Vitamin D-related Genes and Metabolic Disorders
Condition: Metabolic Syndrome; Obesity; Central Obesity
MeSH terms: Obesity; Metabolic Syndrome; Obesity, Abdominal; Syndrome
Study type: Observational

Summary: 
      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.
    

Detailed description: 
      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.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Of the 3,720 baseline participants (mean±SD age(y) of 48.3±9.4, 45.3% men, and 59.1%
        African-American), genetic data were available on 1,024 African-American participants.
        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). 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). There were n=294 MetS-free individuals at baseline (Figure 1).
      
Biospecimen description: 
      Study participants were genotyped to 907,763 single nucleotide polymorphisms (SNPs) using the
      Illumina 1M and 1M-Duo genotyping arrays. Sample quality control inclusion criteria were: (1)
      concordance between self-reported sex and X-chromosome estimated sex; (2) sample call rate
      >95%, (3) concordance between self-reported African ancestry and ancestry estimated using
      genotyped SNPs, and (4) proportional sharing of genotypes < 15% between samples, excluding
      close relatives from the final sample. SNPs in HANDLS were selected when the following
      criteria were met: (1) Hardy-Weinberg equilibrium p-value (HWE P >10-7); (2) Missing by
      haplotype P > 10-7; (3) Minor allele frequency>0.01, and (4) SNP call rate >95%. Quality
      control and data management for each genotype was conducted using PLINKv1.06.
    
Keywords: VDR, MEGALIN, haplotypes, obesity, metabolic syndrome