**8. References**


We have used the multivariate statistical framework of structural equation modeling (SEM) to evaluate multiple genetic determinants of MetSyn and aggregate effects of individual genes by modeling MetSyn as a second-order factor together with multiple putative candidate genes represented by latent constructs, which we mathematically defined by multiple SNPs in each gene (Nock et al., 2009b). Using this approach with the Framingham Heart Study (Offspring Cohort, Exam 7; Affymetrix 50k Human Gene Panel) data, we found that the CETP gene had a very strong association with the Dyslipidemia factor but little effect on MetSyn directly. Furthermore, we found that the effects of the CSMD1 gene diminished when modeled simultaneously with six other candidate genes, most notably CETP and STARD13. Work to identify the genetic determinants of 'Syndrome Z', modeled as a higher-order, unifying syndrome defined by 5 first-order factors (dyslipidemia, insulin resistance, obesity, hypertension, sleep disturbance) (Nock et al., 2009a) using the latent

The use of other forms of 'causal modeling' (edge/node; integrative genetics) has been proposed (Lusis et al., 2008), particularly, to improve our understanding of differential effects by gender as well as to better understand how maternal nutrition and epigenetics affect MetSyn. Furthermore, a complex model for the genetic determinants of MetSyn associated phenotypes was recently proposed and, using gene enrichment analysis and protein-protein interaction network approaches, the retinoid X receptor and farnesoid X receptor (FXR) were identified as key players in MetSyn given their multiple interactions with metabolism, cell proliferation and oxidative stress (Sookoian and Pirola, 2011). However, more elegant kinetic models may be required to understand the true influence of genetic variants on Dsylipidemia and MetSyn given the presence of multiple feedback loops

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polymorphism on serum lipids and lipoprotein changes from childhood to


**7** 

*Osaka University* 

*Japan* 

**Functions of OSBP/ORP Family Proteins** 

The pathway of intracellular cholesterol synthesis, uptake and efflux is much affected by both the positive and the negative feedbacks from direct interaction between cholesterol and its oxygenated derivatives (oxysterols) as well as the regulatory factors such as the sterolregulatory-element-binding protein (SREBP)– cleavage-activating protein–Insig complex (Radhakrishnan, Ikeda et al. 2007), 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (Sever, Song et al. 2003) and liver X receptors (LXRs) (Chen, Chen et al. 2007). Since these regulatory factors are located in the compartments with comparatively low cholesterol density, they can react promptly on acute changes in local cholesterol or oxysterol density. While much is known about the interaction between these regulatory factors and cholesterol, only little has been studied about the mechanism to deliver the cholesterol or

Therefore, there arises a possibility that oxysterol-binding protein/oxysterol-binding protein-related protein (OSBP/ORP) family may regulate such processes by binding oxyterol and/or cholesterol and by functioning as a cholesterol sensor or cholesterol transporter. According to the study about the family members, it is now becoming clear that

For comprehensive information on OSBP/ORP family, please refer to several good reviews already published (Fairn and McMaster 2008; Ngo, Colbourne et al. 2010; Raychaudhuri and Prinz 2010; Vihervaara, Jansen et al. 2011). This review focuses more on the family's association with dyslipidemia from a perspective of the individual features of the structure, the expression, the cellular localization, the molecular functions, and the epidemiologial

**2. Overview of functions of OSBP/ORP family proteins and their relation to** 

It has become widely known that each member of OSBP/ORP family respectively affects diverse processes considered to have an association with dyslipidemia, such as intracellular trafficking of cholesterol or neutral lipid. The first presented is a brief overview of the

they affect the regulation such as the cholesterol or triglyceride level.

members as a whole before the individual explanation of each member.

**1. Introduction** 

oxysterol to its appropriate compartments.

study-based information of each member.

**dyslipidemia** 

**and Their Relation to Dyslipidemia** 

Hiroshi Koriyama, Hironori Nakagami, Tomohiro Katsuya and Ryuichi Morishita

