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Genetic susceptibility to intrauterine survival

Presented at the Neonatal Society 2003 Summer Meeting (programme).

Hanchard N, Herbert M, Kwiatkowski D (introduced by Prof. Andrew Wilkinson)

Department of Paediatrics, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK

Introduction: Approximately 70% of conceptuses are non-viable, and the mechanisms of early intrauterine non-viability are poorly understood. Intrauterine survival may be influenced by genetic selection against unfavourable alleles, and can be studied through analysis of Single Nucleotide Polymorphisms (SNPs)1. Alleles that make the fetus or embryo susceptible to rejection may bias the genetic complement of newborn healthy babies, and this may be reflected in non-Mendelian inheritance patterns referred to as Transmission Distortion. SNPs within and adjacent to inflammatory genes may, in part, define the cytokine responsiveness of the fetus. The MHC class III region is composed of numerous inflammatory genes that may influence in-utero survival.

Methods: 258 family trio DNA samples were obtained with parental consent (derived from parental venous blood, and baby cord blood; OxREC C01.059, C01.241). SNPs were typed using MALDI-TOF mass spectrometry and Transmission Distortion assessed through the Transmission Disequilibrium Test (TDT) using the ASPEX software package.

Results: We genotyped 774 individuals from 258 singleton families and utilized transmissions from heterozygous parents to test for distortion at each SNP (TNF-308 = 148 heterozygote parents; LTA+7 = 188; NFKB-63 = 198; CLIC-2230 = 66). No significant transmission distortion was detected at TNF-308, LTA+7 and NFKB-63 suggesting a limited role for immune rejection in survival in-utero. The CLIC1-2230 allele was found to have a minor allele (CLIC-2230*2) frequency of 10% and a 3.7% genotyping failure rate. The gene showed transmission distortion (42 of 66 transmissions; p=0.04) in favour of the major allele (CLIC-2230*1). This implicates the CLIC1 gene in survival in-utero, either as a direct action of an unfavourable CLIC1 SNP or through linkage with another nearby allele.

Conclusion: Our initial studies indicate that immune mechanisms may have a relatively small role to play in determining the fate of the in-utero baby. Examining the degree to which individual candidate genes exhibit Transmission Distortion is a method of defining the relevance of each gene to early uterine survival. We demonstrate an emerging role for human genetic susceptibility studies in the area of prenatal medicine.

1. Westendorp RG, van Dunne FM, Kirkwood TB, Helmerhorst FM and Huizinga TW. Nat Med 2001;7:873

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