Candidate gene analysis of spontaneous preterm delivery: new insights from re-analysis of a case-control study using case-parent triads and control-mother dyads.
BACKGROUND
Spontaneous preterm delivery (PTD) has a multifactorial etiology with evidence of a genetic contribution to its pathogenesis. A number of candidate gene case-control studies have been performed on spontaneous PTD, but the results have been inconsistent, and do not fully assess the role of how two genotypes can impact outcome. To elucidate this latter point we re-analyzed data from a previously published case-control candidate gene study, using a case-parent triad design and a hybrid design combining case-parent triads and control-mother dyads. These methods offer a robust approach to genetic association studies for PTD compared to traditional case-control designs.


METHODS
The study participants were obtained from the Norwegian Mother and Child Cohort Study (MoBa). A total of 196 case triads and 211 control dyads were selected for the analysis. A case-parent triad design as well as a hybrid design was used to analyze 1,326 SNPs from 159 candidate genes. We compared our results to those from a previous case-control study on the same samples. Haplotypes were analyzed using a sliding window of three SNPs and a pathway analysis was performed to gain biological insight into the pathophysiology of preterm delivery.


RESULTS
The most consistent significant fetal gene across all analyses was COL5A2. The functionally similar COL5A1 was significant when combining fetal and maternal genotypes. PON1 was significant with analytical approaches for single locus association of fetal genes alone, but was possibly confounded by maternal effects. Focal adhesion (hsa04510), Cell Communication (hsa01430) and ECM receptor interaction (hsa04512) were the most constant significant pathways.


CONCLUSIONS
This study suggests a fetal association of COL5A2 and a combined fetal-maternal association of COL5A1 with spontaneous PTD. In addition, the pathway analysis implied interactions of genes affecting cell communication and extracellular matrix.
Department of Genes and Environment, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway. solveig.myking@fhi.no
Solveig
S
Myking
Ronny
R
Myhre
Håkon K
HK
Gjessing
Nils-Halvdan
NH
Morken
Verena
V
Sengpiel
Scott M
SM
Williams
Kelli K
KK
Ryckman
Per
P
Magnus
Bo
B
Jacobsson
D000328:Adult; D016022:Case-Control Studies; D015331:Cohort Studies; D024062:Collagen Type V / Q000235:genetics*; D003627:Data Interpretation, Statistical; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D008297:Male; D008875:Middle Aged; D009664:Norway; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D047928:Premature Birth / Q000235:genetics*; D055815:Young Adult
C530725:COL5A1 protein, human; D024062:Collagen Type V