Ia Pantsulaia

Association of leptin levels with obesity and blood pressure: possible common genetic variation

OBJECTIVE:To ascertain the extent to which relationships between obesity (OB) and blood pressure (BP) can be explained by an individuals leptin plasma levels.DESIGN:Pedigree-based cross-sectional study in an apparently healthy population of European origin.SUBJECTS:The study sample is comprised of 90 nuclear and more complex families totaling 210 male and 213 female subjects aged 18–75 y, randomly recruited in Bashkorstan Autonomic region, Russia.MEASUREMENTS:Various fatness and fat distribution traits (including nine circumferences (CRCs), and eight skinfolds (CKFs) by anthropometry), blood pressure, and plasma leptin levels (by ELISA kits).RESULTS:Adjustment for circulating leptin led to attenuation of the magnitude of correlations between OB and BP, regardless of trait pair and sex cohort. Some of these correlations became statistically nonsignificant. All familial effects were gone, and heritability estimates became virtually zero after adjustment of each of the OB traits and systolic blood pressure (SBP) in offspring for leptin values in parents.CONCLUSION:BP and OB covariation is substantially mediated by circulating leptin levels. As a result, body fat has only a weak independent effect on BP variation after adjustment for leptin levels. Our findings also strongly suggest that genetic variation in body mass index, SKFs, and even body CRCs, as well as of SBP is due to genetic variation of leptin. Genetic variation of diastolic blood pressure in the present sample, however, shared very little with that of leptin.

Genetic variation of circulating leptin is involved in genetic variation of hand bone size and geometry

Leptin is secreted primarily by the adipocytes and plays an important role in the regulation of food intake and energy expenditure. In addition to its adipostatic function, it has been demonstrated that leptin directly enhances stromal cell differentiation to osteoblasts, and since such precursor cells are potential targets for leptin, the latter could possibly mediate the relationship between obesity and bone mass and size. To address this question, we studied phenotypic and genetic correlations between the circulating levels of leptin and hand bone size (BS) and geometry (BG) of the radiographic hand in a healthy and ethnically homogeneous sample of pedigrees. We also attempted to evaluate to what extent potential leptin/BS/BG correlations are modified by an individuals obesity traits, specifically his/her BMI. Our research has shown that leptin, BMI and the corresponding bone measures are clearly inherited traits (0.46±0.11, 0.35±0.16, 0.62±0.12 and 0.51±0.09, respectively). The bivariate variance component analysis revealed very strong and significant genetic and environmental correlations between circulating leptin and BMI (rG=0.86±0.09, rE=0.75±0.05, P<0.001). Furthermore, genetic correlations between leptin and hand bone characteristics proved inverse and statistically significant (rG=–0.35±0.01 and −0.45±0.10 for BS and BG, respectively), while corresponding environmental correlations were low (rE=–0.14±0.15 and −0.07±0.14) and they could be constrained to zero without significant deterioration of the model fit to the data (P>0.10). However, despite the extremely strong relationship between leptin and BMI, we failed to detect phenotypic or genetic correlations between BMI and our two hand bone measures. Thus our study provided evidence that plasma leptin levels may be statistically significant predictor of hand bone size and geometry, and may play a physiological role in maintaining bone mass as well as in regulation of hand bone proportions.

Relationship between obesity, adipocytokines, and blood pressure: possible common genetic and environmental factors.

Adipokines may link adipose tissue to the inflammatory, metabolic, and immune dysregulation. The variation of adipokine levels within individuals, intercorrelations, and relationships to well‐established measures of adiposity are incompletely defined. The main goal of the present study was quantitative evaluation of the genetic interrelationships between obesity and adipokines in normal human population. The study sample comprised 272 families of various sizes, including 530 men and 531 women aged 18–80 years, randomly recruited in rural population living in Russia. Various fatness and fat distribution measures (OB), blood pressure (BP), and plasma levels of several adipokines (AC), such as adiponectin, leptin, resistin, and IGFBP‐1, have been measured. The likelihood ratio tests clearly revealed that genetic effect for all studied phenotypes was highly significant (P < 0.001) and accounted for 45.9% ± 8.1%, 33.7% ± 7.9%, 35.7% ± 9.8% of variation for AC, OB, and BP, respectively. The pairwise bivariate analyses showed that strong phenotypic correlation between the obesity (OB) and adipocytokines (AC) was caused by both common genetic and environmental factors (rG = 0.597 ± 0.116, rE = 0.671 ± 0.051). The phenotypic correlation between BP and OB is explained by shared genetic factors only (rG = 0.532 ± 0.109), whereas the phenotypic correlation between BP and AC has only common environment basis (rE = −0.212 ± 0.081) and was mostly due to the correlation observed in females. Our results suggest that genetic factors play a significant role in regulation of variation of the examined traits. The variation of OB traits is almost fully due to genes influencing variation of AC, whereas the correlation between BP and AC is only marginally significant and caused only by shared environment. Am. J. Hum. Biol., 2009.

Genetic and environmental determinants of circulating levels of angiogenin in community-based sample.

Background  Measurement of angiogenin in plasma provides important prognostic and diagnostic information in variety of malignancies and may even correlate with cancers progression. Nevertheless, nowadays, specific physiological mechanisms of this protein action as well as major factors regulating its circulating levels normally and in pathology are still poorly understood. The main objectives of this study were to examine the contribution of a number of endogenous factors, such as sex, age, body size and genetic effects on the production of angiogenin in apparently healthy individuals, and to assess the correlations in circulating levels between angiogenin and other molecules involved in angiogenesis.

Pedigree-based quantitative genetic analysis of interindividual variation in circulating levels of IGFBP-3

Abstract. Circulating levels of insulin-like growth factor binding protein-3 (IGFBP-3) vary greatly between normal individuals, but until now little attention has been given to the study of the genetic factors involved in IGFBP-3 variability in healthy populations. The present study investigated the extent and pattern of the possible genetic influences on plasma levels of IGFBP-3 in 91 nuclear and more complex families, totaling 396 individuals (201 males and 195 females) of Caucasian ethnic origin. The variance decomposition analysis, was performed using the FISHER statistical package. In the second stage of the analysis, we used complex segregation analysis as implemented in the statistical package MAN. Significant negative correlation was revealed between age and plasma levels of IGFBP-3 in both sexes (r = −0.49; r = −0.23; P < 0.001). Multivariate analysis identified age, body weight, and height as significant covariates in men, but for women only age had a considerable effect. It has been demonstrated that about 57.7% of IGBP-3 variation adjusted for significant confounding factors was attributable to genetic factors. The results of bivariate variance decomposition analysis showed no significant genetic and phenotypic correlation between the mineral density of hand bones and IGFBP-3. Segregation analysis revealed the existence of a potential major gene effect that was able to explain some 27.5% of IGFBP-3 variation. Multifactorial effects, likely, unknown minor genes, contributed an additional 30% to IGFBP-3 variation. The segregation analysis also provided evidence of significant genotype X sex interaction in the determination of plasma levels of IGFBP-3.

The Contribution of Familial Resemblance to Variation in Circulatory Levels of Tissue Inhibitors of Metalloproteinases and Transforming Growth Factor-β1

This study attempted to elucidate the genetic and environmental factors influencing interindividual variation of circulating TIMP-1, TIMP-2 and TGF-β1 and to clarify the relationship between the latter biochemical indices and hand osteoarthritis in an ethnically homogeneous sample. Plasma levels of each of the above biochemical indices were measured in 401 healthy individuals (aged 18–75 years) belonging to 90 nuclear and more complex families. Variance component analysis showed that a major part of the interindividual differences in TGF-β1, TIMP-1 and TIMP-2 levels was credibly attributable to genetic and familial factors. Adjusted for significant covariates, the putative genetic effects on the above three amounted to 0.40 ± 0.10, 0.47 ± 0.11 and 0.72 ± 0.10, respectively. Common environmental factors, shared by members of the same household, also contributed significantly (P < 0.01) to variation of each of the biochemical indices and explained between 27.6% (TIMP-2) and 38.7% (TGF-β1) of their variation. A bivariate analysis revealed a strong and highly significant correlation between TIMP-1 and TGF-β1 (r = 0.58, P < 0.001), which was due to common genetic and environmental sources (rG = 0.62 ± 0.09, rE = 0.31 ± 0.11, both P < 0.001). The analysis also detected modest but significant genetic correlation between TIMP-1 and TIMP-2 (rG = −0.307 ± 0.108, P < 0.01). The present study evinces a strong genetic dependence for the plasma levels of both TIMPs and TGF-β1 and provides a basis for the further analysis of genetic variation affecting and regulating the circulatory concentrations of TIMPs and TGF-β1 in healthy humans.

Genetic and Environmental Determinants of Variation of Soluble Adhesion Molecules

In our research we examined the contribution of putative genetic sources on interindividual variation and cross‐sectional correlations of several adhesion molecules, including intracellular (ICAM‐1) and vascular cell adhesion molecules (VCAM‐1) and E‐selectin, in a population‐based sample of ethnically homogeneous families of European origin. The plasma levels of these molecules were measured in 947 apparently healthy individuals from 217 nuclear families. Quantitative statistical‐genetic analysis implementing the model fitting technique revealed significant parent/offspring and sibling correlations (p < 0.01) for all three molecules. The putative genetic effects explained 55.2 ± 7.2% (VCAM‐1), 63.3 ± 7.5% (ICAM) and 63.8 ± 8.1% (E‐selectin) of the variation. Common family environmental factors also significantly influenced the variation of E‐selectin (13%) and VCAM‐1 (28.6%). The main results of our bivariate analysis showed that the observed phenotypic correlations between ICAM‐1 and VCAM‐1, and between ICAM‐1 and E‐selectin, were mostly attributable to shared environmental factors (rE= 0.896 and 0.737, respectively; p < 0.01). However, the correlation between VCAM‐1 and E‐selectin was likely caused by common genetic effects (rG= 0.334, p < 0.05). Our results show that familial clustering of adhesion molecules is likely due to strong genetic effects, supplemented with shared environmental factors.