Svetlana Trofimov

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.

Transmission Disequilibrium Test for Hand Bone Mineral Density and 11q12-13 Chromosomal Segment

Abstract:The main aim of the present study was to test the hypothesis that the bone mineral density (BMD) assessed from radiographs of the hand phalanges in a random sample of ethnically homogeneous pedigrees is linked to the 11q12-13 chromosomal segment. The data for the study were gathered from 574 Chuvasha individuals belonging to two- and three-generation pedigrees who live in small villages in the Bashkortostan autonomy, Russia. Preliminary statistical-genetic analysis of the BMD in the pedigrees studied showed that potential genetic effects were highly significant (p<0.001, in comparison with the model assuming no genetic effect), and explained at least 36% of the BMD variation adjusted for sex and age differences. For the transmission/disequilibrium test (TDT) used in our study, a total of 163 nuclear families with two sibs on average were available. Seven DNA microsatellite markers (D11S1313, D11S1765, D11S987, D11S913, D11S983, D11S1314, D11S916) with average spacing of 2 cM on the chromosomal area 11q12-13 were selected for the TDT. The nominal p values (p<0.05–0.0015) obtained from three TDT-type tests used for random and extreme-threshold sampling designs pointed consistently to possible linkage disequilibrium between BMD and some of the DNA markers. There was evidence for possible linkage disequilibrium in the upper part of the chromosomal segment studied (markers D11S1313 and D11S1765), and also in the lower part (markers D11S1983 and D11S1314). The lowest nominal p values (0.0015–0.0067) were obtained from three TDT-type tests for marker D11S1313. However, our findings must still be treated with great caution.

Genetic and environmental determinants of hepatocyte growth factor levels and their association with obesity and blood pressure.

Background: Hepatocyte growth factor (HGF) is a member of the adipocytokine family; it is implicated in tissue repair, regeneration, and angiogenesis. Several studies have reported that the HGF plays important role in obesity and cardiovascular disease. Aim: This study examines whether HGF and its phenotypic correlations with obesity and blood pressure (BP), in healthy individuals, are due to shared genetic or common environmental factors. Subjects and methods: Body mass index (BMI), waist-to-hip ratio (WHR), BP, and HGF plasma concentrations were measured in a sample of 733 individuals belonging to 248 pedigrees. Results: The most significant phenotypic correlations were found among HGF, WHR, and systolic BP (p < 0.001). Analysis of the familial aggregation revealed that parent–offspring and sibling correlations in HGF levels, adjusted for age, age2, and sex, were statistically highly significant (p < 0.001). Variance decomposition analysis showed that when adjusted for potential covariates, 48.4% of the HGF variation was due to putative genetic factors. The genetic correlations between all pairs of studied traits (HGF, WHR, and SBP) were statistically significant (p < 0.02) and ranged between 0.23 ± 0.07 and 0.40 ± 0.07. However, correlation between WHR and BP becomes non-significant after adjustment for HGF. Conclusions: The results provide evidence that putative genetic factors involved in regulation of HGF variation contribute also significantly to variation of the obesity and BP. It is possible that the familial resemblance for WHR and the SBP correlation in the studied sample is affected substantially by genetic factors regulating circulating HGF levels.

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.

Significant association between body composition phenotypes and the osteocalcin genomic region in normative human population

Osteocalcin, a major inorganic component of bone matrix and marker of bone formation, is also involved in regulation of glucose and fat mass metabolism. However, much uncertainty remains about whether the above effect on fat mass has a genetic component. Our main aim was to test whether a variation of body composition phenotypes is associated with BGLAP genomic region variants. To achieve this aim, we used an ethnically homogeneous discovery sample of 230 families consisting of 1112 apparently healthy individuals (561 males and 551 females) of European origin. We conducted association analysis between six SNPs and five obesity-related phenotypes: plasma levels of leptin, anthropometrical fat mass (FM), principal component scores of eight skinfold (SK_PC) and nine circumference (CR_PC) measurements, and body mass index (BMI). Two powerful and robust tools were applied: the pedigree disequilibrium test and variance component models, taking into account both familial and genetic effects. Significant association results were observed for all phenotypes. The most significant results were observed between the haplotype composed of three SNPs (rs2758605-rs1543294-rs2241106) and BMI (p=8.07(-7)), and CR_PC (p=5.29(-5)). The association with BMI was tested and confirmed in our replication study, including 2244 unrelated adult US Caucasians, who were previously assessed for whole genome SNP data. In addition, we obtained an evidence of potential non-additive interactions between the above three SNPs concerning their association with BMI. Bioinformatics sources suggest that the aforementioned interaction could originate from different genetic loci in this region; however, ascertaining the exact circumstances requires a detailed molecular-genetic study.

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.

Elevated plasma fractalkine levels are associated with higher levels of IL-6, Apo-B, LDL-C and insulin, but not with body composition in a large female twin sample

OBJECTIVE Plasma fractalkine (FRACT) is involved in the development of numerous inflammatory conditions including atherosclerosis. It is associated with type 2 diabetes mellitus and adipose inflammation. However, whether FRACT is associated with major risk factors for cardiovascular disease, in particular obesity, metabolic syndrome and blood lipids, is virtually unknown. METHODS The study included a large community-based sample of 3306 middle-aged women drawn from the general UK population. Blood samples were analyzed for circulating levels of FRACT, leptin, insulin, glucose, LDL-C, HDL-C, Apo-A, ApoB and IL-6. Obesity was assessed by fat body mass (FBM) using dual-energy x-ray absorptiometry and by body mass index (BMI). RESULTS We found no association between FRACT and body composition, in particular adiposity. Obese and non obese subjects with metabolic syndrome tended to have higher levels of FRACT compared with non-obese subjects without metabolic syndrome but this did not reach statistical significance. Most importantly we report significant correlations between FRACT and circulating IL-6, Apo-B, LDL-C and insulin. The associations with IL-6 and Apo-B were particularly significant (P-value<0.001), and survived correction for multiple testing and adjustment for age and other covariates. CONCLUSION Higher FRACT levels correlated with elevated levels of IL-6, Apo-B, LDL-C and insulin, all known risk factors for several clinical related diseases suggesting a potential role of FRACT in inflammation and tissue injury. Variations of FRACT levels are not influenced by body composition and are not correlated with leptin indicating that fat mass alone is not responsible for elevation of FRACT seen in obese individuals.

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.

Age and genetic determinants of variation of circulating levels of the receptor for advanced glycation end products (RAGE) in the general human population

In stark contrast to many other blood biomarkers, including a variety of inflammatory cytokines, the main factors affecting sRAGE variation in the general human population are virtually unknown. We examined the contribution of age, body composition, and putative genetic sources to the interindividual variation of sRAGE. Its plasma levels were measured in 1557 apparently healthy individuals from 359 nuclear families. Statistical analysis revealed that all the aforementioned factors are statistically significantly associated with sRAGE levels. The levels of sRAGE consistently decreased with age (R=-0.264, p=<0.001) and with the indices of obesity, such as BMI. However, of special interest was the highly significant and previously not reported independent correlation with fat free mass (p<0.001). The putative genetic effects explained 0.291 ± 0.089 of sRAGE variation and were solely responsible for the phenotypic correlations with the obesity phenotypes (genetic correlations, -0.22 ± 0.09 and -0.33 ± 0.09). Taken together, these data suggest that although genetically determined to a substantial degree, the sRAGE levels also depend on age and obesity, which in turn, increase the risk for a variety of pathological conditions associated with sRAGE. Clearly, identifying the metabolic pathways and specific genetic factors is the next important stage in this research area.

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.