romero R, Chaiworapongsa T, Espinoza J, Cutright J, et al The effect of antibiotic therapy on intrauterine infection-induced preterm parturition in rabbits.
The participants are assigned by chance to separate groups; neither the researchers nor the participants can choose to allocate people in groups

Conclusion

Remarks
REMARKS Despite considerable research, no therapies have been shown to be effective across populations in preventing PTB and improving infant outcomes; clearly, new approaches are required [145]. While the analysis of genetic polymorphisms linked to disease is a powerful tool, it has so far provided limited actionable information with respect to the etiology of PTB. Identification of women at risk for delivering preterm based on their genetic predisposition will potentially assist the development and implementation of preventive measures to improve the clinical management of PTB. It will not, however, fully resolve this critical public health problem until we develop a better understanding of how genotype is influenced by environmental factors. PTB is a multifactorial complex syndrome caused by multiple gene interactions and nongenetic environmental factors. It is clear that the genotypes of both mother and fetus are equally important and that both can interact with the environment to affect risk. The search for a genetic contribution to PTB has also been complicated by methodologic challenges such as variations in inclusion/exclusion criteria, population size, and racial differences, which can significantly influence the interpretation of the results.

Participants and statistics

BMI BV C19MC CAPs CCL2 CDX2 COX2 CpG CRH CRHR1 Cx43 CXCL CYP2E1 dbGaP DHCR7 DHFR DNBC DRD2 ECM ENPP1 EP1 EVs FokI FP GENEVA GPN GWAS HDL HPC IGF1R IGFBP3 IL IL2RG IVF LDL MELAS miRNA MMPs MnSOD MoBa mtDNA MT-TL1 NCHS NF-κB OHD OS OTR P4 PGE2 PGF2α PGI2 PGs pPROM PREs PRKCA. body mass index bacterial vaginosis chromosome 19 microRNA cluster contraction-associated proteins C-C motif chemokine ligand 2 caudal type homeobox 2 cyclooxygenase 2 cytosine-phosphate-Guanine corticotropin releasing hormone corticotropin-releasing-hormone receptor 1 connexin 43 C-X-C motif chemokine ligand cytochrome P450, family 2, subfamily E, poly-peptide 1 database of genotypes and phenotypes 7-dehyrocholesterol reductase dihydrofolate reductase Danish National Birth Cohort dopamine receptor D2 extracellular matrix ectonucleotide pyrophosphatase prostaglandin E2 receptor 1 extracellular vesicles flavobacterium okeanokoites prostaglandin F receptor Gene Environment Association Studies Initiative genomic and proteomic network genome wide association high-density lipoproteins hydroxyprogesterone caproate insulin-like growth factor 1 receptor insulin-like growth factor binding protein 3 interleukins IL-2 receptor γ subunit in vitro fertilization low-density lipoproteins mitochondrial encephalomyopathy, lactic acidosis, and stroke-like micro RNA matrix metalloproteinases manganese superoxide dismutase The Norwegian Mother and Child Cohort Study mitochondrial genome mitochondrially encoded tRNA leucine 1 National Center for Health Statistics nuclear factor kappa-light-chain-enhancer of activated B cells hydroxyvitamin D oxidative stress oxytocin receptor progesterone prostaglandin E2 prostaglandin F2α prostacyclin prostaglandins preterm premature rupture of membranes progesterone response elements protein kinase C-α episodes. II
About 0.5 million PTBs occur in Europe and Northern America, and 0.8 million babies are born preterm in Latin America and the Caribbean. In the United States, the PTB rate is on a rise, which results in about 0.4 million babies being born prematurely every year [9]. Similar increases in the incidence of PTB have been reported in Canada and Australia [2]
RNA sequencing is a highly sensitive method that enables the discovery of subtle changes in gene expression directly related to active preterm parturition. In this analysis, we identified significant differences in the expression of 262 genes in the peripheral monocytes and 184 genes in the whole blood of women who were in spontaneous PTL compared to pregnant women of the same gestational age not undergoing labor, with 43 of these genes differentially expressed in both white blood cells and peripheral monocytes [99]. microRNA and Regulation of Labor Onset
Several datasets are publicly available through the Database of Genotypes and Phenotypes (dbGaP). These include the Danish National Birth Cohort (DNBC, a large dataset including 1000 PTB mother-child pairs along with 1000 control pairs) [122], two datasets from the Gene Environment Association Studies initiative (GENEVA, including DNBC and an AfricanAmerican cohort), a Genomic and Proteomic Network (GPN) cohort [123], and another African-American cohort collected by Boston Medical Center [124]. Using these cohorts, a comparison of mother-infant genomes from early PTB versus normal TL control pairs did not detect PTB associations with SNP from the maternal genome while the SNPs in ribonuclease T2 (RNASET2) and in the extended major histocompatibility complex (immune response-related genes) in the fetal genome were associated with PTB [125]
Attention has been diverted toward identifying rare gene variants associated with PTB using high-throughput sequencing of whole genomes and exomes rather than GWAS, which focuses on common variants. One such study evaluated 33 genes among 257 families with a history of PTB, performed parametric and nonparametric analyses on 99 SNPs, and identified several rare variants within (1) the maternal genome, such as ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), insulin-like growth factor binding protein 3 (IGFBP3), 7-dehyrocholesterol reductase (DHCR7), and TNF receptor-associated factor 2 (TRAF2); and (2) the fetal genome, such as corticotropin-releasing-hormone receptor 1 (CRHR1) and cytochrome P450, family 2, subfamily E, poly-peptide 1 (CYP2E1), that were moderately associated with PTB. However, further DNA sequence analysis for CRHR1 and TRAF2 did not reveal any potential causative mutations or variants [130]
In another study using linkage analysis and the same set of Finnish families, two X-chromosomal linked genes were associated with PTB: (1) the androgen receptor (AR) located at Xq12, and (2) the IL-2 Receptor γ subunit (IL2RG) located at Xq13 [133]. A study within a Mexican-American population used linkage analysis on 1439 subjects to identify another PTB susceptibility linkage region on 18q21.33-q23 [134]. It is likely that the PTB syndrome, as with other multifactorial complex diseases, is caused by the combined effects of multiple genes and nongenetic environmental factors
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References

Human Reproductive and Prenatal Genetics https://doi.org/10.1016/B978-0-12-813570-9.00015-2
Many association studies have been conducted to identify the possible risk factors for PTB (both exogenous and endogenous), which include maternal, paternal, fetal, environmental, social, genetic, and hormonal factors (Fig. 15.1). Identification of risk factors aids in categorizing women into a priority group of “threatened preterm labor (PTL)” in order to provide them with risk-specific treatment in a timely manner. In addition, risk factor identification
Risk of PTB increases when the paternal age is greater than 45 years. A comparison between women aged 20–29 years with older partners versus younger ones showed a strong association of early PTB with advanced age of the father [25]. Similarly, increased association was identified between high paternal/maternal age difference and PTB when the comparison was made between older women with young partners versus average age/young couples. However, this association was found only in white women [26]. Importantly, regardless of maternal race, paternal black race was also associated with increased odds of PTB [27]. These studies suggest a paternal contribution to fetal/placental genotype that ultimately influences the risk of a preterm delivery.
Fetal sex is an important factor that has been associated with the incidence of PTB. Most studies that include fetal sex in the analysis (IVF studies) showed a strong association of male fetuses with PTB [28]. Multifetal pregnancy alone accounts for 10% of all PTB. Within this group, twins resulting from assisted reproductive technologies have shown to be at a higher risk of PTB compared to naturally conceived twins [29].
The association of heavy maternal alcohol consumption during pregnancy and various adverse birth outcomes has been well established [40]. A recent systematic review and meta-
The chemical composition of air pollution and tobacco smoke are quite similar and while tobacco use has established associations with PTB (as explained elsewhere in this chapter), air pollution becomes a likely risk factor for PTB. Air pollution has a role in modulating the epigenetic processes such as DNA methylation and histone modifications and is associated with inflammation. DNA methylation of CpG sites has been explored in various tissues from women who experience PTB (compared to the term controls), including the placenta, myometrium, and cervix; however, a direct link between DNA methylation and PTB has not been established. Importantly, a significant association between increased DNA methylation and infection has been unraveled, suggesting an indirect association of air pollution with PTB [53].
While there are no peer-reviewed reports of an association between domestic water fluoridation and an increased risk of PTB, some reports indicate that elevated fluoride levels in pregnant women may be linked to iron-deficiency anemia, which potentially might cause preterm delivery and low-birth weight infants, disruption of gut flora, thyroid disorders, preeclampsia, and placental and vascular calcification [54].
(2) Fetal cortisol augments the maturation of fetal lungs, which secrete surfactant proteins (SPs: SP-A, SP-D) [64] into the amniotic fluid via fetal breathing movements. The synthesis of SP-A by the fetal lung is initiated during late gestation and reaches its peak near parturition [65]. SP-A stimulates the synthesis of PGE in the human amnion [66] and inflammation that leads to the onset of labor.
(3) Fetal cortisol also induces the expression of COX2 in the placenta, resulting in the increased production of PGs [67], which boosts myometrial contractility. In addition, it was suggested that CRH can decrease progesterone synthesis, therefore inducing functional progesterone withdrawal and labor onset.
Despite the clear role for prostaglandins in the regulation of myometrial contractility, no polymorphisms in PG receptors (PTGER and PTGFR) or prostaglandin E synthase (PTGES) have been associated with PTB. Similarly, no associations with PTB were found for SNPs within genes encoding the β2-adrenergic receptor (ADRB2) and the dopamine receptor D2 (DRD2), which promote smooth muscle relaxation. Importantly, two SNPs—Flavobacterium okeanokoites (FokI, rs2228570 A > G) and Caudal Type Homeobox 2 (Cdx-2, rs11568820 T > C)—in the Vitamin D receptor (VDR) were associated with PTB in the Brazilian population. Both SNPs caused significant changes in VDR mRNA levels and in protein structure [118]. The importance of the polymorphisms is strengthened by the important role of the Vitamin D pathway in immune response modulation and the proven association of its deficiency with PTB [52].
Genome-wide association (GWAS) studies have been used to identify biomarkers for disease susceptibility, potential targets for therapeutics, or to provide information about the molecular mechanisms/pathways involved in disease pathology [121]. GWAS are based on a case-control design in which the whole genome is analyzed with hundreds of thousands of DNA markers in large nonrelated population cohorts presenting with a common phenotype. GWAS is considered to be a robust, unbiased, and hypothesis-free methodology; however, it is not problem free. For example, confounding can arise from population stratification when genetically heterogeneous populations are analyzed together without further adjustment, the need for large sample sizes to detect minor effect alleles, and inflated false-positive association rates arising from a thousand tests that are an integral part of any such study.
Family-based designs are more reliable in determining the genetic association of diseases because they increase the control over population-based heterogeneity, the power to detect associations, and to provide information on the effects of allele origin and transmission of the disease phenotype [131]. Linkage analysis is a technique to identify genetic effects and relies on the fact that, if family members affected by the disease share a specific area of a chromosome not shared by unaffected members, then the gene or genes predisposing to the disease is likely to be on or near that area.
Women carrying pathogenic mtDNA mutations (m.3243A > G mutation in the MT-TL1 gene causing MELAS syndrome) who have only mild mitochondrial disease manifestation themselves had a 25.3% incidence of PTB [141]. mtDNA mutations (A4917G, G10398A, and T4216C) in this population were analyzed for association between smoking (as a source of OS) and PTB; however, only marginal association of A4917G and T416C was found [142]. Lastly, a well-performed case-control association study of mtDNA variants was conducted using the DNBC cohort and a Finish-Norwegian cohort (MoBa) where mitochondrial SNPs were analyzed for their association with PTB. However, this study did not uncover any clear linkage between mitochondrial polymorphisms and PTB [143].


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