Vitamin D-related Genes and Metabolic Disorders
Vitamin D-related Genes and Metabolic Disorders
The link between metabolic disturbances and vitamin D receptor (VDR) and MEGALIN (or LRP2)
 gene polymorphisms remains unclear, particularly among African-American adults. The
 associations of single nucleotide polymorphisms (SNPs) for VDR [rs1544410(BsmI:G/A),
 rs7975232(ApaI:A/C), rs731236(TaqI:G/A)] and MEGALIN [rs3755166:G/A,rs2075252:C/T,
 rs2228171:C/T] genes with incident and prevalent metabolic disturbances, including obesity,
 central obesity and metabolic syndrome (MetS) were evaluated.

 From 1,024 African-Americans participating in the Healthy Aging in Neighborhoods of Diversity
 across the Life Span (HANDLS, Baltimore, MD, 2004-2013) study, 539 subjects were selected who
 had complete genetic data as well as covariates selected for metabolic outcomes at two
 consecutive examinations (visits 1 and 2) with a mean follow-up time of 4.64±0.93y. Haplotype
 (HAP) analyses generated polymorphism groups that were linked to incident and prevalent
 metabolic disturbances.
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.
Inclusion Criteria:

 1. 3,720 baseline participants (mean±SD age(y) of 48.3±9.4, 45.3% men, and 59.1%
 African-American),

 2. Genetic data were available on 1,024 African-American participants.

 3. Incomplete covariate data reduced the sample to n=769, while additional exclusions
 lead to a sample size ranging between 574 and 598 participants, with 539 having
 complete data on all baseline and follow-up outcome measures (cross-sectional part of
 the analysis).

 4. In the longitudinal analysis, metabolic disturbance-free at baseline participants were
 selected for each outcome. Sample sizes ranged from n=246 (central obesity-free) to
 n=466 (hyperglycemia-free).

 5. There were n=294 MetS-free individuals at baseline.

 Exclusion Criteria:

 1. Whites in HANDLS, since they did not have any genetic data collected.

 2. All African-Americans in HANDLS without genetic data collected.

 3. All African-Americans in HANDLS with genetic data collected, who had incomplete data
 on key outcome variables and/or basic covariates of interest.