ObjectiveTo explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts.MethodsWe performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI.ResultsThe mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10−8; and LINC00539/ZDHHC20, p = 5.82 × 10−9. Both have been associated with blood pressure (BP)–related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p[BI] = 9.38 × 10−25; p[SSBI] = 5.23 × 10−14 for hypertension), smoking (p[BI] = 4.4 × 10−10; p[SSBI] = 1.2 × 10−4), diabetes (p[BI] = 1.7 × 10−8; p[SSBI] = 2.8 × 10−3), previous cardiovascular disease (p[BI] = 1.0 × 10−18; p[SSBI] = 2.3 × 10−7), stroke (p[BI] = 3.9 × 10−69; p[SSBI] = 3.2 × 10−24), and MRI-defined white matter hyperintensity burden (p[BI] = 1.43 × 10−157; p[SSBI] = 3.16 × 10−106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy.ConclusionIn this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.

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Cathepsins are powerful proteases, once referred to as the lysosomal cysteine proteases, that have been implicated in breast cancer invasion and metastasis, but pharmaceutical inhibitors have suffered failures in clinical trials due to adverse side effects. Scientific advancement from lysosomotropic to cell impermeable cathepsin inhibitors have improved efficacy in treating disease, but off-target effects have still been problematic, motivating a need to better understand cellular feedback and responses to treatment with cathepsin inhibitors. To address this need, we investigated effects of E-64 and cystatin C, two broad spectrum cathepsin inhibitors, on cathepsin levels intra- and extracellularly in MDA-MB-231 breast cancer cells. Cathepsins S and L had opposing responses to both E-64 and cystatin C inhibitor treatments with paradoxically elevated amounts of active cathepsin S, but decreased amounts of active cathepsin L, as determined by multiplex cathepsin zymography. This indicated cellular feedback to selectively sustain the amounts of active cathepsin S even in the presence of inhibitors with subnanomolar inhibitory constant values. These differences were identified in cellular locations of cathepsins L and S, trafficking for secretion, co-localization with endocytosed inhibitors, and longer protein turnover time for cathepsin S compared to cathepsin L. Together, this work demonstrates that previously underappreciated cellular compensation and compartmentalization mechanisms may sustain elevated amounts of some active cathepsins while diminishing others after inhibitor treatment. This can confound predictions based solely on inhibitor kinetics, and must be better understood to effectively deploy therapies and dosing strategies that target cathepsins to prevent cancer progression.

Background Chromosome 9p21 variants have been strongly associated with coronary heart disease in genome-wide association studies, but questions remain on the mechanism of risk, specifically whether the locus contributes to coronary atheroma burden or plaque instability. We investigated the relationship of 9p21 locus with (1) angiographic coronary artery disease (CAD) burden and (2) myocardial infarction (MI) in individuals with underlying CAD. Methods:We established a collaboration of 21 studies consisting of 33,673 subjects with information on both CAD (clinical or angiographic) and MI status along with 9p21 genotype. Tabular data were provided for each cohort on the presence and burden of angiographic CAD; MI cases with underlying CAD; and the diabetic status of all subjects. Results We first confirmed an association between 9p21 and CAD using angiographically defined cases and controls ( pooled OR=1.31 (95% CI 1.20 to 1.43)). Among subjects with angiographic CAD (n=20,987), random-effects model identified an association with multi-vessel CAD, compared to those with single-vessel disease (OR=1.10 (95% CI 1.04 to 1.17) per copy of risk allele). Genotypic models showed an OR of 1.15 (95% CI 1.04 to 1.26) for heterozygous carrier and 1.23 (95% CI 1.08 to 1.39) for homozygous carrier. Finally, there was no significant association between 9p21 and prevalent MI when both cases (n=17 791) and controls (n=15 882) had underlying CAD (OR=0.99 (95% CI 0.95 to 1.03) per risk allele). Conclusions The 9p21 locus shows convincing association with greater burden of CAD, but not with MI in the presence of underlying CAD. This adds further weight to the hypothesis that 9p21 locus primarily mediates an atherosclerotic phenotype.

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