Integrative studies implicate matrix metalloproteinase-12 as a culprit gene for large-artery atherosclerotic stroke.

BACKGROUND: Ischaemic stroke and coronary heart disease are important contributors to the global disease burden and share atherosclerosis as the main underlying cause. Recent evidence from a genome-wide association study (GWAS) suggested that single nucleotide polymorphisms (SNP) near the MMP12 gene at chromosome 11q22.3 were associated with large-vessel ischaemic stroke. Here, we evaluated and extended these results by examining the relationship between MMP12 and atherosclerosis in clinical and experimental studies. METHODS AND RESULTS: Plasma concentrations of MMP12 were measured at baseline in 3394 subjects with high-risk for cardiovascular disease (CVD) using the Olink ProSeek CVD I array. The plasma MMP12 concentration showed association with incident cardiovascular and cerebrovascular events (130 and 67 events, respectively, over 36 months) and carotid intima-media thickness progression (P = 3.6 × 10-5 ). A GWAS of plasma MMP12 concentrations revealed that SNPs rs499459, rs613084 and rs1892971 at chr11q22.3 were independently associated with plasma MMP12 (P < 5 × 10-8 ). The lead SNPs showed associations with mRNA levels of MMP12 and adjacent MMPs in atherosclerotic plaques. MMP12 transcriptomic and proteomic levels were strongly significantly increased in carotid plaques compared with control arterial tissue and in plaques from symptomatic versus asymptomatic patients. By combining immunohistochemistry and proximity ligation assay, we demonstrated that MMP12 localizes to CD68 + macrophages and interacts with elastin in plaques. MMP12 silencing in human THP-1-derived macrophages resulted in reduced macrophage migration. CONCLUSIONS: Our study supports the notion that MMP12 is implicated in large-artery atherosclerotic stroke, functionally by enhancing elastin degradation and macrophage invasion in plaques.

Is there a justification for differential a priori weighting in coding sequences? A case study from rbcL and Apocynaceae s.l.

Functional constraints are often assumed to influence the performance of nucleotide characters in phylogenetic analysis: First and second codon positions and sites of structural importance are considered to show less homoplasy. We investigate the performance of rbcL characters with differential functional constraints in a cladistic analysis of the plant family Apocynaceae s.l. (Sennblad and Bremer, in prep.). Performance is measured as rescaled consistency indices (rc). We show there is no significant difference in performance between parsimony-informative sites constrained by function in the enzyme, and sites that are not. Furthermore, the substitutions in third-codon position performed significantly better than those in first and second. The variation of rc within the different classes was high, however. Consequently, there is no support for routinely applied a priori differential weighting, neither of codon positions, nor of different functional classes from the present analysis of rbcL data in the Apocynaceae s.l.

Morphology and molecular data in phylogenetic fraternity: the tribe Wrightieae (Apocynaceae) revisited.

The monophyly and classification of the tribe Wrightieae of the subfarnily Apocynoideae (Apocynaceae) are cladistically investigated. Nine taxa from the Wrightieae sensu Leeuwenberg, nine from other Apocynoideae sensu lato (s.I., including two from the traditional Asclepiadaceae), and two outgroup taxa from the Plumerioideae (Apocynaceae) were scored for rcbL sequence data and morphological data, mainly floral characters, and analyzed using successive weighting parsimony analysis. The Wrightieae sensu Leeuwenberg are shown to be largely paraphyletic, the constituent taxa being dispersed among four monophyletic clades. Previously not suggested relationships indicated by the study are the association of Pachypodium with Funtumia, Holarrhena, and Mascarenhasia and the position of Beaumontia close to Trachelospermum. A reclassification of the Wrightieae is discussed, in which three of the identified clades are recognized as tribes, the Wrightieae sensu stricto (s.s.), the Nerieae, and the Malouetieae. The support for the Wrightieae s.s. is very strong, as evaluated with Bremer support and bootstrap analysis. The Malouetieae are also strongly supported, but the Nerieae less so. Using Potential morphological synapomorphies identified in the study, circumscription of the tribes is discussed. A potential pseudogene of rcbL is reported tot Beaumontia.