Whole-genome sequencing of chronic lymphocytic leukemia identifies subgroups with distinct biological and clinical features

The value of genome-wide over targeted driver analyses for predicting clinical outcomes of cancer patients is debated. Here, we report the whole-genome sequencing of 485 chronic lymphocytic leukemia patients enrolled in clinical trials as part of the United Kingdom’s 100,000 Genomes Project. We identify an extended catalog of recurrent coding and noncoding genetic mutations that represents a source for future studies and provide the most complete high-resolution map of structural variants, copy number changes and global genome features including telomere length, mutational signatures and genomic complexity. We demonstrate the relationship of these features with clinical outcome and show that integration of 186 distinct recurrent genomic alterations defines five genomic subgroups that associate with response to therapy, refining conventional outcome prediction. While requiring independent validation, our findings highlight the potential of whole-genome sequencing to inform future risk stratification in chronic lymphocytic leukemia

GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility

Effect of age on calcium absorption in postmenopausal women

© 2004 American Society for Clinical NutritionBackgroundIt is assumed that calcium absorption decreases with age, but this is not well documented. We report a study that addresses this issue.ObjectiveThe aim was to establish the extent and timing of any age-related change in calcium absorption in postmenopausal women.DesignWe measured radiocalcium absorption (alpha) in 262 healthy postmenopausal women aged 40-87 y. We also measured the serum vitamin D metabolites, parathyroid hormone (PTH), and other biochemical variables.ResultsRadiocalcium absorption decreased with age (P = 0.018); it was 28% lower in the 25 women aged >75 y than in the rest (P ConclusionsA late age-related decrease in calcium absorption is seen in postmenopausal women in addition to the decline that occurs at menopause. This decrease could be due to a decline in either the active calcium transport or diffusion component of the calcium absorption system.BE Christopher Nordin, Allan G Need, Howard A Morris, Peter D O’Loughlin, and Michael Horowit

Vitamin D status: effects on parathyroid hormone and 1,25-dihydroxyvitamin D in postmenopausal women

BackgroundLow serum 25-hydroxyvitamin D ¿25(OH)D concentrations are commonly found in the elderly and are associated with hip fracture. Treatment with vitamin D and calcium can reduce the risk of fracture. The relation between the rise in parathyroid hormone (PTH) with age and the decrease in 25(OH)D is not clear. Neither is there any consensus on the serum concentration of 25(OH)D required for bone health.ObjectiveOur objective was to study the relations between serum PTH, serum vitamin D metabolites, and other calcium-related variables in postmenopausal women.DesignThis was a cross-sectional study of 496 postmenopausal women without vertebral fractures attending our menopausal osteoporosis clinics.ResultsPTH was significantly positively related to age and serum 1, 25-dihydroxyvitamin D ¿1,25(OH)(2)D and inversely related to 25(OH)D and plasma ionized calcium. There was a step-like increase in PTH as serum 25(OH)D fell below 40 nmol/L. In women with 25(OH)D concentrations >40 nmol/L, 1,25(OH)(2)D was positively related to 25(OH)D; in women with 25(OH)D concentrations 40 nmol/L, 1,25(OH)(2)D was most closely (inversely) related to plasma creatinine. Therefore, with serum 25(OH)D concentrations increasingly ConclusionThe data suggest that aging women should maintain 25(OH)D concentrations >40 nmol/L (which is the lower limit of our normal range for healthy young subjects) for optimal bone health

Calcium malabsorption does not cause secondary hyperparathyroidism

We challenge the widespread assumption that malabsorption of calcium per se causes secondary hyperparathyroidism. Serum parathyroid hormone (PTH) does not rise at the menopause despite the fall in calcium absorption, nor is it raised in osteoporotic women with vertebral fractures despite their low calcium absorption. The age-related rise in serum PTH can be accounted for by the age-related fall in serum 25(OH)D and/or decline in renal function with consequent loss of the calcemic action of vitamin D on bone. The reference interval for serum PTH is established in the fasting state when it is at the top of its diurnal cycle and is maintaining serum ionized calcium at the expense of bone to meet the calcium being lost through skin, bowel, and kidneys. There is no evidence that the fasting PTH is influenced by the previous day’s intake or absorption of calcium, although it can be lowered by a large evening calcium supplement. Malabsorption of calcium—like dietary calcium deficiency—is a risk factor for osteoporosis because it reduces or prevents the normal food-related daytime fall in PTH and bone resorption, not because it causes secondary hyperparathyroidism.B. E. Christopher Nordin, Howard A. Morris, Michael Horowitz, Penelope S. Coates, Peter D. O’Loughlin and Allan G. Nee

Suppression of parathyroid hormone and bone resorption by calcium carbonate and calcium citrate in postmenopausal women

The original publication can be found at www.springerlink.comThis study was conducted to compare the suppressive effects of calcium carbonate and calcium citrate on bone resorption in early postmenopause. Calcium citrate is thought to be better absorbed. We therefore tested the hypothesis that calcium as citrate is more effective than calcium as carbonate in suppressing parathyroid hormone (PTH) and C-terminal telopeptide. Twenty-five healthy postmenopausal women were recruited in this double blind crossover study. The subjects were randomly allocated to receive either 1,000 mg of elemental calcium as carbonate or 500 mg of calcium as citrate. They were given the alternate calcium dose 1 week later. Serum measurements of total and ionized calcium, phosphate, PTH, and CrossLaps were repeated 12 hours after each dose. Analysis of variance found no significant difference between measures for the two salts. Tests for equivalence indicated that 500 mg of calcium citrate may be superior to 1,000 mg of calcium carbonate in raising serum total and ionized calcium (P = 0.04 and 0.05, respectively). For all parameters measured, 500 mg of calcium citrate was at least as beneficial as 1,000 mg of calcium carbonate. Calcium citrate is at least as effective as calcium carbonate in suppressing PTH and C-terminal telopeptide cross-links, at half the dose. This may be because calcium as citrate is better absorbed than calcium as carbonate. If calcium citrate can be used in lower doses, it may be better tolerated than calcium carbonate.Sunethra D. C. Thomas, Allan G. Need, Graeme Tucker, Peter Slobodian, Peter D. O’Loughlin and B. E. Christopher Nordi

Seasonal change in osteoid thickness and mineralization lag time in ambulant patients

Low vitamin D levels are common. Bone biopsies taken from 121 ambulant patients were therefore reviewed. Seasonal changes in mineralization correlated inversely with serum 25-hydroxyvitamin D but not the more active metabolite, 1,25-dihydroxyvitamin D. This implies that the latter is produced in bone.Allan G Need, Michael Horowitz, Howard A Morris, Robert Moore, Christopher Nordi

Discordance between bone turnover and bone loss: effects of aging and ovariectomy in the rat

Mechanical strain maintains bone architecture even under conditions of increased bone turnover such as occurs with ovarian hormone deficiency. The rat distal femur contains two sites that apparently experience different levels of mechanical strain and therefore the rat is a suitable model for investigating such effects. The femoral epiphysis experiences higher strain energy compared with the metaphysis and we report the effects of aging between 7 and 12 months and the postovariectomy effects over the same time period on cancellous bone variables measured at these two sites. Age-related bone loss in sham-operated (Sham) animals occurred in both regions, with a greater fall in the metaphysis than in the epiphysis (trabecular bone volume [BV/TV, %] Mean [SEM] Metaphysis: day 0, 25.9 [2.4]; day 150, 8.8 [1.3]: Epiphysis: day 0, 44.8 [1.7]; day 150, 36.7 [1.4] [p < 0.0001]). With ovariectomy (OVX) there was a 73% reduction in cancellous bone at the metaphysis compared with no specific loss at the epiphysis (BV/TV [%] OVX: Metaphysis: day 150, 2.4 [0.4] [p < 0.01 compared with Sham]: Epiphysis: day 150 29.3 [2.7] [NS]). Osteoblast cell activity and osteoclast surface were increased after ovariectomy in both regions. The mineral apposition rate decreased at 9.5 months of age in both regions (p < 0.0001), independent of ovariectomy, and was coincident with a reduction in trabecular number in the epiphyses of both operative groups and in the metaphysis of the ovary-intact group. These data suggest that local mechanical strain governs bone balance with aging and that architectural changes resulting from age-related bone loss may mirror those following estrogen deficiency but occur via a different cellular mechanism.Paul A. J. Baldock, Allan G. Need, Robert J. Moore, Timothy C. Durbridge,. Howard A. Morri