Transcript Document 7681530

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.
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
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.)
~15-45%.
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.,
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.
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
Monogenic bone diseases
Disease
Osteopetrosis/renal tubular acidosis
Pycnodysostosis
Camurati Engelmann disease
Osteopetrosis, autosomal recessive
Sclerosteosis/Van Buchem’s disease
Osteoporosis-pseudoglioma
High bone mass
Osteopetrosis,autosomal dominant
Osteopetrosis, autosomal recessive
Craniometaphyseal dysplasia, autosomal dominant
Diastrophic dysplasia
Familial expansile osteolysis
Paget’s disease
Spondylocostal dystosis, autosomal recessive
Oculodentodigital dysplasia
Acromegaly
Gene (Locus)
Carbonic anhydrase II
Cathepsin K
TGFβ1
TCIRG1 (11q12)
SOST
LRP-5 (11q12)
LRP-5 (11q12)
CLCN7
CLCN7
ANKH
DTDST
TNFRSFl1A/RANK
TNFRSFl1A/RANK
DLL3
6q22-24
2p-16-12
Reference
Nakai et al., 1987
Shi et al., 1995
Janssens et al., 2000
Frattini et al., 2000
Balemans et al., 2002
Gong et al., 2001
Little et al., 2002
Cleiren et al., 2001
Kornak et al., 2001
Nurnberg et al., 2001
Hastbacka et al., 1994
Hughes et al., 2000
Hughes et al., 2000
Bulman et al., 2000
Gladwin et al., 1997
Gadelha et al., 2000
Knockout and transgenic mice (1)
Candidate gene
Tnrfgf1 1b
Tgfb2
K1
Abl1
Lrp5
Colla1
Colla1
Colla2
Colla1
Tgfb1
Nos3
Sparc
Bgn
Mmp 14
Manipulation
Knockout
Targeted overexpression
Knockout
Knockout
Knockout
Mutation
Knock-in mutation
Mutation
Knockout (+/-)
Knockout
Knockout
Knockout
Knockout
Knockout
Phenotype
Osteoporosis
Osteoporosis
Osteoporosis
Osteoporosis
Osteoporosis
Osteopenia, fractures
Osteopenia, fractures
Osteopenia, fractures
Bone fragility
Osteopenia
Osteopenia
Osteopenia
Osteopenia
Osteopenia
Reference
Bucay et al., 1998
Erlebacher et al., 1996
Kuro-o et al., 1997
Li et al., 2000
Levasseur et al., 2001
Pereira et al., 1993
Forlino et al., 1999
Chipman et al., 1993
Bonadio et al., 1990
Geiser et al., 1998
Aguirre et al., 2001
Delany et al., 2000
Xu et al., 1998
Holmbeck et al., 1999
Knockout and transgenic mice (2)
Candidate gene
Igf1
Tgfbr2
Vdr
Lep/lepr
Gsn
Fosl 1
Fosb
Traf6
Ctsk
Itgb3
Fos
Tnfrgfl 1a
TcirgI
Nfkb1/2
Src
Csf1
Sfpi 1
Tnfrsfl 1b
Manipulation
Targeted overexpression
Targeted truncation
Targeted overexpression
Knockout
Knockout
Overexpression
Overexpression
Knockout
Knockout
Knockout
Knockout
Knockout
Knockout
Double knockout
Knockout
Mutation
Knockout
Overexpression
Phenotype
Increased bone mass
Increased bone mass
Increased bone mass
Increased bone mass
Increased bone mass
Osteoclerosis
Osteoclerosis
Osteopetrosis
Osteopetrosis
Osteopetrosis
Osteopetrosis
Osteopetrosis
Osteopetrosis
Osteopetrosis
Osteopetrosis
Osteopetrosis
Osteopetrosis
Osteopetrosis
Reference
Zhao et al., 2000
Filvaroff et al., 1999
Gardiner et al., 2000
Ducy et al., 2000
Chellaiah et al., 2000
Jochum et al., 2000
Sabatakos et al., 2000
Naito et al., 1999
Saftig et al., 1998
McHugh et al., 2000
Wang et al., 1992
Li et al., 1999
Li et al., 1999
Iotsova et al., 1997
Soriano et al., 1991
Yoshida et al., 1990
Tondavi et al., 1997
Simonet et al., 1997
Approaches
Association studies
Linkage studies
Transmission Disequilibrium Test (TDT)
QTL mapping in mice
gene expression studies
Proteomics
Association studies in random
samples
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
Calciotropic hormones
and receptors
Cytokins, growth
factors, and receptors
Candidate Gene
VDR
ER-
ER-
CT
CTR
PTH
PTHR1
CYP19
GCCR
CASR
AR
TGF-1
IL-6
IGF-1
IL-1RA
OPG
TNF-
TNFR2
Chromosome Location
12q12-14
6q25
14q22-24
11p15
7q21
11p15
3p22-21
15q21
5q31
3q13-21
Xq11-12
19q13
7p21
12q22-24
2q14
8q24
6p21
1p36
Reference
Morrison et al., 1994
Sano et al., 1995
Ogawa et al., 2000
Miyao et al., 2000
Masi et al., 1998
Hosoi et al., 1999
Minagawa et al., 2002
Masi et al., 2001
Huizenga et al., 1998
Tsukamoto et al., 2000
Sowers et al., 1999
Langdahl et al., 1997
Murray et al., 1997
Miyao et al., 1998
Keen et al., 1998
Arko et al., 2002
Fontova et al., 2002
Spotila et al., 2000
Candidate Genes Associated with Bone Phenotypes (2)
Biological Classification
Bone matrix proteins
Miscellaneous
Candidate Gene
COL1A1
COL1A2
BGP
MGP
AHSG
ApoE
MTHFR
P57(KIP2)
HLA-A
PPAR-
FRA-1
RUNX-2
Klotho gene
WRN (Werner
syndrome gene)
Chromosome Location
17q21-22
7q22
1q25-31
12p13-12
3q27
19q13
1p36
11p15
6p21
3p25
11q13
6p21
13q12
8p12-11
Reference
Grant et al., 1996
Suuriniemi et al., 2002
Dohi et al., 1998
Tsukamoto et al., 2000
Dickson et al., 1994
Shiraki et al., 1997
Miyao et al., 2000
Urano et al., 2000
Tsuji et al., 1998
Ogawa et al., 1999
Albagha et al., 2002
Vaughan et al., 2002
Kawano et al., 2002
Ogata et al., 2001
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.
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).
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
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.
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)
2003).
(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).