Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.</p

A new 4,20-dideoxy-5-hydroxyphorbol ester from the latex of <i>Euphorbia lateriflora</i>

From the latex of E. lateriflora, a new diterpene ester, 12-O-benzoyl-13-O-[2-methylpropanoyl]-4,20-dideoxy-5-hydroxyphorbol (1), was isolated. Its structure was established by spectral analysis of 1 and its derivatives 2 - 4

The structure of enukokurin, a new jatrophane diterpenoid from the latex of <i>Euphorbia lateriflora</i>

The structure of enukokurin [1], a novel jatrophane ester from the latex of Euphorbia lateriflora, has been assigned on the basis of its 1H and 13C nmr spectroscopic properties. The positions of its ester linkages were determined using 2D δC/δH long-range correlation experiments and its relative stereochemistry by nOe difference spectroscopy

A novel penta-ester of 19-hydroxyingol from the latex of <i>Euphorbia poisonii</i>

A novel penta-ester of 19-hydroxyingol (2) has been isolated from the latex of E. poisonii. Its structure was elucidated by spectral correlation with (1), earlier isolated from the same source

Enukokurin B and C, two other new jatrophane diterpenoid esters from the latex of <i>Euphorbia lateriflora</i>

Two additional new jatrophane diterpenoid esters Enukokurin B (2) and C (3) were isolated from the latex of E. lateriflora. Their structures were elucidated by spectral correlation with Enukokurin A (1), earlier isolated from the same source, and by 2D δC/δH direct and long-range correlation experiments

A novel penta-ester of 19-hydroxyingol from the latex of <i>Euphorbia poisonii</i>

A novel penta-ester of 19-hydroxyingol (2) has been isolated from the latex of E. poisonii. Its structure was elucidated by spectral correlation with (1), earlier isolated from the same source

A reassessment of the relative stereochemistry of ingol tetra-acetate

Re-examination of the published X-ray crystallographic data for ingol tetra-acetate has revealed that the relative configurations at C-8 and C-13 are opposite to those previously reported; the revised structure is shown in (2)

A novel 19-hydroxyingol ester from the latex of <i>Euphorbia poisonii</i>; specification of ester linkages using n.m.r. methods, including two-dimensional long-range ¹³C/¹H chemical shift correlation.

Two n.m.r. methods for the definitive assignment of ester linkages have been applied to the structural elucidation of a new 19-hydroxyingol ester from the latex of Euphorbia poisonii

Five ingol esters and a 17-hydroxyingenol ester from the latex of <i>Euphorbia kamerunica</i>. Assignment of esters using ¹³C n.m.r. methods.

The structures of five ingol esters and a 17-hydroxyingenol ester from the latex of Euphorbia kamerunica have been determined. The 13C n.m.r. spectra of these compounds have been assigned using 2D δC/δH correlations. The specific positions of attachment of esters have been assigned unambiguously using 13C n.m.r. methods including 2D long range δC/δH correlations