TRENDS IN ABUNDANCE OF ALASKA HARBOR SEALS, 1983–2001

We estimated trends in abundance of harbor seals ( Phoca vitulina richardsii ) using over dispersed, multinomial models and counts obtained during aerial surveys conducted during 1983–2001 in the Ketchikan, Sitka, Kodiak, and Bristol Bay areas of Alaska. Harbor seal numbers increased significantly at 7.4%/yr during 1983–1998 and 5.6%/yr during 1994–1998 in the Ketchikan area, and 6.6%/yr during 1993–2001 in the Kodiak area. Counts were stable (trends not significant) during 1984–2001 (0.7%/yr) and 1995–2001 (-0.4%/yr) in Sitka, and during 1998–2001 (-1.3%/yr) in Bristol Bay. The influence of covariates ( e.g. , survey date, tide height) on trend estimates was significant and varied among areas and across years, demonstrating the need to include covariates in statistical analyses to accurately estimate trend. Our increasing trend estimate for Kodiak represents the first documented increase in harbor seal numbers over a relatively expansive area in the Gulf of Alaska. However, the trend for the Gulf of Alaska stock is equivocal due to the continued decline in Prince William Sound. Similarly, the trend for the Southeast Alaska stock is equivocal based on our increasing (Ketchikan) and stable (Sitka) trend estimates, and a recent decline reported for Glacier Bay. The Bering Sea stock appears stable after a period of possible decline.     

Polymorphisms in genes involved in the NF-κB signalling pathway are associated with bone mineral density, geometry and turnover in men

Introduction

In this study, we aimed to investigate the association between single nucleotide polymorphisms (SNPs) within two genes involved in the NF-κB cascade (GPR177 and MAP3K14) and bone mineral density (BMD) assessed at different skeletal sites, radial geometric parameters and bone turnover.

Methods

Ten GPR177 SNPs previously associated with BMD with genome-wide significance and twelve tag SNPs (r²≥0.8) within MAP3K14 (±10 kb) were genotyped in 2359 men aged 40–79 years recruited from 8 centres for participation in the European Male Aging Study (EMAS). Measurement of bone turnover markers (PINP and CTX-I) in the serum and quantitative ultrasound (QUS) at the calcaneus were performed in all centres. Dual energy X-ray absorptiometry (DXA), at the lumbar spine and hip, and peripheral quantitative computed tomography (pQCT), at the distal and midshaft radius, were performed in a subsample (2 centres). Linear regression was used to test for association between the SNPs and bone measures under an additive genetic model adjusting for study centre.

Results

We validated the associations between SNPs in GPR177 and BMD_a previously reported and also observed evidence of pleiotrophic effects on density and geometry. Rs2772300 in GPR177 was associated with increased total hip and LS BMD_a, increased total and cortical vBMD at the radius and increased cortical area, thickness and stress strain index. We also found evidence of association with BMD_a, vBMD, geometric parameters and CTX-I for SNPs in MAP3K14. None of the GPR177 and MAP3K14 SNPs were associated with calcaneal estimated BMD measured by QUS.

Conclusion

Our findings suggest that SNPs in GPR177 and MAP3K14 involved in the NF-κB signalling pathway influence bone mineral density, geometry and turnover in a population-based cohort of middle aged and elderly men. This adds to the understanding of the role of genetic variation in this pathway in determining bone health.     

The ESR1 (6q25) locus is associated with calcaneal ultrasound parameters and radial volumetric bone mineral density in European men

Purpose

Genome-wide association studies (GWAS) have identified 6q25, which incorporates the oestrogen receptor α gene (ESR1), as a quantitative trait locus for areal bone mineral density (BMD_a) of the hip and lumbar spine. The aim of this study was to determine the influence of this locus on other bone health outcomes; calcaneal ultrasound (QUS) parameters, radial peripheral quantitative computed tomography (pQCT) parameters and markers of bone turnover in a population sample of European men.

Methods

Eight single nucleotide polymorphisms (SNP) in the 6q25 locus were genotyped in men aged 40–79 years from 7 European countries, participating in the European Male Ageing Study (EMAS). The associations between SNPs and measured bone parameters were tested under an additive genetic model adjusting for centre using linear regression.

Results

2468 men, mean (SD) aged 59.9 (11.1) years had QUS measurements performed and bone turnover marker levels measured. A subset of 628 men had DXA and pQCT measurements. Multiple independent SNPs showed significant associations with BMD using all three measurement techniques. Most notably, rs1999805 was associated with a 0.10 SD (95%CI 0.05, 0.16; p = 0.0001) lower estimated BMD at the calcaneus, a 0.14 SD (95%CI 0.05, 0.24; p = 0.004) lower total hip BMD_a, a 0.12 SD (95%CI 0.02, 0.23; p = 0.026) lower lumbar spine BMD_a and a 0.18 SD (95%CI 0.06, 0.29; p = 0.003) lower trabecular BMD at the distal radius for each copy of the minor allele. There was no association with serum levels of bone turnover markers and a single SNP which was associated with cortical density was also associated with cortical BMC and thickness.

Conclusions

Our data replicate previous associations found between SNPs in the 6q25 locus and BMD_a at the hip and extend these data to include associations with calcaneal ultrasound parameters and radial volumetric BMD.     

Genetic Copy Number Variation and General Cognitive Ability

Differences in genomic structure between individuals are ubiquitous features of human genetic variation. Specific copy number variants (CNVs) have been associated with susceptibility to numerous complex psychiatric disorders, including attention-deficit-hyperactivity disorder, autism-spectrum disorders and schizophrenia. These disorders often display co-morbidity with low intelligence. Rare chromosomal deletions and duplications are associated with these disorders, so it has been suggested that these deletions or duplications may be associated with differences in intelligence. Here we investigate associations between large (≥500kb), rare (<1% population frequency) CNVs and both fluid and crystallized intelligence in community-dwelling older people. We observe no significant associations between intelligence and total CNV load. Examining individual CNV regions previously implicated in neuropsychological disorders, we find suggestive evidence that CNV regions around SHANK3 are associated with fluid intelligence as derived from a battery of cognitive tests. This is the first study to examine the effects of rare CNVs as called by multiple algorithms on cognition in a large non-clinical sample, and finds no effects of such variants on general cognitive ability.     

HSD3B and Gene-Gene Interactions in a Pathway-Based Analysis of Genetic Susceptibility to Bladder Cancer

Bladder cancer is the 4^th most common cancer among men in the U.S. We analyzed variant genotypes hypothesized to modify major biological processes involved in bladder carcinogenesis, including hormone regulation, apoptosis, DNA repair, immune surveillance, metabolism, proliferation, and telomere maintenance. Logistic regression was used to assess the relationship between genetic variation affecting these processes and susceptibility in 563 genotyped urothelial cell carcinoma cases and 863 controls enrolled in a case–control study of incident bladder cancer conducted in New Hampshire, U.S. We evaluated gene–gene interactions using Multifactor Dimensionality Reduction (MDR) and Statistical Epistasis Network analysis. The 3′UTR flanking variant form of the hormone regulation gene HSD3B2 was associated with increased bladder cancer risk in the New Hampshire population (adjusted OR 1.85 95%CI 1.31–2.62). This finding was successfully replicated in the Texas Bladder Cancer Study with 957 controls, 497 cases (adjusted OR 3.66 95%CI 1.06–12.63). The effect of this prevalent SNP was stronger among males (OR 2.13 95%CI 1.40–3.25) than females (OR 1.56 95%CI 0.83–2.95), (SNP-gender interaction P = 0.048). We also identified a SNP-SNP interaction between T-cell activation related genes GATA3 and CD81 (interaction P = 0.0003). The fact that bladder cancer incidence is 3–4 times higher in males suggests the involvement of hormone levels. This biologic process-based analysis suggests candidate susceptibility markers and supports the theory that disrupted hormone regulation plays a role in bladder carcinogenesis.     

Thyroid hormone increases glyceraldehyde 3-phosphate dehydrogenase gene expression in rat liver

Livers from hypophysectomized rats had low levels of glyceraldehyde 3-phosphate dehydrogenase mRNA. Administration of L-triiodothyronine increased these levels over 20-fold. The peak response was seen 72 h after hormone administration. A half-maximal response was obtained with 5 micrograms of T3 per 100 g of body weight. Thus the expression of hepatic glyceraldehyde 3-phosphate dehydrogenase appears to be regulated by thyroid hormone.     

Sulfhydryl/disulfide forms of rat liver 3-hydroxy-3-methylglutaryl coenzyme A reductase

Using radiation inactivation and immunoblotting techniques, evidence for functionally active forms of rat liver 3-hydroxy-3-methylglutaryl coenzyme A reductase with molecular weights of about 100,000 and 200,000 was obtained. In liver microsomes isolated from rats fed both mevinolin and colestipol, the Mr 100,000 form was the predominant species, whereas in microsomes from animals fed only colestipol, the Mr 200,000 species was the major form. This Mr 200,000 form could be converted to the Mr 100,000 form by addition of dithiothreitol or beta-mercaptoethanol. Although both forms appear to possess catalytic activity, the Mr 200,000 species displays sigmoidal kinetics with respect to the concentration of NADPH, whereas the Mr 100,000 form exhibits typical hyperbolic kinetics.