Vitamin D Receptor and Megalin Gene Polymorphisms and Their Association With Obesity, Central Obesity and the Metabolic Syndrome

Adiposity, especially central adiposity, is a key component of the metabolic syndrome (MetS), which is accompanied by hyperglycemia, elevated blood pressure, lower HDL cholesterol and hypertriglyceridemia.(Ford, et al., 2003,Grundy, 1999)_ENREF_4 MetS increases the risk of type 2 diabetes (T2D) and cardiovascular disease by 1.7- and 5-folds, respectively.(Alberti, et al., 2009,Ford, et al., 2003,Galassi, et al., 2006) MetS is heritable and polygenic.(Maes, et al., 1997) Genetic variability contributes to 16%-85% of changes in Body Mass Index (BMI)(Yang, et al., 2007) and 37%-81% in waist circumference (WC) (e.g.(Ochs-Balcom, et al., 2011)). MetS is a major public health concern, increasing all-cause mortality rates, disability and health care costs.(Appels and Vandenbroucke, 2006,Bender, et al., 2006,Colditz, 1999,Doig, 2004,Ferrucci and Alley, 2007,Hill, et al., 2004,Solomon and Manson, 1997,Stevens, 2000,Wolf and Colditz, 1998) Obesity is implicated in the etiology of vitamin D deficiency. Serum 25-hydroxyvitamin D [25(OH)D] concentration correlates inversely with adiposity.(Beydoun, et al., 2010,Dorjgochoo, et al., 2012) Conversely, vitamin D3 may play a role in obesity by modulating intracellular calcium homeostasis, because higher intracellular calcium triggers lipogenesis and suppresses lipolysis.(Zemel, 2003) Many organs express vitamin D receptor (VDR), a part of the nuclear hormone receptor super-family. The VDR-1,25(OH)2D3 complex modulates transcription of vitamin D responsive genes(Kato, 2000) and influences adipocyte differentiation both in vitro and in vivo.(Wood, 2008) Epidemiological studies have shown associations of VDR gene polymorphisms with adiposity and related metabolic disorders.(Filus, et al., 2008,Grundberg, et al., 2004,Gu, et al., 2009,Ochs-Balcom, et al., 2011,Oh and Barrett-Connor, 2002,Ortlepp, et al., 2001,Ortlepp, et al., 2003,Speer, et al., 2001,Ye, et al., 2001) However, studies specifically examining adiposity outcomes either had small sample sizes (<400), (e.g.(Filus, et al., 2008,Grundberg, et al., 2004,Speer, et al., 2001)) or were restricted to one sex, (e.g. (Grundberg, et al., 2004,Ochs-Balcom, et al., 2011)) but more importantly were all cross-sectional or case-control by design.(Filus, et al., 2008,Grundberg, et al., 2004,Gu, et al., 2009,Ochs-Balcom, et al., 2011,Oh and Barrett-Connor, 2002,Ortlepp, et al., 2001,Ortlepp, et al., 2003,Speer, et al., 2001,Ye, et al., 2001) MEGALIN (aka low-density lipoprotein receptor-related protein-2 [LRP-2]), is the endocytic vitamin D-binding protein receptor which allows vitamin D entry into cells and whose expression is directly regulated by both vitamin D (Gressner, et al., 2008)) and vitamin A.(Liu, et al., 1998) MEGALIN may influences obesity by mediating leptin transport through the blood-brain barrier and modulating leptin signaling,(Dietrich, et al., 2008) or by facilitating transcytosis of its precursor hormone thyroglobulin.(Lisi, et al., 2005) Collectively, leptin and thyroid hormones affect adiposity through energy metabolism regulation.(Beydoun, et al., 2011) MEGALIN acting also as the receptor for sex-hormone binding globulin (SHBG) may play a role in the interaction between estrogen, vitamin D and intracellular calcium in adipocytes, resulting in sex-specific effects of MEGALIN polymorphisms on obesity phenotypes.(Ding, et al., 2008) In this study, it is hypothesized that selected polymorphisms in VDR and MEGALIN genes have sex-specific associations with several key metabolic disturbances in a longitudinal study of African-American urban adults.