Genetics of Osteoporosis

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Genetics of Osteoporosis

• Hong-Wen Deng, Ph.D.
• Osteoporosis Research Center
• Creighton University, Omaha, NE, USA

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Osteoporosis

• Excessive skeletal fragility leading to low
  trauma fractures.
• Intrinsic skeletal factors low bone mass,
  unfavorable geometry at cortical bone sites,
  small bone size, poor bone structure at
  cancellous bone sites and sluggish or ineffective
  repair of microdamage.
• Extrinsic factors propensity to fall.

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• Osteoporosis
• 1.7 million hip fractures 1990
• 6.3 million hip fractures 2050

• 40 of postmenopausal women, on average, will
  suffer at least one osteoporotic fracture

• Osteoporosis incurs 14 billion dollars in the
  US alone in 1997

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WHO Criteria bone mass values that is gt2.5 SD
below the young adult mean value.
BMD (bone mineral density) measured by
techniques such as DXA (dual energy x-ray
absorptiometry).
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Determination of BMD

• By environmental factors (individual factors as
  well as E x E interaction) (Smoking, nutrition,
  exercises, diseases, medication, alcohol
  consumption etc.) 15-45.
• By genetic factors
• (individual genes as well as epistasis)
  55-85.
• By G x E Interaction ? .

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Segregation analyses

• No major genes
  (Guegen et al., 1995)
• Major genes
  (Livshits et al., 1996 1999 2002 Cardon
  et al., 2000 Deng et al., 2002 Liu et al.,
  2003a, b).

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Genetic correlation

• Significant between BMD at different sites
  (Pocock et al., 1987 Nguyen et al., 1998 Deng
  et al., 1999 Kobyliansky et al., 2000)
• Not significant between BMD and osteoporotic
  fractures (OF) (Deng et al., 2002). At hip,
• h2 BMD 0.65, h2 OF 0.53
• genetic correlation between BMD and OF 0.05.

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Goals of Molecular Genetics of Osteoporosis

• To identify genes for risk of osteoporotic
  fractures
• develop molecular genetic markers for diagnosis,
  prevention, early intervention, and
  individualized treatment
• study molecular and cell functions of mutations
  of genes identified for development of drug and
  effective treatment

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Monogenic bone diseases
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Knockout and transgenic mice (1)
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Knockout and transgenic mice (2)
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Approaches

• Association studies
• Linkage studies
• Transmission Disequilibrium Test (TDT)
• QTL mapping in mice
• gene expression studies
• Proteomics

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Association studies in random samples
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Linkage studies in pedigrees
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Linkage studies in relative pairs
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TDT analyses in children from nuclear families
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QTL mapping in mice (F2 design)
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Candidate Genes Associated with Bone Phenotypes
(1)
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Candidate Genes Associated with Bone Phenotypes
(2)
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VDR Gene (12q12-14)

• VD modulates intestinal calcium absorption,
  osteoclastic and osteoblastic activities, PTH
  production.
• VDR mediates the biological actions of
  1,25(OH)2D3.
• Mutations in VDR gene cause hereditary vitamin
  D-resistant rickets.
• VDR gene knockout mice possess low bone mass,
  hypocalcemia, and hyperparathyroidism.

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Cdx-2
Taq I RFLP

• Morrison et al. (1994) a significant association
  between the Bsm I polymorphism and BMD.
• Meta-analyses BMD is associated with VDR gene
  (Cooper et al., 1996 Gong et al., 1999).

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ER-? Gene (6q25)

• ER-? mediates the physiologic effects of the
  estrogen.
• ER-? expression found in human osteoblasts and
  osteoclasts.
• Estrogen resistance due to a nonsense mutation in
  ER-? gene causes severe osteoporosis (Smith et
  al. 1994).

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• Sano et al. (1995) associations between the TA
  repeat polymorphism and BMD in Japanese women.
• Meta-analysis Xba I polymorphism is associated
  with BMD and OF (Ioannidis et al., 2002).

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COLIA1 Gene (17q21-q22)

• COLIA1 gene encodes the ?1(I) protein chain of
  type I collagen, the most abundant extracellular
  bone matrix protein.
• Mutations in the coding regions of the COLIA1
  gene result in osteogenesis imperfecta.
• COLIA1 knock-out mice exhibits low bone mass and
  high risk fractures.

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• Grant et al. (1996) described an association
  between a G?T polymorphism in a binding motif for
  Sp1 with BMD and OF.
• Meta-analysis Sp1 polymorphism is associated
  with BMD and OF (Mann et al., 2001 Efstathiadou
  et al., 2001).
• Sp1 polymorphism may be functional (Mann et al.,
  2001).

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TDT of candidate genes

• TGF-?1 gene (hip BMD) (Keen et al., 2001)
• VDR (hip BMD), BGP (spine BMD) and PTH genes
  (Deng et al., 2002)
• BGP gene (spine BMD and ultrasound measurements
  of bone) (Andrew et al., 2002)
• ER-? gene (hip and spine BMD) (Qin et al., 2003).

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Interaction studies

• ER-? and VDR genes for BMD (Willings et al.,
  1998)
• VDR and COL1a1 genes for OF (Uitterlinden et al.
  2001)
• VDR gene and Ca2 intake for BMD change (Ferrari
  et al., 1995 Krall et al., 1995 Kiel et al.,
  1997)
• ER-? and VDR genes for BMD change during HRT
  (Deng et al., 1998).

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Genetic basis of racial differentiation

• VDR BsmI and hip OF (Young et al., 1996).
• Sp1 and RsaI of Col1a1,174G/C of IL-6, Asn363Ser
  of GR, and the T-gtC of TGF- ?1 (Lei et al.,
  2002).
• BsaHI of CASR, SacI of AHSG, PvuII and XbaI ER-a,
  ApaI VDR, and BstBI PTH (Dvornyk et al., 2003).