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Variants of certain haemostatic genes (such as that encoding factor V Leiden) are involved in the development of venous thrombosis, but studies of such variants in coronary disease have reported apparently conflicting results. We did meta-analyses on seven such haemostatic genetic variants for which the available evidence on each comprises at least 5000 coronary disease cases and at least 5000 controls. Meta-analyses were done of 191 studies in relation to factor V G1691A (ie, factor V Leiden), factor VII G10976A, prothrombin G20210A, plasminogen activator inhibitor-1 (PAI-1) [−675] 4G/5G, and three platelet glycoprotein (GP) receptor variants (GPIa C807T, GPIbα T[−5]C, GPIIIa C1565T), involving a total of 66 155 coronary disease cases and 91 307 controls. We explored potential sources of heterogeneity. In a combined analysis of all studies, the per-allele relative risks (RR) for coronary disease of factor V 1691A and of prothrombin 20210A were 1·17 (95% CI 1·08–1·28) and 1·31 (1·12–1·52), respectively. Combined analyses of studies of the PAI-1 [−675] 4G variant yielded a per-allele relative risk for coronary disease of 1·06 (1·02–1·10), but there was an indication of publication bias in these studies. Combined analyses of the factor VII 10976A, GPIa 807T, GPIbα [−5]C, and GPIIIa 1565T variants showed no significant overall associations with coronary disease, yielding per-allele RRs of 0·97 (0·91–1·04), 1·02 (0·97–1·08), 1·05 (0·96–1·13), and 1·03 (0·98–1·07), respectively. The 1691A variant of the factor V gene and the 20210A variant of the prothrombin gene, both of which increase circulating thrombin generation, might each be moderately associated with the risk of coronary disease. Further studies are merited to assess these associations in greater detail (including any gene–gene and gene–environment interactions) and to determine any implications with regard to potential therapies designed to reverse patients' prothrombotic phenotype, such as selective plasma factor V or factor Xa inhibition.

Although there have been suggestions that serum paraoxonase is important in protecting against coronary heart disease (CHD), a large number of studies of genetic determinants of serum paraoxonase have reported apparently conflicting results about their association with CHD. We conducted a meta-analysis of 43 studies of the Q192R, L55M, and T(–107)C polymorphisms in the paraoxonase PON1 gene and the S311C polymorphism in the PON2 gene (all of which are in moderately strong linkage disequilibrium with one another), involving a total of 11 212 CHD cases and 12786 controls. We explored potential sources of heterogeneity. In a combined analysis of all studies, the per-allele relative risk of R192 for CHD was 1·12 (95% CI 1·07–1·16), but in the five largest studies it was only 1·05 (0·98–1·13). Combined analyses of studies of the M55, (–107)T, and C311 variants showed no significant overall associations with CHD, yielding per-allele relative risks of 1·00 (0·95–1·06), 1·02 (0·92–1·14), and 1·04 (0·93–1·17), respectively. In contrast to previous suggestions, this meta-analysis shows no significant association of CHD with the L55M or T(–107)C polymorphism in PON1 or with the S311C polymorphism in PON2. The weak overall association between the Q192R polymorphism and CHD is of uncertain relevance, particularly since there was no significant association among the larger studies which should be less prone to selective publication. These findings reinforce the need for much larger and more rigorous investigations of the genetic determinants of complex diseases than is now customary, as well as for regularly updated systematic appraisals of such studies to help improve interpretation and prioritise hypotheses.

Congenital Heart Disease (CHD) affects approximately 7-9 children per 1000 live births. Numerous genetic studies have established a role for rare genomic variants at the copy number variation (CNV) and single nucleotide variant level. In particular, the role of de novo mutations (DNM) has been highlighted in syndromic and non-syndromic CHD. To identify novel haploinsufficient CHD disease genes we performed an integrative analysis of CNVs and DNMs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm (TAA). We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed mutation rate testing for DNMs identified in 2,489 parent-offspring trios. Our combined analysis revealed 21 genes which were significantly affected by rare genomic deletions and/or constrained non-synonymous de novo mutations in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in singletons and small cases series, or show new associations with CHD. In addition, a systems level analysis revealed shared contribution of CNV deletions and DNMs in CHD probands, affecting protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes.