Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci.

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity

Renal and Brain Isoforms of WNK3 Have Opposite Effects on NCCT Expression

Mutations in the WNK kinases WNK1 and WNK4 cause a rare familial form of hypertension (Gordon syndrome) by increasing expression of the thiazide-sensitive co-transporter NCCT in the kidney. Regulation of NCCT expression involves a scaffold of proteins composed of several kinases, including the third member of the WNK kinase family, WNK3. This protein, expressed in several tissues including kidney and brain, displays splice variation around exons 18 and 22. We expressed these proteins in Xenopus oocytes and found that the renal isoform of WNK3 increased but the brain isoform decreased NCCT expression and activity. Introduction of a kinase-inactivating mutation into renal WNK3 reversed its action on NCCT, and the same mutation in the brain isoforms led to loss of function. We also studied the effect of phosphorylation of a key NCCT threonine (T58) on the effects of WNK3/4 coexpression; NCCT mutants with a T58A or T58D substitution had the same surface expression as T58 but had significantly altered transporter activity; however, both isoforms of WNK3 as well as WNK4 still modulated expression of these NCCT mutants. Finally, experiments using kinase-dead STE20/SPS1-related proline/alanine-rich kinase (SPAK), a putative downstream target for WNKs, revealed that brain WNK3 acts in tandem with SPAK, whereas renal WNK3 seems to upregulate NCCT through a SPAK-independent pathway. Taken together, these results suggest that the C-terminal motifs contributed by exons 18 and 22 play an important role in the actions of WNK3 isoforms on NCCT

Action learning: the possibility of differing hierarchies in learning sets

This paper presents the proposition that a variety of differing hierarchies exist in an action learning set at any one time, and each hierarchy has the potential to affect an individual’s behaviour within the set. An interpretivist philosophy underpins the research framework adopted in this paper. Data was captured by means of eleven in depth interviews that formed part of wider research into set members’ perceptions of what makes an effective action learning set. The interviewees were all former students of the researcher and her colleagues. The research draws upon grounded theory as a dominant research paradigm and uses thematic analysis to interpret the research findings. The findings of the research serve to simply illustrate that there is the potential for a variety of differing hierarchies to exist in an action learning set at any one time. Some of the hierarchies may exist for the full duration of the set, others are somewhat ephemeral. The findings from this research also present themselves as points of consideration for academics and practioners who have used or are about to use action learning as a learning vehicle

Role of the WNK-activated SPAK kinase in regulating blood pressure

Mutations within the with-no-K(Lys) (WNK) kinases cause Gordon's syndrome characterized by hypertension and hyperkalaemia. WNK kinases phosphorylate and activate the STE20/SPS1-related proline/alanine-rich kinase (SPAK) protein kinase, which phosphorylates and stimulates the key Na(+):Cl(−) cotransporter (NCC) and Na(+):K(+):2Cl(−) cotransporters (NKCC2) cotransporters that control salt reabsorption in the kidney. To define the importance of this pathway in regulating blood pressure, we generated knock-in mice in which SPAK cannot be activated by WNKs. The SPAK knock-in animals are viable, but display significantly reduced blood pressure that was salt-dependent. These animals also have markedly reduced phosphorylation of NCC and NKCC2 cotransporters at the residues phosphorylated by SPAK. This was also accompanied by a reduction in the expression of NCC and NKCC2 protein without changes in messenger RNA (mRNA) levels. On a normal Na(+)-diet, the SPAK knock-in mice were normokalaemic, but developed mild hypokalaemia when the renin–angiotensin system was activated by a low Na(+)-diet. These observations establish that SPAK plays an important role in controlling blood pressure in mammals. Our results imply that SPAK inhibitors would be effective at reducing blood pressure by lowering phosphorylation as well as expression of NCC and NKCC2. See accompanying Closeup by Maria Castañeda-Bueno and Gerald Gamba (DOI 10.1002/emmm.200900059)

Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations

Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤ 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis

Genome-wide association for serum calcium in discovery analysis in Europeans.

<p>Manhattan plot showing −log₁₀(P values) for all SNPs in the discovery GWAS for uncorrected serum calcium in Europeans (N = 39,400), ordered by chromosomal position. The plot is truncated at −log10 P values of 10 (truncated −log₁₀P values for GCKR and CASR). The values correspond to the association of uncorrected serum calcium, including age and sex as covariates in the model as well as study-specific covariates if needed. The gene closest to the SNP with the lowest P value is listed at each locus. Six loci reached genome-wide significance (<i>P</i><5E-08) at discovery analysis (<i>GCKR</i>, <i>DGKD</i>, <i>CASR</i>, <i>VKORC1L1</i> (in grey on chromosome 7), <i>CARS</i> and <i>CYP24A1</i>. The seven loci that reached genome-wide significance at the combined analysis following replication are highlighted in red (<i>GCKR</i>, <i>DGKD</i>, CASR, <i>GATA3</i>, <i>CARS</i>, <i>DGKH</i>-KIAA0564 and <i>CYP24A1</i>).</p