title: Investigation of genetic risk factors for chronic adult diseases for association with preterm birth.
abstract: Preterm birth (PTB) is the leading cause of infant mortality. PTB pathophysiology overlaps with those of adult cardiovascular, immune and metabolic disorders (CIMD), with mechanisms including inflammation, immunotolerance, thrombosis, and nutrient metabolism. Whereas many genetic factors for CIMD have been identified, progress in PTB has lagged. We hypothesized that highly validated genetic risk factors for CIMD may also be associated with PTB. We conducted case-control study of four female cohorts with spontaneous PTB (n = 673) versus term (n = 1119). Of 35 SNPs genotyped, there were 13 statistically significant associations (P < 0.05), which were more than expected (binomial test; P = 0.02). In US White (307 cases/342 controls), the G allele of HLA-DQA1 (A/G) rs9272346 was protective for PTB in the initial discovery cohort (P = 0.02; OR = 0.65; 95 % CI 0.46, 0.94). This protective association replicated (P = 0.02; OR = 0.85; 95 % CI 0.75, 0.97) nominally in the Danish Cohort (883 cases, 959 controls), but lost significance upon multiple testing correction. We observed more statistically significant associations than expected, suggesting that chance is an unlikely explanation for one or more of the associations. Particularly, a protective association of the G allele of HLA-DQA1 was found in two independent cohorts, and in previous studies, this same allele was found to protect against type-1-diabetes (meta-analysis P value 5.52 × 10(-219)). Previous investigations have implicated HLA phenotypic variation in recurrent fetal loss and in chronic chorioamnionitis. Given the limited sample size in his study, we suggest larger studies to further investigate possible HLA genetic involvement in PTB.
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, USA. falahnadia@gmail.com
authors.forename: Nadia
authors.initials: N
authors.lastname: Falah
authors.forename: Jude
authors.initials: J
authors.lastname: McElroy
authors.forename: Victoria
authors.initials: V
authors.lastname: Snegovskikh
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Lockwood
authors.forename: Errol
authors.initials: E
authors.lastname: Norwitz
authors.forename: Jeffey C
authors.initials: JC
authors.lastname: Murray
authors.forename: Edward
authors.initials: E
authors.lastname: Kuczynski
authors.forename: Ramkumar
authors.initials: R
authors.lastname: Menon
authors.forename: Kari
authors.initials: K
authors.lastname: Teramo
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Muglia
authors.forename: Thomas
authors.initials: T
authors.lastname: Morgan
mesh_terms: D000328:Adult; D002318:Cardiovascular Diseases / Q000150:complications / Q000235:genetics; D016022:Case-Control Studies; D002908:Chronic Disease; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007154:Immune System Diseases / Q000150:complications / Q000235:genetics; D007231:Infant, Newborn; D008659:Metabolic Diseases / Q000150:complications / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D047928:Premature Birth / Q000235:genetics*; D012307:Risk Factors