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Pre-eclampsia and its related syndromes are significant causes of maternal and fetal death, but much remains unclear about the underlying disease mechanisms. Epidemiological research has consistently demonstrated a familial predisposition to pre-eclampsia, which has encouraged genetic research in this area. The goal is the discovery of susceptibility genes which will inform understanding of the pathophysiology of pre-eclampsia, and may prove to be targets for therapeutic or preventative strategies. This review examines the application of molecular technologies to the search for genetic clues in pre-eclampsia and emphasizes the importance of integrative approaches. The results of recent genome-wide linkage studies have been particularly encouraging, identifying a number of loci which merit closer examination. Candidate gene studies have proved less fruitful, generating conflicting and inconclusive results. Possible explanations and remedies for this deficiency are discussed with a view to stimulating closer collaboration between researchers in this field.

BackgroundGenetic factors play a role in chronic obstructive pulmonary disease (COPD) but are poorly understood. A number of candidate genes have been proposed on the basis of the pathogenesis of COPD. These include the matrix metalloproteinase (MMP) genes which play a role in tissue remodelling and fit in with the protease - antiprotease imbalance theory for the cause of COPD. Previous genetic studies of MMPs in COPD have had inadequate coverage of the genes, and have reported conflicting associations of both single nucleotide polymorphisms (SNPs) and SNP haplotypes, plausibly due to under-powered studies.MethodsTo address these issues we genotyped 26 SNPs, providing comprehensive coverage of reported SNP variation, in MMPs- 1, 9 and 12 from 977 COPD patients and 876 non-diseased smokers of European descent and evaluated their association with disease singly and in haplotype combinations. We used logistic regression to adjust for age, gender, centre and smoking history.ResultsHaplotypes of two SNPs in MMP-12 (rs652438 and rs2276109), showed an association with severe/very severe disease, corresponding to GOLD Stages III and IV.ConclusionsThose with the common A-A haplotype for these two SNPs were at greater risk of developing severe/very severe disease (p = 0.0039) while possession of the minor G variants at either SNP locus had a protective effect (adjusted odds ratio of 0.76; 95% CI 0.61 - 0.94). The A-A haplotype was also associated with significantly lower predicted FEV1 (42.62% versus 44.79%; p = 0.0129). This implicates haplotypes of MMP-12 as modifiers of disease severity.

The results support the concept of a regulatory role for MIF in CF.