Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Changes in the amount of nonhaem iron in the plasma, whole body, and selected organs during the postlarval life of the lamprey Geotria australis

The concentration of plasma nonhaem iron and the concentration and weight of all nonhaem iron in the whole body and selected organs, together with its partitioning into ferritin and haemosiderin iron, have been measured during the metamorphosis and upstream spawning migration of the Southern Hemisphere lamprey Geotria australis. Some nonhaem iron was lost from the animal during metamorphosis. However, the concentration and weight of nonhaem iron in the liver rose sharply at this time, following its release from important storage sites in adipose tissue and the degradation of larval haemoglobins. The nephric fold of larval and metamorphosing stages contained over 40% of all nonhaem iron in the body at the commencement of metamorphosis. This was predominantly in the form of haemosiderin. While the rise in liver iron during the transition from larva to adult primarily reflected an increase in the weight of ferritin iron, the amount of iron stored as haemosiderin rose conspicuously towards the end of metamorphosis. The rise in ferritin iron in the liver was accompanied by a decrease in ferritin iron in the plasma, which implies that changes in the liver during metamorphosis result in a greater filtering of circulating ferritin. Such a process would account for the very much lower plasma nonhaem iron concentrations which characterise later adult stages. The weight of nonhaem iron increased markedly in the liver and adult opisthonephros and in the whole animal during the nontrophic upstream spawning migration. This was primarily due to a marked rise in ferritin which in turn could be related to the degradation of adult haemoglobins. The concentration of nonhaem iron (54,700 μg/g) and of its ferritin component (52,300 μg/g) in the liver of animals approaching sexual maturity are apparently by far the highest yet recorded for any vetrebrate

The relationship between total non-haem, ferritin and haemosiderin iron in larvae of Southern Hemisphere lampreys (Geotria australis andMordacia mordax)

The major iron binding protein (IBP) of larvalM. mordax has an estimated molecular weight (354,000), subunit molecular weight (18,000) and pI (5.1) identical to those recorded previously for larvalG. australis. The IBP in larvalG. australis has also been shown to be relatively heat stable and to react immunologically with antihorse spleen ferritin. The weight of total non-haem iron in the whole body, and both the ferritin and haemosiderin iron components, increased with increasing body weight in larvalG. australis. While the concentration of ferritin iron remained similar throughout larval life, the concentration of total non-haem iron and haemosiderin iron increased rapidly in animals up to a body weight of 0.1–0.2 g, but thereafter rose only slowly throughout the rest of larval life. This implies that any iron in excess of the amount required for the maintenance of a constant ferritin concentration is converted into haemosiderin iron, and that once non-haem iron has reached a particular concentration (c. 500–600 mgrg g–1), the rate of iron accumulation is greatly reduced. While the larvae of bothG. australis andM. mordax had very high plasma iron levels (>19,000 mgrg 100 ml–1), the former had significantly greater concentrations of iron in the whole body (702vs. 267 mgrg g–1) and more particularly in the nephric fold (7382vs. 224 mgrg g–1). A greater reservoir of non-haem iron could facilitate the maintenance of the large amounts of haem and erythrocytic ferritin present in this species as a result of an exceptionally high haemoglobin concentration and red blood cell number. The greater concentration of non-haem iron in the intestine ofM. mordax than ofG. australis (1338vs. 824 mgrg g–1), when considered in conjunction with histological studies, indicates thatMordacia mordax eliminates a larger amount of iron during the extrusion of its intestinal columnar cells

Isomeric Character of the Lowest 4+4_+ State in 44^{44}S

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