A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Repositioning of the global epicentre of non-optimal cholesterol

High blood cholesterol is typically considered a feature of wealthy western countries1,2. However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world3 and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health4,5. However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol—which is a marker of cardiovascular risk—changed from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million–4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world.</p

Repositioning of the global epicentre of non-optimal cholesterol

High blood cholesterol is typically considered a feature of wealthy western countries1,2. However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world3 and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health4,5. However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol�which is a marker of cardiovascular risk�changed from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95 credible interval 3.7 million�4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world. © 2020, The Author(s), under exclusive licence to Springer Nature Limited

Formation of alkyne bridged multicobalt carbonyl complexes with tris(2-thienyl)phosphine or bis(trimethylsilyiethynyl)phenylphosphine ligand

Treatment of Co-4(CO)(12) with an excess of trimethylsilylacetylene (TMSA) in the presence of tri(2-thienyl)phosphine in THF at 25 degreesC for 2 hours yielded six compounds. Two pseudo-octahedral, alkyne-bridged tetracobalt clusters, [Co-4(mu(4)-eta(2)-HCequivalent toCSiMe(3))(CO)(10)(mu-CO)(2)] (4) and [Co-4(mu(4)-eta(2)-HCequivalent toCSiMe(3))-(CO)(9)( (mu-CO)(2){P(C4H4S)(3)}](6), along with an alkyne-bridged dicobalt complex, [Co-2(CO)(5)(mu-HCequivalent toCSiMe(3))-{P(C4H4S)(3)}](5), (5), were obtained as new compounds. The addition of the thienylphosphine ligand, in fact, facilitates the reaction rate. Reaction of an alkyne-bridged dicobalt complex, [(eta(2) -H-Cequivalent toC-SiMe3)Co-2(CO)(6)] (3), with a bi-functional ligand, PPh(-Cequivalent toC-SiMe3)(2), yielded an unexpected six-membered, cyclic compound, {[(Ph)(Me3Si-Cequivalent toC)P-[(eta(2)-Cequivalent toC-SiMe3)Co-2(CO)(5)]}(2)(7). (7). All of these new compounds were characterized by spectroscopic means; the solid-state structures of (5), (6) and (7) have been established by X-ray crystallography

Synthesis and characterization of aluminum ethyl-(S)-lactate complexes and VT NMR studies of (Bu2Al)-Al-i((S)-(-)-mu(2)-OC(H)(Me)C(O)OEt)) (2)

The reactions of ethyl-(S)-(-)-lactate with R3Al in diethyl ether yield the pentacoordinated complexes [R2Al((S)-(-)-mu(2)-OC(H)(Me)C(O)OEt))](2) (1: R = Me; 2: R = Et; 3: R = Bu-i). These compounds have been characterized by spectroscopic studies as wells as crystallographic method. These structures show dimeric features containing unusual 5.4.5-fused rings with an Al2O2 core and the ester group bonded to Al through the C=O. VT NMR studies of compound 3 suggest that the weak (C=O)-->M dative bond may undergo dissociation in solution, giving rise to the equilibrium with a four-coordinate species among two five-coordinate species at ambient temperature. (C) 1998 Elsevier Science Ltd. All rights reserved

Electronic and steric factors affecting the formation of four or five-coordinated aluminum complexes: syntheses and crystal structures of some aluminum alkoxides

The reaction of 2-phenoxyethanol with AlX3 affords a five-coordinated dimeric product [(mu-OCH2CH2OPh)AlX2](2) (1, X = Cl; 2, X = Br) in high yields. However, the reaction of 2-phenoxyethanol with Al(Bu-i)(3), yields a four-coordinated dimeric product [(mu-O(CH2)(2)OPh)Al(Bu-i)(2)](2), (3). A mixture, [(mu-O(CH2)(2)OPh)Al(Et)(0.75)(Cl)(1.25)](2) (4) is Obtained from the reaction of 2-phenoxyethanol with one equivalent of Et2AlCl. The reaction of 2-methoxybenzyl alcohol with AlR3 gives a semi-pentacoordinated dimeric product [(mu-OCH2C6H4OMe)AlR2](2) (5, R = Me; 6, X = Bu-i) in high yields. Crystal structure studies of these compounds reveal that the distance between Al and the phenoxy oxygen or the methoxy oxygen is 3 > 6 > 5 much greater than 4 > 1 similar to 2. Although both the electronic and steric effect influence the nature of the O,O'-bifunctional ligand chelating on the aluminum center to generate a five- or four-coordinated aluminum, the electronic effect is considered to play a major role. The interaction of aluminum and ethereal oxygen can be monitored by C-13-NMR spectroscopic studies. (C) 1999 Elsevier Science S.A. All rights reserved