On the association of common and rare genetic variation influencing body mass index: a combined SNP and CNV analysis

Background

As the architecture of complex traits incorporates a widening spectrum of genetic variation, analyses integrating common and rare variation are needed. Body mass index (BMI) represents a model trait, since common variation shows robust association but accounts for a fraction of the heritability. A combined analysis of single nucleotide polymorphisms (SNP) and copy number variation (CNV) was performed using 1850 European and 498 African-Americans from the Study of Addiction: Genetics and Environment. Genetic risk sum scores (GRSS) were constructed using 32 BMI-validated SNPs and aggregate-risk methods were compared: count versus weighted and proxy versus imputation.

Results

The weighted SNP-GRSS constructed from imputed probabilities of risk alleles performed best and was highly associated with BMI (p = 4.3×10⁻¹⁶) accounting for 3% of the phenotypic variance. In addition to BMI-validated SNPs, common and rare BMI/obesity-associated CNVs were identified from the literature. Of the 84 CNVs previously reported, only 21-kilobase deletions on 16p12.3 showed evidence for association with BMI (p = 0.003, frequency = 16.9%), with two CNVs nominally associated with class II obesity, 1p36.1 duplications (OR = 3.1, p = 0.009, frequency 1.2%) and 5q13.2 deletions (OR = 1.5, p = 0.048, frequency 7.7%). All other CNVs, individually and in aggregate, were not associated with BMI or obesity. The combined model, including covariates, SNP-GRSS, and 16p12.3 deletion accounted for 11.5% of phenotypic variance in BMI (3.2% from genetic effects). Models significantly predicted obesity classification with maximum discriminative ability for morbid-obesity (p = 3.15×10⁻¹⁸).

Conclusion

Results show that incorporating validated effect sizes and allelic probabilities improve prediction algorithms. Although rare-CNVs did not account for significant phenotypic variation, results provide a framework for integrated analyses.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-368) contains supplementary material, which is available to authorized users.     

Crosstalk between Adipocytes and Immune Cells in Adipose Tissue Inflammation and Metabolic Dysregulation in Obesity

Recent findings, notably on adipokines and adipose tissue inflammation, have revised the concept of adipose tissues being a mere storage depot for body energy. Instead, adipose tissues are emerging as endocrine and immunologically active organs with multiple effects on the regulation of systemic energy homeostasis. Notably, compared with other metabolic organs such as liver and muscle, various inflammatory responses are dynamically regulated in adipose tissues and most of the immune cells in adipose tissues are involved in obesity-mediated metabolic complications, including insulin resistance. Here, we summarize recent findings on the key roles of innate (neutrophils, macrophages, mast cells, eosinophils) and adaptive (regulatory T cells, type 1 helper T cells, CD8 T cells, B cells) immune cells in adipose tissue inflammation and metabolic dysregulation in obesity. In particular, the roles of natural killer T cells, one type of innate lymphocyte, in adipose tissue inflammation will be discussed. Finally, a new role of adipocytes as antigen presenting cells to modulate T cell activity and subsequent adipose tissue inflammation will be proposed.     

Mammalian non-classical major histocompatibility complex I and its receptors: Important contexts of gene,evolution, and immunity

The evolutionary conserved, less-polymorphic, nonclassical major histocompatibility complex (MHC) class I molecules: Qa-1 and its human homologue human leukocyte antigen-E (HLA-E) along with HLA-F, G and H cross-talk with the T-cell receptors and also interact with natural killer T-cells and other lymphocytes. Moreover, these nonclassical MHC molecules are known to interact with CD94/NKG2 heterodimeric receptors to induce immune responses and immune regulations. This dual role of Qa-1/HLA-E in terms of innate and adaptive immunity makes them more interesting. This review highlights the new updates of the mammalian nonclassical MHC-I molecules in terms of their gene organization, evolutionary perspective and their role in immunity.     

The discovery of reverse tricyclic pyridone JAK2 inhibitors. Part 2: Lead optimization

This communication discusses the discovery of novel reverse tricyclic pyridones as inhibitors of Janus kinase 2 (JAK2). By using a kinase cross screening approach coupled with molecular modeling, a unique inhibitor–water interaction was discovered to impart excellent broad kinase selectivity. Improvements in intrinsic potency were achieved by utilizing a rapid library approach, while targeted structural changes to lower lipophilicity led to improved rat pharmacokinetics. This multi-pronged approach led to the identification of 31, which demonstrated encouraging rat pharmacokinetics, in vivo potency, and excellent off-target kinase selectivity.     

Body mass index and relative handgrip strength are associated with the prevalence of hypertension in Korean elderly: Korean national fitness assessment in 2019

[Purpose]This study aimed to analyze the prevalence of hypertension according to the body mass index (BMI) and relative handgrip strength (RHGS) among elderly individuals in Korea. [Methods]We analyzed the data of 44,183 Korean elderly individuals over 65 years old (men: n = 15,798, age = 73.31 ± 5.04 years, women: n = 28,385, age = 72.14 ± 5.04 years) obtained from the Korean National Fitness Assessment in 2019. All the participants were categorized into three groups according to the BMI and RHGS; additionally, one-way ANOVA and logistic regression analysis were performed. [Results]Overweight (men: 1.16 odds ratio [OR] 1.06–1.26, 95% confidence interval [CI]; women: 1.15 OR, 1.07–1.23 95% CI) and obese (men: 1.54 OR, 1.42–1.66 95% CI; women: 1.44 OR, 1.36–1.53 95% CI) elderly individuals showed a higher prevalence of hypertension than elderly individuals with normal weight, after controlling for age. In men, a lower RHGS was associated with a higher prevalence of hypertension after controlling for age (weak RHGS: 1.09 OR, 1.00–1.17 95% CI; middle RHGS: 1.21 OR, 1.12–1.31 95% CI vs. strong RHGS). [Conclusion]A higher BMI was associated with the prevalence of hypertension in the elderly Korean population. In addition, a lower RHGS was associated with the prevalence of hypertension in elderly Korean men.     

A karyological study of some Dianthus L. species (Caryophyllaceae) in Northeast of Iran

This study focuses on karyological investigation of four taxa of Dianthus (Caryophyllaceae) including D. crossopetalus, D. orientalis subsp. stenocalyx, D. orientalis subsp. gorganicus, and Dianthus sp. distributed in Northeast of Iran. The karyotype asymmetry/symmetry was evaluated using two methods: 1) CVCL (coefficient of variation of chromosome length) and CVCI (heterogeneity of the centromeric index); and 2) MCA (mean centromeric asymmetry). The karyotype asymmetry was also used to investigate the relationships among the taxa. Results obtained from the current study revealed that there are two different ploidy levels (2n = 2x = 30 and 2n = 4x = 60) among the investigated taxa. The indices CVCL and MCA described karyotype asymmetry correctly based on variation in chromosome length. Diagram of CVCL vs. MCA seems to be appropriate for karyological delimitation and taxonomic relationships among the Dianthus taxa under study. (© 2014 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)     

A biophysical characterization of the folded domains of KCTD12: insights into interaction with the GABAB2 receptor

Recent investigations have shown that members of the KCTD family play important roles in fundamental biological processes. Despite their roles, very limited information is available on their structures and molecular organization. By combining different experimental and theoretical techniques, we have here characterized the two folded domains of KCTD12, an integral component and modulator of the GABA_B2 receptor. Secondary prediction methods and CD spectroscopy have shown that the N‐terminal domain KCTD12_BTB assumes an α/β structure, whereas the C‐terminal domain KCTD12_H1 is predominantly characterized by a β‐structure. Binding assays indicate that the two domains independently expressed show a good affinity for each other. This suggests that the overall protein is likely endowed with a rather compact structure with two interacting structured domains joint by a long disordered region. Notably, both KCTD12_BTB and KCTD12_H1 are tetrameric when individually expressed. This finding could modify the traditional view that ascribes only to POZ/BTB domain a specific oligomerization role. The first quantification of the affinity of KCTD12_POZ/BTB for the C‐terminal region of GABA_B2 shows that it falls in the low micromolar range. Interestingly, we also demonstrate that a GABA_B2‐related peptide is able to bind KCTD12_BTB with a very high affinity. This peptide may represent a useful tool for modulating KCTD12/GABA_B2 interaction in vitro and may also constitute the starting point for the development of peptidomimetic compounds with a potential for therapeutic applications. Copyright © 2013 John Wiley & Sons, Ltd.     

Allosteric Inhibition as a New Mode of Action for BAY 1213790, a Neutralizing Antibody Targeting the Activated Form of Coagulation Factor XI

Factor XI (FXI), the zymogen of activated FXI (FXIa), is an attractive target for novel anticoagulants because FXI inhibition offers the potential to reduce thrombosis risk while minimizing the risk of bleeding. BAY 1213790, a novel anti-FXIa antibody, was generated using phage display technology. Crystal structure analysis of the FXIa–BAY 1213790 complex demonstrated that the tyrosine-rich complementarity-determining region 3 loop of the heavy chain of BAY 1213790 penetrated deepest into the FXIa binding epitope, forming a network of favorable interactions including a direct hydrogen bond from Tyr102 to the Gln451 sidechain (2.9 Å). The newly discovered binding epitope caused a structural rearrangement of the FXIa active site, revealing a novel allosteric mechanism of FXIa inhibition by BAY 1213790. BAY 1213790 specifically inhibited FXIa with a binding affinity of 2.4 nM, and in human plasma, prolonged activated partial thromboplastin time and inhibited thrombin generation in a concentration-dependent manner.     

Synthesis,Molecular Structure,and Chiroptical Properties of Dibenzylidene Derivatives of Bicyclo[3.3.1]nonane and Brexane

Synthesis of several enantiomerically pure unsaturated bicyclo[3.3.1]nonane and related brexane (tricyclo[4.3.0.0^3,7]nonane) derivatives bearing exocyclic benzylidene substituents from readily available (+)‐(1S,5S)‐bicyclo[3.3.1]nonane‐2,6‐dione was accomplished. Molecular geometry and chiroptical properties of compounds with enone and styrene chromophores were studied by X‐ray diffraction analysis, molecular modeling, and circular dichroism (CD) spectroscopy. Difunctional 3,7‐dibenzylidenebicyclo[3.3.1]nonanes, such as 2 and 7 , 8 , 9 , exhibited intense CD couplets, arising from the exciton coupling between the two unsaturated chromophores. The observed negative sign of the exciton couplets is congruent with the negative twist (negative chirality) defined by the two interacting transition dipoles. The sign of the Cotton effect corresponding to the π→π* transitions in the CD spectra of monoenone 4 and tricyclic brexane acetate 11 was correlated with the intrinsic dissymmetry (helicity) of the styrene chromophore. Chirality 27:728–737, 2015. © 2015 Wiley Periodicals, Inc.