Parent-of-origin transmission of thrombophilic alleles to intrauterine growth-restricted newborns and transmission-ratio distortion in unaffected newborns

Findings on the role of thrombophilic polymorphisms in adverse pregnancy outcomes, particularly intrauterine growth restriction, are inconsistent. Such inconsistencies may be partly due to two types of effects which have not been considered before with regard to thrombophilic genes: parent-of-origin effects (imprinting) and transmission-ratio distortion effects (allele transmission differing from that expected in unaffected subjects). In this study of infants born at a Canadian hospital (1998-2000), the authors investigated both types of effects. Cases (n = 493) were defined as newborns whose birth weight for gestational age and sex was below the 10th percentile by national standards, and controls (n = 472) as newborns at or above the 10th percentile. Log-linear models were used to analyze the transmission of variant alleles among case- and control-parent trios. A single copy of a common polymorphism, Val34Leu in factor XIII, increased the risk of intrauterine growth restriction approximately 70% when the parent of origin was the father as opposed to the mother (p < 0.05). Among unaffected newborns, transmission of A1298C in the methylenetetrahydrofolate reductase gene (p < 0.005), transmission of the G1691A variant in factor V Leiden (p < 0.002), and transmission of the G20210A variant in the prothrombin (factor II) gene (p < 0.001) occurred significantly less often than expected (transmission-ratio distortion). Affected newborns also inherited the prothrombin G20210A variant significantly less often than expected. These results suggest that these three genes exhibit segregation distortion or reduce gestational survival.