Osteoporosis Excessive skeletal fragility leading to low trauma

Osteoporosis ØExcessive skeletal fragility leading to low trauma fractures. ØIntrinsic 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. ØExtrinsic factors: propensity to fall.

Osteoporosis ð 1. 7 million hip fractures 1990 ð 6. 3 million hip fractures 2050 Ø 40% of postmenopausal women, on average, will suffer at least one osteoporotic fracture Ø 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 FBy environmental factors (individual factors as well as E x E interaction) (Smoking, nutrition, exercises, diseases, medication, alcohol consumption etc. ) ~15 -45%. FBy genetic factors w (individual genes as well as epistasis) ~ 55 -85%. FBy 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. , 2003 a, b).

Genetic correlation ØSignificant between BMD at different sites (Pocock et al. , 1987; Nguyen et al. , 1998; Deng et al. , 1999; Kobyliansky et al. , 2000); ØNot significant between BMD and osteoporotic fractures (OF) (Deng et al. , 2002). At hip, ²h 2 BMD: 0. 65, h 2 OF: 0. 53; ²genetic correlation between BMD and OF: 0. 05.

Goals of Molecular Genetics of Osteoporosis Ø 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

Knockout and transgenic mice (1)

Knockout and transgenic mice (2)

Approaches Ø Association studies Ø Linkage studies Ø Transmission Disequilibrium Test (TDT) Ø QTL mapping in mice Ø gene expression studies Ø 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 (F 2 design)

Candidate Genes Associated with Bone Phenotypes (1)

Candidate Genes Associated with Bone Phenotypes (2)

VDR Gene (12 q 12 -14) Ø VD modulates intestinal calcium absorption, osteoclastic and osteoblastic activities, PTH production. Ø VDR mediates the biological actions of 1, 25(OH)2 D 3. Ø Mutations in VDR gene cause hereditary vitamin D-resistant rickets. Ø VDR gene knockout mice possess low bone mass, hypocalcemia, and hyperparathyroidism.

Cdx-2 Taq I RFLP Ø Morrison et al. (1994): a significant association between the Bsm I polymorphism and BMD. Ø Meta-analyses: BMD is associated with VDR gene (Cooper et al. , 1996; Gong et al. , 1999).

ER- Gene (6 q 25) Ø ER- mediates the physiologic effects of the estrogen. Ø ER- expression found in human osteoblasts and osteoclasts. Ø Estrogen resistance due to a nonsense mutation in ER- gene causes severe osteoporosis (Smith et al. 1994).

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

COLIA 1 Gene (17 q 21 -q 22) COLIA 1 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 COLIA 1 gene result in osteogenesis imperfecta. COLIA 1 knock-out mice exhibits low bone mass and high risk fractures.

Ø Grant et al. (1996) described an association between a G T polymorphism in a binding motif for Sp 1 with BMD and OF. Ø Meta-analysis: Sp 1 polymorphism is associated with BMD and OF (Mann et al. , 2001; Efstathiadou et al. , 2001). Ø Sp 1 polymorphism may be functional ( Mann et al. , 2001).

TDT of candidate genes ØTGF- 1 gene (hip BMD) (Keen et al. , 2001); ØVDR (hip BMD), BGP (spine BMD) and PTH genes (Deng et al. , 2002) ØBGP gene (spine BMD and ultrasound measurements of bone) (Andrew et al. , 2002); ØER- gene (hip and spine BMD) (Qin et al. , 2003).

Interaction studies Ø ER- and VDR genes for BMD (Willings et al. , 1998); Ø VDR and COL 1 a 1 genes for OF (Uitterlinden et al. 2001); Ø VDR gene and Ca 2+ intake for BMD change (Ferrari et al. , 1995; Krall et al. , 1995; Kiel et al. , 1997); Ø ER- and VDR genes for BMD change during HRT (Deng et al. , 1998).

Genetic basis of racial differentiation Ø VDR Bsm. I and hip OF (Young et al. , 1996). Ø Sp 1 and Rsa. I of Col 1 a 1, – 174 G/C of IL-6, Asn 363 Ser of GR, and the T->C of TGF- 1 (Lei et al. , 2002). Ø Bsa. HI of CASR, Sac. I of AHSG, Pvu. II and Xba. I ER-α, Apa. I VDR, and Bst. BI PTH (Dvornyk et al. , 2003).