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Investigation of genetic risk factors for chronic adult diseases for association with preterm birth

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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.

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Abbreviations

PTB:

Preterm birth

CIMD:

Chronic inflammatory metabolic disease

GWAS:

Genome-wide association study

US White:

United States White

US Black:

United States Black

US Hispanic:

United States Hispanic

SNPs:

Single nucleotide polymorphisms

OR:

Odds ratio

CI:

Confidence interval

HWE:

Hardy–Weinberg equilibrium

CEU population:

Commissions of the European Union population

DNBC:

Danish National Birth Cohorts

PPROM:

Preterm premature rupture of membrane

NHGRI:

National Human Genome Research Institute

MHC/HLA:

Major histocompatibility complex/human leukocyte antigen

MOD:

March of Dimes

FY:

Fiscal year

dbGaP:

The database of Genotypes and Phenotypes

DNA:

Deoxyribonucleic acid

N :

Sample size

HIV:

Human immunodeficiency virus

P :

Probability

MALDI-TOF:

Matrix-assisted laser desorption/ionization-time of flight

PS:

Power and sample size calculation

rs#:

Reference SNP ID

MAF:

Minor allele frequencies

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Acknowledgments

Turner-Hazinski grant award; March of Dimes; Cara Sutcliffe and Rachel Wiseman in the DNA Resources Core at Vanderbilt University Medical Center for their assistance with genotyping. Funding support for the GWAS of Prematurity and its Complications study was provided through the NIH Genes, Environment and Health Initiative [GEI] (U01HG004423). The GWAS of Prematurity and its Complications study is one of the genome-wide association studies funded as part of the Gene Environment Association Studies (GENEVA) under GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438) and the NIH contract “High throughput genotyping for studying the genetic contributions to human disease” (HHSN268200782096C). The datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap through dbGaP accession number phs000103.v1.p1.

Conflict of interest

The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, USA

    Nadia Falah, Jude McElroy, Louis J. Muglia & Thomas Morgan

  2. Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT, USA

    Victoria Snegovskikh, Charles J. Lockwood & Errol Norwitz

  3. Department of Pediatrics, University of Iowa, Iowa City, IA, USA

    Jeffey C. Murray

  4. Biology and Biochemistry Department, University of Houston, Houston, TX, USA

    Edward Kuczynski

  5. Department of Obstetrics and Gynecology, University of Texas, Galveston, TX, USA

    Ramkumar Menon

  6. Department of Obstetrics and Gynecology, University Central Hospital, Helsinki, Finland

    Kari Teramo

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  1. Nadia Falah
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  2. Jude McElroy
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  3. Victoria Snegovskikh
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  4. Charles J. Lockwood
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  5. Errol Norwitz
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  6. Jeffey C. Murray
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  7. Edward Kuczynski
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  8. Ramkumar Menon
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  9. Kari Teramo
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  10. Louis J. Muglia
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  11. Thomas Morgan
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Corresponding author

Correspondence to Nadia Falah.

Additional information

N. Falah and J. McElroy contributed equally.

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Falah, N., McElroy, J., Snegovskikh, V. et al. Investigation of genetic risk factors for chronic adult diseases for association with preterm birth. Hum Genet 132, 57–67 (2013). https://doi.org/10.1007/s00439-012-1223-x

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