Genetics of recurrent miscarriage

Only few studies have focused on the occurence of RM among relatives of women with RM. As summarized, the first-degree blood relatives of affected fe-males have 2–7 fold increased risk of miscarriage compared to controls (Christiansen 1996).

The molecular genetic studies on RM have addressed both the aberrant ex-pression of functional candidate genes at materno-fetal interface, and the

poly-morphisms of the genes in the physiological pathway involved in pathogenesis of pregnancy loss.

Thrombophilia-related genes

Mutations in several genes have been found to be related with adverse preg-nancy outcomes: factor V (Leiden factor) G1691A, H1299R, Y1702C, factor II prothrombin G20210A, factor XIII V34L, β-fibrinogen (-455G>A), plasmi-nogen activator inhibitor-I 4G/5G, human platelet antigen 1 a/b(L33P, MTHFR C677T, A1298C (Goodman et al. 2006). Leiden factor G1691A mutation and prothrombin G20210A increase the risk of RM before 13 gestational weeks at least by two fold (Rey et al. 2003; Rai and Regan 2006). Although elevated plasma homocysteine concentration has been suggested as a risk factor for RM, two meta-analyses focusing on the polymorphism C667T in MTHFR gene reducing the enzyme activity have given controversial results (Nelen et al. 2000;

Ren and Wang 2006).

Immune response related genes

Since the conceptus produces the gene products originated from both parents, the immunological mechanisms responsible for the development of the tole-rance to semiallogenic fetal “graft” by the maternal immune system is the most attractive target for genetic studies.

The expression of HLA-G, the most dominant HLA antigen in blastocysts and/or trophoblastic tissue, has been shown to be different in successful and failed pregnancies in some studies (Hviid 2006). 14 bp deletion/insertion polymorphism in exon 8 of the 3’UTR in HLA-G is related to decreased expres-sion of the molecule. In contrary a “G” nucleotide at position -725 in promoter area of HLA-G increases the expression of HLA-G (Ober et al. 2003; Hviid et al. 2004). Both polymorphisms have been associated with the increased risk for RM (Hviid 2006), thus the expression level of the molecule has an ambiguous effect on reproductive success. The polymorphisms G*010103, G*0105N, G*010401 in HLA-G as well some variants of the other non-classical in HLA class Ib genes, HLA-E, C and F have been found to be related to RM with controversial effect (Hviid 2006; Tripathi et al. 2006; Kano et al. 2007; Hiby et al. 2008). In normal gestation, the HLA II class antigens located on maternal antigen-presenting cells should not recognize the trophoblastic tissue and present the trophoblast-derived peptides to maternal autoreactive T cells. Some HLA II class antigens, e.g. HLA-DRB1*03 tend to contribute to the patho-genesis of RM by presenting the fetal antigens to mother and/or enhancing the embryotoxic effect of several molecules (Kruse et al. 2004).

The aberrations in cytokine and chemokine levels have been shown both in maternal and fetal tissues and biological fluids during pathological pregnancies in multiple studies (Lim et al. 1996; Salamonsen et al. 2007; Whitcomb et al.

2007) but the underlying polymorphisms that lead to increased or decreased expression of a cytokine are still addressed in limited number of experiments.

Adhesion and angiogenesis related genes

Matrix metalloproteinase-2 (MMP-2), plasminogen activator inhibitor (PAI), integrin, TGF-β, VEGF, basic fibroblast growth factor (bFGF) and mucin 1 have been shown to have a decreased expression level in chorionic villi from RM patients compared to those from normal controls (Baek et al. 2002; Choi et al. 2003).

The polymorphisms in most of the angiogenesis-related genes that have been demonstrated to be associated with the implantation failure and poor pregnancy outcome are also important in several other pathologies: benign and malignant tumors, coronary artery disease, cerebro-vascular diseases, asthma, etc.

Apoptosis-related genes

The expression of several apoptosis-related genes: caspase 3, 6, 7, 8, 9, 10, 12, BAD, BAX, BID, Fas, and FasL, has increased in trophoblastic tissue from RM patients compared to normal controls (Choi et al. 2003). The most targeted apoptosis related genes are also involved in multiple physiological and pathological processes. For example, p53 tumor suppressor gene polymorphism resulting in substitution of arginine with proline at codon 72 in exon 4 is related to poor prognosis of cancers (Boldrini et al. 2008), development of neurodegenera-tive and cardiovascular diseases, etc (Mercer et al. 2007; Zhang et al. 2007), but it is also been associated with increased longevity (Orsted et al. 2007).

Oxidative stress-related genes

The absence or null genotype of glutathione S-transferases M1 gene, one of the GST family (class mu) members that is a potent antioxidant, has been demonstrated to be a risk factor of several diseases. The patients with RM carry the null genotype of glutathione S-transferase M1 gene more frequently compared to fertile women (Sata et al. 2003). The absence of the gene increases the risk for RM more than 2-fold (Sata et al. 2003).

Candidate genes from animal models

One way to identify new genes associated with RM is to studygenes required for the development of mice. A homozygous insertion mutationin Amnionless gene and the polymorphism in codon 511 of the aryl hydrocarbon receptor nuclear translocator gene cause the fetal loss in mice. In humans, the Amnionless gene is needed for absorption of cobalamin. Aryl hydrocarbon receptor-associated protein 9 acts as a chaperone involved in intracellular signal transmission. Despite the high similarity between the respective mouse and human genes, the association of studied polymorphisms with RM was not found (Kaare et al. 2006; Sullivan et al. 2006).

In summary, most of the studied candidate genes are involved in several physio-logical processes: inflammation, immunotolerance, apoptosis, tissue remodeling, regulation of vascular tone and metabolism. The polymorphisms in these genes are associated with different complex diseases and their contribution for patho-genesis of RM is not specific. The placental proteins coded by the fetal genome certainly have a direct influence on pregnancy success and would be suitable candidates for genetic studies of RM. However, the number of genetic studies focusing on the pregnancy-specific placentally expressed genes is still limited.