Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol- increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels

Effects of topical 0.2% Cyclosporine A on corneal neovascularization induced by xenologous amniotic membrane implantation into a corneal stroma micropocket of rats Efeitos do uso tópico da Ciclosporina A (CsA) 0,2% na neovascularização corneal induzida pelo implante de membrana amniótica xenógena em microbolsa no estroma da córnea de ratos

The objective of the study was to evaluate the topical effects of 0.2% Cyclosporine A (CsA) on corneal neovascularization of rats following surgical implantation of equine amniotic membrane into a corneal stroma micropocket. The implantation of xenologous amniotic membrane was performed bilaterally in 90 rats. In the same day of the surgery each right eye started receiving topical CsA twice a day. The left eye received no medication and served as a control. The evaluation of corneal neovascularization was performed by computerized image analysis and histopathological evaluation at 1, 3, 7, 15, 30 and 60 days postoperatively. For the image analysis 10 animals were used per time period, and for the histopathological examination, five animals were used per time period. Image analysis found that corneal neovascularization began on the 3rd postoperative day, reached its peak on the 7th day, and then progressively and rapidly decreased. Statistic analysis indicated that neovascularization of the CsA treated eye on the 7th day was significantly higher than that observed in untreated eyes. On the 30th day, however, this pattern was reversed with the neovascularization observed in the CsA treated eyes declining to the low levels observed on the 3rd day. The degree of neovascularization in the untreated eyes on the 30th day declined to the baseline levels found on day 3 at the 60th day. Histopathological analysis indicated that deposition of collagen in the implanted tissue was completed by the 15th day. Therefore, we concluded that (1) equine amniotic membrane in rat corneal stroma produced an intense neovascularization until the 15th day postoperatively and then regressed, (2) deposition of collagen of the implanted tissue was completed on the 15th day postoperatively, and (3) use of CsA was associated with increase in the corneal neovascularization initially, followed by a quick and intense regression.<br>Este estudo teve como objetivo a avaliação dos efeitos tópicos da Ciclosporina a 0,2% (CsA) sobre a neovascularização corneana de ratos após implante cirúrgico de membrana amniótica eqüina em microbolsa do estroma corneana. O implante da membrana foi feito bilateralmente em 90 ratos. O tratamento com CsA iniciou-se no mesmo dia da cirurgia, nos olhos direitos dos animais, duas vezes ao dia. Os olhos esquerdos não receberam nenhum tratamento e serviram de controle. A avaliação da neovascularização corneana foi feita por análise de imagem computadorizada e por exame histopatológico aos dias 1, 3, 7, 15, 30 e 60 de pós-cirúrgico. Para a análise de imagem foram utilizados 10 animais por período, e para o exame histopatológico, 5 por período. A análise de imagem demonstrou que a neovascularização iniciou-se no 3° dia pós-cirúrgico, alcançou seu pico no 7° dia e então regrediu rápida e progressivamente até o 60° dia. A análise estatística indicou que a neovascularização no 7º dia nos olhos tratados com CsA foi significantemente mais acentuada do que aquela observada nos olhos não tratados. Entretanto, no 30º dia este fato se reverteu, e a neovascularização observada nos olhos tratados com CsA diminuíra a níveis baixos comparáveis àquela do 3º dia. Já nos olhos não tratados, o grau de neovascularização somente pôde ser comparado àquele nível básico encontrado no 3º dia aos 60 dias de pós-operatório. A análise histopatológica demonstrou que a deposição de colágeno no tecido implantado se completou no 15º dia. Desta maneira, foi possível concluir que (1) a membrana amniótica em estroma corneano de ratos produz intensa neovascularização até o 15º dia de pós-operatório com posterior regressão, (2) a deposição de colágeno do tecido implantado foi completa ao 15º dia de pós-operatório, e que (3) o uso de CsA esteve associado com aumento inicial da neovascularização corneana, seguido de rápida e intensa regressão

Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks

Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121-], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited

Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol

Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98th or <2nd percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previous

Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation.

We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P &lt; 5 × 10-9), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with &gt;50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background