Genetic Variant Raises Risk of Prematurity in African- American Babies

RICHMOND, Va., Aug. 28 -- A single genetic variation may help explain why African Americans women have a higher risk of having premies because of early rupture of the amniotic membrane.

Presence of the genotype, called -the SERPINH1 gene -656 minor T allele, significantly raised the risk of preterm, premature rupture, (PPROM) particularly in African American women, reported Jerome F. Strauss III, M.D., Ph.D., of the Virginia Commonwealth University, and colleagues, in the Proceedings of the National Academy of Sciences.

Preterm birth is known to be two to three times more common in African American than European-American women, but socioeconomic status and access to health care do not fully explain the difference, the authors said.

When Dr. Strauss's group looked at ethnic distribution in more than 900 participants with ancestry from around the world, they found the T allele was significantly more common in African-American individuals compared with European-Americans (12.4% versus 4.1%, P<0.024).

PPROM is the leading identifiable cause of preterm birth and occurs in about 3% of all pregnancies and one-third of all preterm births. Knowledge of this genotype --could be used to identify women who might benefit from therapeutic interventions, such as lifestyle change or medical therapy before onset of preterm labor, the investigators wrote.

Dr. Strauss and colleagues found that the T allele of the gene, which is less common than the C allele, reduces production of a protein essential for collagen synthesis in the amnion fibroblasts therefore reducing the strength of the amnion membrane and making it more prone to rupture early in the pregnancy.

Two case-control studies by the investigators also found association of the genetic variant with preterm birth due to rupture of the amniotic membrane.

In the first, the T allele was found in 11.51% of 152 African American babies who were born prematurely due to complications involving rupture of the amniotic membrane compared to 4.05% of 174 controls born at term in normal pregnancies (P<0.0009). Furthermore, C/T allele heterozygotes were 2.68 times more likely to experience premature birth for this reason than C/C homozygotes while T/T allele homozygotes had an even greater risk (odds ratios 2.68 compared to C/T allele heterozygotes).

Likewise, the second case-control study on a separate sample of 92 premature rupture cases and 194 controls again showed a significant association between preterm, premature birth due to amniotic rupture and presence of the T allele (P<0.0076) even controlling for differences in ancestry using 29 ancestry-informative markers.

In vitro and animal tests also indicated that the T allele reduced transcription of the SERPINH1 gene compared with the C allele.

Interestingly, while the genetic variant decreased collagen in amniotic fibroblasts compared with the C allele, in vitro tests showed that it had "higher activity" in skin fibroblasts and uterine smooth muscle cells.

"Because both keloids, a fibrotic response in skin, and uterine fibroid tumors, which have a dense collagen matrix, are more prevalent in African Americans, it is intriguing to speculate that a single SNP could contribute to multiple phenotypes," Dr. Strauss and colleagues wrote.

In a related commentary, Jeremy F. Taylor, Ph.D., of the University of Missouri in Colombia, and colleagues said the study provided compelling evidence for "the first ancestry-informative mutation responsible for an increased risk of preterm premature rupture of membranes" in African-Americans.

They cautioned that the study does not answer whether the presence of the T allele is associated with increased risk of premature amniotic rupture in European-Americans.