Human Molecular Genetics Advance Access originally published online on February 19, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 7 683-691
DOI: 10.1093/hmg/ddh091
A candidate gene association study on preterm delivery: application of high-throughput genotyping technology and advanced statistical methods
1Program for Population Genetics, Harvard School of Public Health, Boston, MA, USA, 2Department of Pediatrics, Boston University Medical Center, Boston, MA and the Mary Ann and J. Milburn Smith Child Health Research Program, Children's Memorial Hospital, Chicago, IL, USA, 3Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA and 4Department of Biostatistics, Harvard School of Public Health, Boston, MA USA
Received November 12, 2003; Accepted February 4, 2004
Preterm delivery (PTD) is the leading cause of infant mortality and morbidity worldwide. The etiology of PTD is largely unknown but is believed to be complex, encompassing multiple genetic and environmental determinants. To date, reports of genetic studies on PTD are sparse. We conducted a large-scale case–control study exploring the associations of 426 single-nucleotide polymorphisms with PTD in 300 mothers with PTD and 458 mothers with term deliveries at the Boston Medical Center. Twenty-five candidate genes were included in the final haplotype analysis, and a significant association of F5 gene haplotype with PTD was revealed and remained significant after Bonferroni correction for multiple testing (P=0.025). We applied different statistical algorithms (both Gibbs sampling and expectation-maximization) in reconstructing haplotype phases and different tests (both likelihood ratio test and permutation test) in association analyses, and all yielded similar results. We also performed exploratory ethnicity-specific analyses, which confirmed the consistent findings of the F5 gene across the ethnic groups. Moreover, IL1R2 (P=0.002 in Blacks), NOS2A (P<0.001 in Whites) and OPRM1 (P=0.004 in Hispanics) gene haplotypes were associated with PTD in specific ethnic groups but not at global significance level. In summary, our results underscore the potentially important role of F5 gene variants in the pathogenesis of PTD, and demonstrate the utility of high-throughput genotyping and a haplotype-based approach in dissecting genetic basis of complex traits.
* To whom correspondence should be addressed at: Program for Population Genetics, Harvard School of Public Health, 665 Huntington Avenue FXB101, Boston, MA 02115, USA. Email: xu{at}hsph.harvard.edu
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