This project aims to investigate the maternal and fetal genetic contributions to pre-eclampsia and pregancy complications, and will attempt to identify common HLA genetic variants from GWAS within ALSPAC.

Pre-eclampsia is a pregnancy-specific syndrome diagnosed by the accompanying increase in maternal blood pressure and proteinuria (Roberts and Cooper, 2001). The condition generally affects around 3-5% of pregnancies, though among women with complete obstetric data within ALSPAC , 2% had pre-eclampsia and 16% had gestational hypertension (Lawlor et al, 2011). In pre-eclampsia, endovascular invasion of the maternal spiral arteries by the cytotrophoblast is compromised and placental perfusion is weakened. It is believed that this decreased placental perfusion is in part the result of immunogenetic components of the mother and fetus.

The genetic constitution of mother and baby might be an important determinant of successful implantation and therefore pregnancy complications such as pre-eclampsia. Immune mechanisms are linked to the hypothesis that the maternal immune system is challenged by a genetically foreign fetus to different extents depending on the maternal and fetal genotypes.

According to Redman and Sargent (2010), maternal adaptation to fetal (paternal) alloantigens is crucial in the early stages of pregnancy. Observational studies support this idea and point to risk factors for pre-eclampsia such as primiparity, a short interval between first coitus and conception with the same partner, oocyte donation, artificial donor insemination and a change in partner, all of which may have an immunological basis (e.g. Dekker 2002; Dekker et al, 2011). Dekker et al (2011), predict that 35% of the variance in susceptibility to PE is attributable to maternal genetic effects; 20% to fetal genetic effects and 13% to the couple effect. Supporting this is the identification of paternal SNPs with associations with PE in the SCOPE consortium (http://www.scopestudy.net/default.aspx).

However, pre-eclampsia is proposed to be a two-step disorder, with the first step relating to poor endovascular invasion (placental pre-eclampsia) and the second relating to maternal constitutional factors that might increase sensitivity to placental ishaemia and increased oxidative stress (maternal pre-eclampsia). In this study, we are investigating the immunogenetic components of the mother and fetus in particular, and therefore will attempt to separate any common variants which relate to maternal constitution. This will be done by focusing in particular on the Human Leukocyte Antigen (HLA) system related to immunotolerance.

In terms of previous successes at identifying genetic loci predisposing to pre-eclampsia, numerous candidate gene studies and linkage studies have been performed, and various alleles have been identified, includes human leukocyte antigen variants. For example, pre-eclampsia is more frequent in women who are homozygous for inhibitory A haplotypes (AA) of KIR, especially if the fetus is homozygous for the HLA-C2 genotype (Hiby et al, 2004). However, there has been limited success at identifying common variants through GWAS studies, such as GOPEC (http://www.gopec.org/) and GENPE (http://www.genpe.org/). We propose that this limited success is due to the fact that only the maternal genome has been considered in these association studies, and we would like to investigate the contribution of both maternal and fetal genomes, and in particular the HLA variants.

Gestational hypertension may also be considered as an outcome in our search for HLA variants as it has been proposed that pre-eclampsia is at the upper range of a normal distribution in blood pressure and maternal vascular stress during pregnancy. Intra-uterine growth restrictuion and pre-term birth may also be associated with similar abnormal physiological changes during placentation, and therefore potentially to immunogenetic processes. In addition, inclusion of gestational hypertension, pre-term births and low birth weight would provide a higher sample size of cases for genotyping.

AIMS:

- To genotype and impute variants within the HLA region in both mothers and children in ALSPAC.

- To investigate associations between:

- Maternal HLA types and maternal phenotypes (pre-eclampsia, gestational hypertension)

- Maternal HLA types and child phenotypes (gestational age and birthweight)

- Child HLA types and maternal phenotypes (pre-eclampsia, gestational hypertension)

- Child HLA types and child phenotypes (gestational age and birthweight)

- HLA discordance between mother and child and maternal/child phenotypes (pre-eclampsia, gestational hypertension, gestational age, birthweight)

HYPOTHESES:

- The limited success of previous GWAS's investigating pre-eclampsia is due to the fact that only the maternal genome has been considered. This study will therefore investigate both the maternal and fetal HLA genotypes using HLA imputation of GWAS data in ALSPAC.

- Hypotheses to be considered during this task are:

- Specific maternal or child HLA variants are related to immuno-incompetence in pregnancy and the onset of pre-eclampsia and other pregnancy complications.

- The immune/immunogenetic maladaptation hypothesis (Dekker and, 1988)

- Parental sharing of human leukocyte antigens (HLA) may be associated with adverse pregnancy outcome (Ober, 1998)

-Mismatch of certain maternal and fetal HLA alleles may be associated with adverse pregnancy outcome.

EXPOSURE VARIABLES:

- HLA variants (those expressed by the trophoblast HLA-E and HLA-F, HLA-G and HLA-C; those not expression by the trophoblast e.g. HLA-A, HLA-B HLA-DR1/DR2, soluble class I antigens which may interact with HLA-G (Hvid et al, 2005) ) in mother and child.

OUTCOME VARIABLES:

- pre-eclampsia

- maternal hypertension

- pre-term birth

- low birth weight

CONFOUNDING VARIABLES:

No confounders, but potential mediators e.g. maternal BMI, previous history of hypertension and diabetes, parity, age of mother.

BIBLIOGRAPHY

Roberts, JM, Cooper, DW. Pathogenesis and genetics of pre-eclampsia. Lancet. 2001. 357:53-56.

Lawlor, DA, Macdonald-Wallis, C, Fraser, A, Nelson, SM., Hingorani, A, Davey Smith, G, Sattar, N and Deanfield, J (2012) Cardiovascular biomarkers and vascular function during childhood in the offspring of mothers with hypertensive disorders of pregnancy: findings from the Avon Longitudinal Study of Parents and Children. Eur. Heart J. 33, 335-345

Redman CW, Sargent IL. Immunology of pre-eclampsia. Am J Reprod Immunol. 2010;63:534 -543.

Dekker, G, 2002. The partner's role in the etiology of preeclampsia. J. Reprod. Immunol. 57, 203-215.

Dekker G, Robillard PY, Roberts C. The etiology of preeclampsia: the

role of the father. J Reprod Immunol. 2011;89(2):126-132.

Dekker, G, Robillard, PY, Hulsey, TC. Immune maladaptation in the etiology of preeclampsia: a review of corroborative epidemiologic studies. Obstet Gynecol Surv 1998. 53:377-382.

Ober, C, 1998. HLA and pregnancy: the paradox of the fetal allograft. Am. J. Hum. Genet. 62, 1-5.