AUTHOR=Zheng Xiaojing , Feingold Eleanor , Ryckman Kelli K., Shaffer John R., Boyd Heather A., Feenstra Bjarke , Melbye Mads , Marazita Mary L., Murray Jeffrey C., T.Cuenco Karen 

TITLE=Association of maternal CNVs in GSTT1/GSTT2 with smoking, preterm delivery, and low birth weight

JOURNAL=Frontiers in Genetics

VOLUME=4

YEAR=2013

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2013.00196

DOI=10.3389/fgene.2013.00196

ISSN=1664-8021

ABSTRACT=<p>Preterm delivery (PTD) is an adverse birth outcome associated with increased infant mortality and negative lifelong health consequences. PTD may be the result of interactions between genetics and maternal/fetal environmental factors including smoking exposure (SMK). A common deletion in the <italic>GSTT1</italic> gene was previously reported to affect birth outcomes in smokers. In this study, we dissect the associations among SMK, birth outcomes, and copy number variations (CNVs) in the <italic>GSTT1</italic>/<italic>GSTT2</italic> region. A preterm birth case-control dataset of 1937 mothers was part of the GENEVA preterm birth study, which included genome-wide genotyping used to identify CNVs. We examined the association of SMK with birth outcomes, detected CNVs within the <italic>GSTT1/GSTT2</italic> region using PennCNV, and examined associations of the identified CNVs with preterm birth and with birth weight (BW) in full term birth controls, including interactions with SMK. Finally, we tested the association of CNVs in <italic>GSTT1/GSTT2</italic> with SMK. We confirmed the association of smoking with low BW and PTD. We identified 2 CNVs in <italic>GSTT2</italic> (<italic>GSTT2</italic><sup><italic>a</italic></sup> and <italic>GSTT2</italic><sup><italic>b</italic></sup>), 1 CNV in <italic>GSTTP1</italic> and 2 CNVs in GSTT1 (<italic>GSTT1</italic><sup><italic>a</italic></sup> and <italic>GSTT1</italic><sup><italic>b</italic></sup>). The <italic>GSTT2</italic><sup><italic>a</italic></sup> deletion was associated with reduced BW (−284 g, <italic>p</italic> = 2.50E-7) in smokers, and was more common in smokers [odds ratio(OR) = 1.30, <italic>p</italic> = 0.04]. We found that the size of the reported common deletion CNV in <italic>GSTT1</italic> was larger than previously shown. The <italic>GSTTP1</italic> and <italic>GSTT1</italic><sup><italic>b</italic></sup> null genotypes were in high linkage disequilibrium (LD) (<italic>D</italic>′ = 0.89) and less common in smokers (OR = 0.68, <italic>p</italic> = 0.019 and OR = 0.73, <italic>p</italic> = 0.055, respectively). These two deletions were in partial LD with <italic>GSTT2</italic><sup><italic>a</italic></sup> and <italic>GSTT2</italic><sup><italic>b</italic></sup> duplications. All 5 CNVs seem to be associated with increased risk of preterm birth before 35 completed weeks. CNVs in the <italic>GSTTT1</italic>/<italic>GSTT2</italic> region appear associated with low BW and PTD outcomes, but LD complicated these CNVs in <italic>GSTT1</italic>/<italic>GSTT2</italic>. In genetic association studies of BW, multiple CNVs in this region need to be investigated instead of a single polymorphism.</p>