mutation in the β₂-adrenergic receptor, the predominant β-adrenergic receptor subtype that relaxes myometrial muscle fibers at term (Liu et al., 1998), changed the amino acid glutamic acid to glutamine at codon 27 and is associated with preterm labor.

Investigators generally agree that the “one gene, one risk factor” approach to understanding the etiology of complex human diseases will not likely yield great progress in understanding the causes of human diseases and syndromes, and as mentioned earlier in this report, preterm birth is increasingly recognized as a syndrome with multiple etiologies. Therefore, because of the heterogeneous nature of preterm birth, it is necessary to study a large number of candidate genes to better understand genetic influences on preterm birth. However, the numbers of published studies of this kind are limited. One study simultaneously investigated the relationships of polymorphisms in six cytokine genes associated with inflammation (IL-1α, IL-1β, IL-2, IL-6, TNF-α, and lymphotoxin alpha [LTA]) with spontaneous preterm birth and the birth of infants who are small for gestational age in a nested case-control study with women from a prospective pregnancy cohort (Engel et al., 2005a). Two haplotypes spanning the TNF-α and LTA-α genes were associated with an increased risk for spontaneous preterm birth in white subjects (for the AGG haplotype, odds ratio [OR] 1.5; 95% confidence interval [CI] 0.8–2.6; for the GAC haplotype, OR 1.6; 95% CI 0.9– 2.9). Additionally, carriers of the GAG haplotype were found to have a decreased risk of spontaneous preterm birth (OR 0.6; 95% CI 0.3–1.0). The TNF-α and LTA variants TNF-α(–488)A and LTA(IVS1-82)C, constituents of the AGG and GAC haplotypes, respectively, were also strongly associated with an increased risk of spontaneous preterm birth.

A large-scale case-control study explored the associations of 426 SNPs with preterm birth in 300 mothers with preterm deliveries (cases) and 458 mothers with term deliveries (controls) (Hao et al., 2004). Twenty-five candidate genes were included in the final haplotype analysis, and a significant association of the Factor V (F5) gene haplotype with preterm birth was revealed and remained significant after Bonferroni correction for multiple testing (p = 0.025). That study also performed exploratory ethnicity-specific analyses, which confirmed the findings that the association of the F5 gene haplotype with preterm birth is consistent across ethnic groups.

Until now, the discovery of genes found to be associated with preterm birth has been limited to studies of candidate genes. Although it is not possible for this report to cover all candidate genes, a list of potential candidate genes affecting preterm birth is provided in Table 7-1. On the other hand, the availability of SNP gene microarrays and high-throughput genotyping