TUB is a candidate gene for late-onset obesity in women.

AIMS/HYPOTHESES: We recently reported significant associations between BMI and three TUB single nucleotide polymorphisms (SNPs) in two Dutch cohorts enriched for type 2 diabetes. Here, we attempted a replication of these associations in a large population-based cohort of female twins comprehensively phenotyped for measures of general and central obesity. METHODS: Two TUB SNPs (rs2272382, rs2272383) and a third (rs1528133), 22 kb distal to RIC3, were genotyped in 2694 Europid women from the St Thomas' UK Adult Twin Registry (Twins UK) (mean age +/- SD: 47.6 +/- 12.7 years; 42.8% postmenopausal). We explored the hypothesis that TUB is a candidate gene for late-onset obesity in humans through testing the interaction of the SNPs by menopausal status. RESULTS: In the whole cohort, none of the three SNPs showed a significant main effect on measures of general or central obesity. However, for central obesity the rs2272382 SNP showed a significant interaction with menopausal status (p = 0.036). Postmenopausal women homozygous for the minor allele of rs2272382 showed significantly more general obesity (p = 0.022) and central obesity (p = 0.009) than carriers of the major allele. Differences (beta [95% CI]) between the two genotype groups were 0.92 kg/m2 (0.03-1.81) for BMI (p = 0.036), 2.73 cm (0.62-4.84) for waist circumference (p = 0.013) and 2.43% (0.27-4.60) for per cent central fat (p = 0.027). These associations were confirmed by a sibling transmission disequilibrium test for central obesity, waist circumference and per cent central fat. CONCLUSIONS/INTERPRETATION: We have replicated associations of TUB SNP rs2272382 with measures of general and central obesity in normal postmenopausal women. These findings confirm TUB as a candidate gene for late-onset obesity in humans.

Serum adiponectin and bone mineral density in women.

CONTEXT: Bone mineral density (BMD) is positively associated with body weight. This association persists even at non-load bearing sites, suggesting that a nonmechanical factor such as an adipocyte-derived hormone may modulate BMD. OBJECTIVE: The objective of the study was to evaluate the relationship between adiponectin, an adipocyte-derived hormone, and BMD. DESIGN, SETTING, PARTICIPANTS: A total of 1735 nondiabetic women were recruited from a large, population-based cohort (mean age, 50.0 yr). We employed linear regression methods to estimate the relationship between adiponectin and BMD. MAIN OUTCOME MEASURES: Percentage change in BMD (as measured at total hip, spine, femoral neck, and forearm) and markers of bone turnover associated with a doubling of fasting serum adiponectin levels were measured. RESULTS: Employing age-adjusted analysis, each doubling of serum adiponectin was associated with a mean 2.7% decrease in BMD [total hip, -3.2% (95% confidence interval, -4.1, -2.3); femoral neck, -3.1% (-4.0, -2.1); forearm, -2.0 (-2.6, -1.4); spine, -2.6 (-3.5, -1.7)]. After adjustment for potential confounding factors, including BMI, serum leptin, central fat mass, hormone replacement therapy, smoking, and exercise, this relationship persisted, although decreased in magnitude. When stratified by menopausal status, the relationship between serum adiponectin and BMD strengthened in postmenopausal women but disappeared in premenopausal women. Serum adiponectin was positively associated with serum osteocalcin but not with urine deoxypyridinoline. CONCLUSIONS: After adjustment of measures of body fat, increasing levels of adiponectin were associated with a decrease in BMD, even at non-load bearing sites. These data suggest that adiponectin, an adipocyte-derived hormone, may play a role in bone metabolism through nonmechanical mechanisms and that this effect may be mediated by menopausal status.

AMP-kinase alpha2 subunit gene PRKAA2 variants are associated with total cholesterol, low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol in normal women.

BACKGROUND: 5'-AMP-activated protein kinase (AMPK) inactivates critial ensymes in fatty acid and cholesterol synthesis. We hypothesised that the serum lipid profile may be influenced by genetic variation in the AMPK catalytic alpha2 subunit. METHOD: We examined association of 5 tagging SNPs (tSNPs) in the PRKAA2 gene with serum lipids in 2777 normal Caucasian females (mean age 47.4+/-12.5 years). RESULTS: All tSNPs were associated with total- and LDL-cholesterol, (p<0.001 to 0.034), explaining variances of 0.13-0.59% and 0.11-0.55% respectively. One haplotype (frequency 34.7%) showed lower total- and LDL-cholesterol compared with the most common haplotype (frequency 45.7%) (p< or =0.001), explaining 0.78% of total- and 0.75% of LDL-cholesterol. Another haplotype (frequency 10.5%) was significantly associated with lower HDL-cholesterol (p = 0.005), explaining 0.59% of variance. CONCLUSIONS: PRKAA2 gene variants are significantly associated with serum lipoproteins in a large sample of normal female Caucasians.

Heritability of central systolic pressure augmentation: a twin study.

Less than 50% of the variance in left ventricular mass is explained by conventional factors such as age, blood pressure, and body size. Genetic influences may account for part of the unexplained variance. The central (aortic) pressure augmentation index has been suggested as a noninvasive measure of pulsatile load, which is a likely determinant of left ventricular mass. We quantified the genetic influence on augmentation index and determined the extent to which this influence is dependent on the effects of age, height, heart rate, and blood pressure. We performed a classical twin study composed of 225 monozygotic and 594 dizygotic female white twin pairs aged 18 to 73 years. Augmentation index and mean arterial pressure were based on the central pressure wave derived from the radial waveform as measured by applanation tonometry. Quantitative genetic modeling techniques were used to analyze the data. The heritability of augmentation index was 37%, whereas heritabilities for blood pressure traits varied between 13% and 25%. Most of the variance in augmentation index could be explained by genetic and environmental factors specifically influencing augmentation index. Only a relatively small part of the total variance in augmentation index could be attributed to genes in common with height (3.1%), heart rate (4.6%), and mean arterial pressure (5.6%). Age explained 19% of the total variation in augmentation index. In conclusion, augmentation index has a significant heritable component, which is largely independent of the influence of blood pressure, heart rate, height, and age. Finding genes for the augmentation index could help to unravel pathophysiological mechanisms causing left ventricular hypertrophy and lead to improvements in prevention, diagnosis, and treatment of at-risk populations.