Genetic determinants of serum testosterone concentrations in men

Testosterone concentrations in men are associated with cardiovascular morbidity, osteoporosis, and mortality and are affected by age, smoking, and obesity. Because of serum testosterone''s high heritability, we performed a meta-analysis of genome-wide association data in 8,938 men from seven cohorts and followed up the genome-wide significant findings in one in silico (n = 871) and two de novo replication cohorts (n = 4,620) to identify genetic loci significantly associated with serum testosterone concentration in men. All these loci were also associated with low serum testosterone concentration defined as <300 ng/dl. Two single-nucleotide polymorphisms at the sex hormone-binding globulin (SHBG) locus (17p13-p12) were identified as independently associated with serum testosterone concentration (rs12150660, p = 1.2×10⁻⁴¹ and rs6258, p = 2.3×10⁻²²). Subjects with ≥3 risk alleles of these variants had 6.5-fold higher risk of having low serum testosterone than subjects with no risk allele. The rs5934505 polymorphism near FAM9B on the X chromosome was also associated with testosterone concentrations (p = 5.6×10⁻¹⁶). The rs6258 polymorphism in exon 4 of SHBG affected SHBG''s affinity for binding testosterone and the measured free testosterone fraction (p<0.01). Genetic variants in the SHBG locus and on the X chromosome are associated with a substantial variation in testosterone concentrations and increased risk of low testosterone. rs6258 is the first reported SHBG polymorphism, which affects testosterone binding to SHBG and the free testosterone fraction and could therefore influence the calculation of free testosterone using law-of-mass-action equation.     

Strength training and determinants of VO2max in older men

The effects of strength training on maximal aerobic power (VO2max) and some of its determinants were studied in 12 healthy older men (60-72 yr). They underwent 12 wk of strength conditioning of extensors and flexors of each knee with eight repetitions per set, three sets per session, and three sessions per week at 80% of the one repetition maximum (1 RM). Left knee extensors showed a 107% increase in 1 RM, a 10% increase in isokinetic strength at 60 degrees/s, and a 23% increase in total work performed during 25 contractions on an isokinetic dynamometer. Strength measurements of the untrained left elbow extensors showed no change. Leg cycle ergometer VO2max per unit fat-free mass increased by an average 1.9 ml (P = 0.034) whereas arm cycle VO2max was unchanged. Pulmonary function, hemoglobin concentration, erythrocyte volume, plasma volume, and total blood volume did not change. Biopsies of the vastus lateralis showed a 28% increase in mean fiber area, no change in fiber type distribution, a 15% increase in capillaries per fiber, and a 38% increase in citrate synthase activity. The data suggest that the small increase in leg cycle VO2max in older men may be due to adaptations in oxidative capacity and increased mass of the strength-trained muscles.     

Muscle strength and body composition as determinants of blood pressure in young men

The correlations of blood pressure to various indices of muscularity and fatness were studied in 183 young healthy men (mean age 19.7, SD 2.1 years). Systolic pressure showed significant positive correlations with body fat percentage, isometric strength of trunk extensors, body mass index, lean body mass, strength of leg extensors, heart rate, and the sum of four skinfolds. Diastolic pressure had significant positive correlations with body mass index, lean body mass, body fat percentage, sum of skinfolds, strength of leg extensors, strength of trunk extensors, and age. A stepwise selective multiple regression analysis for systolic pressure resulted in four significantly correlating variables: body fat percentage (p less than 0.001), heart rate (p less than 0.01), lean body mass (p less than 0.05), and strength of trunk extensors per kg body weight (p less than 0.05). For diastolic pressure the analysis resulted in two explaining variables: body mass index (p less than 0.001) and age (p less than 0.05). In a regression equation with 13 variables the strength of trunk flexors was negatively correlated with diastolic pressure. It is concluded that both fatness and muscularity are factors related to blood pressure in young men. The muscularity effect is more clearly associated with trunk and leg extensor strength.     

The HLA-D determinants

Stimulating cells assumed to be homozygous at theHLA-D locus were used to identify nine different MLC-activating HLA-D determinants in a population of unrelated Norwegians. The results suggest that the HLA-D determinants typed for, which account for a combined gene frequency of approximately 0.80, are controlled by mutually exclusive codominant alleles at one locus. Some of the HLA-D determinants showed highly significant association to certain HLA-B antigens.     

The epidemiology of low- and high-energy distal radius fracture in middle-aged and elderly men and women in southern norway

Background

Distal radius is one of the most frequent sites for fractures in the elderly population. Despite this, there is a paucity of epidemiological data for distal radius fracture, in particular, distinguishing between high- and low-energy fractures. Our aim was to study the epidemiology of high- and low-energy distal radius fracture in middle-aged and elderly men and women in Southern Norway, and search for associates with high- or low-energy distal radius fracture in this population.

Methodology/Principal Findings

Patients with distal radius fractures aged ≥50 years were identified from all four hospitals in Southern Norway between 2004 and 2005. Age-adjusted and age-specific incidence rates for men and women were calculated, and potential associates with high- and low-energy distal radius fracture were explored both in univariate and multivariate analyses. A total of 799 individuals (118 men and 681 women) aged ≥50 years with low-energy and 84 (48 men and 36 women) with high-energy distal radius fracture were identified. The overall age-adjusted incidence rate per 10,000 person-years was 18.9 for men (low energy, 12.8 vs. high-energy, 6.1) and 75.1 for women (low energy, 71.1 vs. high energy, 4.0). In multivariate model, younger age, male gender, summer season, and living in a rural area were independently associated with an increased risk of high-energy fracture.

Conclusion

An approximately fourfold higher age-adjusted incidence rate for distal radius fracture was found among women, when compared with men. However, the proportion of patients with high-energy distal radius fracture was approximately fivefold higher in men than in women. Our data suggest that younger age, male gender, summer seasons, and living in rural areas are independent risk factors for increased risk of high-energy distal radius fracture.     

The determinants of delivery care in Kenya

This paper examines the determinants of place of delivery and childbirth attendant in Kenya based on the 1993 Kenya Demographic and Health Survey data. The analysis utilizes multilevel logistic and multilevel multinomial regression models for the place of delivery and the type of childbirth attendant, respectively. The results show that delivery care in Kenya is determined by a wide range of factors: socioeconomic and cultural factors associated with the individual woman or her household, her demographic status or reproductive behavior relating to a specific birth, as well as availability and accessibility of health services within her community. In addition, a significant variation in delivery care behavior is observed between women and between communities, implying that there are unobserved factors within families and communities that have a significant effect on delivery care. The woman or family effect on delivery care is particularly strong, but varies by distance to the nearest delivery care facility.     

The determinants of contractility in the heart

The contraction-relaxation cycle of the heart represents the combined action of a variety of different components of the myocytes. For many years an ‘index’ of contractility has been sought as a means of describing and integrating the large amount of information available from the studies of heart muscle contraction. This review will undertake to show that dF/dt, recorded from the whole heart, and dT/dt, recorded in isometric studies of isolated heart muscle preparations, should not be considered as the ‘index’ of contractility. Examples will be presented in which an increasing dT/dt is paradoxically accompanied by a lower tension, while a decreasing dT/dt can occur concomitantly with an increased contractile tension. Arguments are further presented in support of the concept that Ca²⁺, in conjunction with troponin C, is the main determinant of cardiac contractility and that dT/dt reflects a dynamic equilibrium between free and troponin-bound Ca²⁺. Peak tension is thus the net result of overlapping events competing for Ca²⁺ during the latter part of contraction, that is, during Phase II of contraction as defined below. These suggestions are based upon the following considerations: (a) The Ca²⁺ pumps are active even during rest and serve to maintain low cytosolic Ca²⁺ levels, (b) As cytosolic Ca²⁺ concentration increases, Ca²⁺ pump activity also increases, (c) In addition, the Na⁺Ca²⁺ exchange is activated by elevated Ca²⁺ concentrations and serves to decrease cytosolic Ca²⁺ levels, (d) The net result is a decline in free Ca²⁺ concentration during Phase II and a reduction in the rate of cross-bridge formation until peak tension is reached. Thus, the Ca²⁺ handling elements of the myocyte serve as a finely tuned feedback device, regulating troponin C-Ca²⁺ interactions controlling the Ca²⁺ concentration of the cytosol and as a result, the actin and myosin interaction. Factors which influence the function of these elements will change the contractility of the heart.     

The determinants of grain texture in cereals

Kernel hardness is an important agronomic trait that influences end-product properties. In wheat cultivars, this trait is determined by thePuroindoline a (Pina) andPuroindoline b (Pinb) genes, located in theHardness locus (Ha) on chromosome 5DS of the D genome. Wild type alleles code puroindoline a (PINA) and puroindoline b (PINB) proteins, which form a 15-kDa friabilin present on the surface of water-washed starch granules. Both the proteins are accumulated in the starch endosperm cells and aleurone of the mature kernels.Puroindoline-like genes coding puroindoline-like proteins in the starch endosperm occur in some of the genomes of Triticeae and Aveneae cereals. Orthologs are present in barley, rye and oats. However, some genomes of these diploid and polyploid cereals, like that ofTriticum turgidum var.durum (AABB) lack thepuroindoline genes, having a very hard kernel texture. The two wild type alleles in opposition (dominant loci) control the soft pheno-type. Mutation either inPina orPinb or in both leads to a medium-hard or hard kernel texture. The most frequent types ofPin mutations are point mutations within the coding sequence resulting in the substitution of a single amino acid or a null allele. The latter is the result of a frame shift determined by base deletion or insertion or a one-point mutation to the stop codon. The lipid-binding properties of the puroindolines affect not only the dough quality but also the plants’ resistance to pathogens. Genetic modification of cereals withPuroindoline genes and/or their promoters enable more detailed functional analyses and the production of plants with the desired characteristics.     

Social determinants of self-reported health in women and men: understanding the role of gender in population health

Background

Women and men share similar health challenges yet women report poorer health. The study investigates the social determinants of self-reported health in women and men, and male-female differences in health.

Methods

Data on 103154 men and 125728 women were analysed from 57 countries in the World Health Survey 2002–2004. Item Response Theory was used to construct a composite measure of health. Associations between health and determinants were assessed using multivariate linear regression. Blinder-Oaxaca decomposition partitioned the inequality in health between women and men into an “explained" component that arises because men and women differ in social and economic characteristics, and an “unexplained" component due to the differential effects of these characteristics. Decomposition was repeated for 18 countries in the World Health Organization (WHO) African region and 19 countries in the WHO European region.

Results

Women''s health was significantly lower than men''s. Health was associated with education, household economic status, employment, and marital status after controlling for age. In the pooled analysis decomposition showed that 30% of the inequality was “explained", of which almost 75% came from employment, education, marital status. The differential effects of being in paid employment increased the inequality. When countries in Africa and Europe were compared, the “explained" component (31% and 39% respectively) was largely attributed to the social determinants in the African countries and to women''s longevity in the European countries. Being in paid employment had a greater positive effect on the health of males in both regions.

Conclusions

Ways in which age and the social determinants contribute to the poorer health status of women compared with men varies between groups of countries. This study highlights the need for action to address social structures, institutional discrimination and harmful gender norms and roles that differently influence health with ageing.     

Genetic determinants for body iron store and type 2 diabetes risk in US men and women

Background

High body iron store has been associated with an increased risk of type 2 diabetes (T2D); it remains unknown whether the genetic variants related to body iron status affect T2D risk. We aimed at comprehensively investigating the associations between the genetic variants related to body iron status and the T2D risk.

Methodology/Principal Findings

Six common SNPs related to body iron status from recent genome-wide association (GWA) studies were determined in the Nurses’ Health Study (NHS; 1,467 diabetic cases and 1,754 controls) and the Health Professionals Follow-up Study (HPFS; 1,124, diabetic cases and 1,298 controls). Plasma levels of ferritin, soluble transferrin receptor (sTfR), and transferrin were measured in NHS. Significant associations were observed for loci in TPMRSS6 with sTfR (P = 3.47×10⁻⁶), TF with transferrin (P = 0.0002 to 1.72×10⁻¹⁰); and HFE with ferritin (P = 0.017 to 1.6×10⁻⁸), sTfR (P = 0.007 to 7.9×10⁻⁶), and transferrin (P = 0.006 to 0.0007). The six SNPs together explained 5.7%, 2.7%, and 13.3% of the variation in plasma levels of ferritin, sTfR, and transferrin. After adjustment for the conventional risk factors, the T allele of SNP rs855791 in the TPMRSS6 gene was significantly associated with a 19% decreased risk of T2D (OR = 0.81; 95% CI = 0.66–0.98; P = 0.03) in men. Multiple tests attenuated this significant association to null. No associations were observed in women. SNPs at HFE and TF were not associated with diabetes risk in either sex. Dietary iron intake did not modify the associations of the newly identified loci with diabetes risk.

Conclusions/Significance

The newly identified iron-related SNP rs855791 in TPMRSS6 was nominally associated with a decreased risk of T2D in men but not in women. The apparent differences by gender warrant further study.     

The determinants of gene order conservation in yeasts

Background

Why do some groups of physically linked genes stay linked over long evolutionary periods? Although several factors are associated with the formation of gene clusters in eukaryotic genomes, the particular contribution of each feature to clustering maintenance remains unclear.

Results

We quantify the strength of the proposed factors in a yeast lineage. First we identify the magnitude of each variable to determine linkage conservation by using several comparator species at different distances to Saccharomyces cerevisiae. For adjacent gene pairs, in line with null simulations, intergenic distance acts as the strongest covariate. Which of the other covariates appear important depends on the comparator, although high co-expression is related to synteny conservation commonly, especially in the more distant comparisons, these being expected to reveal strong but relatively rare selection. We also analyze those pairs that are immediate neighbors through all the lineages considered. Current intergene distance is again the best predictor, followed by the local density of essential genes and co-regulation, with co-expression and recombination rate being the weakest predictors. The genome duplication seen in yeast leaves some mark on linkage conservation, as adjacent pairs resolved as single copy in all post-whole genome duplication species are more often found as adjacent in pre-duplication species.

Conclusion

Current intergene distance is consistently the strongest predictor of synteny conservation as expected under a simple null model. Other variables are of lesser importance and their relevance depends both on the species comparison in question and the fate of the duplicates following genome duplication.

     

The genomic determinants of alcohol preference in mice

Searches for the identity of genes that influence the levels of alcohol consumption by humans and other animals have often been driven by presupposition of the importance of particular gene products in determining positively or negatively reinforcing effects of ethanol. We have taken an unbiased approach and performed a meta-analysis across three types of mouse populations to correlate brain gene expression with levels of alcohol intake. Our studies, using filtering procedures based on QTL analysis, produced a list of eight candidate genes with highly heritable expression, which could explain a significant amount of the variance in alcohol preference in mice. Using the Allen Brain Atlas for gene expression, we noted that the candidate genes' expression was localized to the olfactory and limbic areas as well as to the orbitofrontal cortex. Informatics techniques and pathway analysis illustrated the role of the candidate genes in neuronal migration, differentiation, and synaptic remodeling. The importance of olfactory cues, learning and memory formation (Pavlovian conditioning), and cortical executive function, for regulating alcohol intake by animals (including humans), is discussed.     

The national determinants of deforestation in sub-Saharan Africa

For decades, the dynamics of tropical deforestation in sub-Saharan Africa (SSA) have defied easy explanation. The rates of deforestation have been lower than elsewhere in the tropics, and the driving forces evident in other places, government new land settlement schemes and industrialized agriculture, have largely been absent in SSA. The context and causes for African deforestation become clearer through an analysis of new, national-level data on forest cover change for SSA countries for the 2000–2005 period. The recent dynamic in SSA varies from dry to wet biomes. Deforestation occurred at faster rates in nations with predominantly dry forests. The wetter Congo basin countries had lower rates of deforestation, in part because tax receipts from oil and mineral industries in this region spurred rural to urban migration, declines in agriculture and increased imports of cereals from abroad. In this respect, the Congo basin countries may be experiencing an oil and mineral fuelled forest transition. Small farmers play a more important role in African deforestation than they do in southeast Asia and Latin America, in part because small-scale agriculture remains one of the few livelihoods open to rural peoples.     

Responsiveness and habituation of soluble ICAM-1 to acute psychosocial stress in men: determinants and effect of stress-hemoconcentration

We studied the psychophysiology of soluble intercellular adhesion molecule-1 (sICAM-1) in 25 apparently healthy middle-aged men who underwent an acute psychosocial stressor three times with one week apart. Measures of the biological stress response were obtained at week one and three. The magnitude of the sICAM-1 stress response showed no habituation between individual visits. At week one, cognitive stress appraisal independently predicted integrated sICAM-1 area under the curve (AUC) between rest, immediately post-stress, and 45 min and 105 min post-stress (beta=0.67, p=0.012, deltaR(2)=0.41). Diastolic blood pressure AUC (beta=-0.45, p=0.048, deltaR(2)=0.21) and heart rate AUC (beta=0.44, p=0.055, deltaR(2)=0.21) were independent predictors of sICAM-1 AUC at week three. Adjustment for hemoconcentration yielded a decrease in sICAM-1 levels from rest to post-stress (p<0.001). Stress responsiveness of plasma sICAM-1 was predicted by stress perception and hemodynamic reactivity and affected by stress-hemoconcentration but unrelated to cortisol reactivity and not readily adapting to repeated stress.     

The determinants of alpha-amylase pH-activity profiles

The glycosyl hydrolases present a large family of enzymes that are of great significance for industry. Consequently, there is considerable interest in engineering the enzymes in this family for optimal performance under a range of very diverse conditions. Until recently, tailoring glycosyl hydrolases for specific industrial processes mainly involved stability engineering, but lately there has also been considerable interest in engineering their pH-activity profiles. We mutated four neutral residues (N190, F290, N326 and Q360) in the chimeric Bacillus Ba2 alpha-amylase to both charged and neutral amino acids. The results show that the pH-activity profile of the Ba2 alpha-amylase can be changed by inserting charged residues close to the active site. The changes in the pH-activity profile for these neutral --> charged mutations do not, however, correlate with the predictions from calculations of the p K(a) values of the active site residues. More surprisingly, the neutral --> neutral mutations change the pH-activity profile as much as the neutral --> charged mutations. From these results, it is concluded that factors other than electrostatics, presumably the dynamic aspects of the active site, are important for the shape of the pH-activity profiles of the alpha-amylases.