Genetics of Osteoporosis. Part I

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Genetics of Osteoporosis. Part I Powered By Docstoc
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.
  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
WHO Criteria: bone mass values
that is >2.5 SD below the young
adult mean value.

BMD (bone mineral density):
measured by techniques such as
DXA (dual energy x-ray absorptiometry).
    Determination of BMD
By environmental factors (individual
factors as well as E x E interaction)
(Smoking, nutrition, exercises, diseases,
medication, alcohol consumption etc.)

By genetic factors
 (individual genes as well as epistasis )
  ~ 55-85%.

By G x E Interaction ~ ? %.
 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).
       Genetic correlation
Significant between BMD at different
sites (Pocock et al., 1987; Nguyen et al.,
1998; Deng et al., 1999; Kobyliansky et al.,

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:
  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
                 Monogenic bone diseases
Disease                                           Gene (Locus)            Reference
Osteopetrosis/renal tubular acidosis              Carbonic anhydrase II   Nakai et al., 1987
Pycnodysostosis                                   Cathepsin K             Shi et al., 1995
Camurati Engelmann disease                        TGFβ1                   Janssens et al., 2000
Osteopetrosis, autosomal recessive                TCIRG1 (11q12)          Frattini et al., 2000
Sclerosteosis/Van Buchem’s disease                SOST                    Balemans et al., 2002
Osteoporosis-pseudoglioma                         LRP-5 (11q12)           Gong et al., 2001
High bone mass                                    LRP-5 (11q12)           Little et al., 2002
Osteopetrosis,autosomal dominant                  CLCN7                   Cleiren et al., 2001
Osteopetrosis, autosomal recessive                CLCN7                   Kornak et al., 2001
Craniometaphyseal dysplasia, autosomal dominant   ANKH                    Nurnberg et al., 2001
Diastrophic dysplasia                             DTDST                   Hastbacka et al., 1994
Familial expansile osteolysis                     TNFRSFl1A/RANK          Hughes et al., 2000
Paget’s disease                                   TNFRSFl1A/RANK          Hughes et al., 2000
Spondylocostal dystosis, autosomal recessive      DLL3                    Bulman et al., 2000
Oculodentodigital dysplasia                       6q22-24                 Gladwin et al., 1997
Acromegaly                                        2p-16-12                Gadelha et al., 2000
           Knockout and transgenic mice (1)
Candidate gene   Manipulation              Phenotype               Reference
Tnrfgf1 1b       Knockout                  Osteoporosis            Bucay et al., 1998
Tgfb2            Targeted overexpression   Osteoporosis            Erlebacher et al., 1996
K1               Knockout                  Osteoporosis            Kuro-o et al., 1997
Abl1             Knockout                  Osteoporosis            Li et al., 2000
Lrp5             Knockout                  Osteoporosis            Levasseur et al., 2001
Colla1           Mutation                  Osteopenia, fractures   Pereira et al., 1993
Colla1           Knock-in mutation         Osteopenia, fractures   Forlino et al., 1999
Colla2           Mutation                  Osteopenia, fractures   Chipman et al., 1993
Colla1           Knockout (+/-)            Bone fragility          Bonadio et al., 1990
Tgfb1            Knockout                  Osteopenia              Geiser et al., 1998
Nos3             Knockout                  Osteopenia              Aguirre et al., 2001
Sparc            Knockout                  Osteopenia              Delany et al., 2000
Bgn              Knockout                  Osteopenia              Xu et al., 1998
Mmp 14           Knockout                  Osteopenia              Holmbeck et al., 1999
           Knockout and transgenic mice (2)
Candidate gene   Manipulation              Phenotype             Reference
Igf1             Targeted overexpression   Increased bone mass   Zhao et al., 2000
Tgfbr2           Targeted truncation       Increased bone mass   Filvaroff et al., 1999
Vdr              Targeted overexpression   Increased bone mass   Gardiner et al., 2000
Lep/lepr         Knockout                  Increased bone mass   Ducy et al., 2000
Gsn              Knockout                  Increased bone mass   Chellaiah et al., 2000
Fosl 1           Overexpression            Osteoclerosis         Jochum et al., 2000
Fosb             Overexpression            Osteoclerosis         Sabatakos et al., 2000
Traf6            Knockout                  Osteopetrosis         Naito et al., 1999
Ctsk             Knockout                  Osteopetrosis         Saftig et al., 1998
Itgb3            Knockout                  Osteopetrosis         McHugh et al., 2000
Fos              Knockout                  Osteopetrosis         Wang et al., 1992
Tnfrgfl 1a       Knockout                  Osteopetrosis         Li et al., 1999
TcirgI           Knockout                  Osteopetrosis         Li et al., 1999
Nfkb1/2          Double knockout           Osteopetrosis         Iotsova et al., 1997
Src              Knockout                  Osteopetrosis         Soriano et al., 1991
Csf1             Mutation                  Osteopetrosis         Yoshida et al., 1990
Sfpi 1           Knockout                  Osteopetrosis         Tondavi et al., 1997
Tnfrsfl 1b       Overexpression            Osteopetrosis         Simonet et al., 1997

Association studies
Linkage studies
Transmission Disequilibrium Test (TDT)
QTL mapping in mice
gene expression studies
Association studies in random
Linkage studies in pedigrees
Linkage studies in relative pairs
TDT analyses in children from
      nuclear families
QTL mapping in mice (F2 design)
Candidate Genes Associated with Bone Phenotypes (1)
Biological Classification   Candidate Gene   Chromosome Location   Reference
Calciotropic hormones       VDR              12q12-14              Morrison et al., 1994
and receptors               ER-             6q25                  Sano et al., 1995
                            ER-             14q22-24              Ogawa et al., 2000
                            CT               11p15                 Miyao et al., 2000
                            CTR              7q21                  Masi et al., 1998
                            PTH              11p15                 Hosoi et al., 1999
                            PTHR1            3p22-21               Minagawa et al., 2002
                            CYP19            15q21                 Masi et al., 2001
                            GCCR             5q31                  Huizenga et al., 1998
                            CASR             3q13-21               Tsukamoto et al., 2000
                            AR               Xq11-12               Sowers et al., 1999
Cytokins, growth            TGF-1           19q13                 Langdahl et al., 1997
factors, and receptors      IL-6             7p21                  Murray et al., 1997
                            IGF-1            12q22-24              Miyao et al., 1998
                            IL-1RA           2q14                  Keen et al., 1998
                            OPG              8q24                  Arko et al., 2002
                            TNF-            6p21                  Fontova et al., 2002
                            TNFR2            1p36                  Spotila et al., 2000
 Candidate Genes Associated with Bone Phenotypes (2)
Biological Classification   Candidate Gene   Chromosome Location   Reference
Bone matrix proteins        COL1A1           17q21-22              Grant et al., 1996
                            COL1A2           7q22                  Suuriniemi et al., 2002
                            BGP              1q25-31               Dohi et al., 1998
                            MGP              12p13-12              Tsukamoto et al., 2000
                            AHSG             3q27                  Dickson et al., 1994
Miscellaneous               ApoE             19q13                 Shiraki et al., 1997
                            MTHFR            1p36                  Miyao et al., 2000
                            P57(KIP2)        11p15                 Urano et al., 2000
                            HLA-A            6p21                  Tsuji et al., 1998
                            PPAR-           3p25                  Ogawa et al., 1999
                            FRA-1            11q13                 Albagha et al., 2002
                            RUNX-2           6p21                  Vaughan et al., 2002
                            Klotho gene      13q12                 Kawano et al., 2002
                            WRN (Werner      8p12-11               Ogata et al., 2001
                            syndrome gene)
      VDR Gene (12q12-14)
VD modulates intestinal calcium absorption,
osteoclastic and osteoblastic activities, PTH

VDR mediates the biological actions of

Mutations in VDR gene cause hereditary
vitamin D-resistant rickets.

VDR gene knockout mice possess low bone
mass, hypocalcemia, and hyperparathyroidism.

                                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).
       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).
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).
 COLIA1 Gene (17q21-q22)
COLIA1 gene encodes the 1(I) protein
chain of type I collagen, the most
abundant extracellular bone matrix

Mutations in the coding regions of the
COLIA1 gene result in osteogenesis

COLIA1 knock-out mice exhibits low
bone mass and high risk fractures.
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).
    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.,
       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).
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->C of TGF- 1
(Lei et al., 2002).

BsaHI of CASR, SacI of AHSG, PvuII and
XbaI ER-α, ApaI VDR, and BstBI PTH
(Dvornyk et al., 2003).

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