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					Genetics of Osteoporosis

         Dr. Tuan V. Nguyen
    Associate Professor, Senior Fellow
   Bone and Mineral Research Program
   Garvan Institute of Medical Research
            Sydney, Australia
                   Overview

   Osteoporosis – definition and consequences
   Risk factors of fracture
   Genetics of bone mineral density
   Gene hunting
   Candidate genes
   Future ?
             Increase in life expectancy

        80                                                          75
        70
        60                                            55
        50                              43
Years




        40                33
        30    22
        20
        10
         0
             Roman    Middle Age     Mid-19th     Early 1900        Now
             Empire                  century


                      WHO. Human Population: Fundamentals of Growth World Health, 2000.
              The ageing of population

                     Percent of population aged 65+
    25
                        World   Australia

    20


    15
Percent




    10


          5


          0
              1996    2001      2011        2021    2031        2041

                                                   ABS and US Bureau of Census, 1996.
          Osteoporosis – definitions
“[…] compromised bone strength predisposing a
  person to an increased risk of fracture. Bone
  strength primarily reflects the integration of bone
  density and bone quality” (NIH Consensus Development
  Panel on Osteoporosis JAMA 285:785-95; 2001)




                   Osteoporosis  Risk factor
                       Fracture  Outcome
                        Incidence of all-limb fractures

                              500
Rate per 100,000 population




                              400


                              300


                              200


                              100


                                0
                                    0-4   5-14   15-24 25-34 35-44 45-54 55-64 65-74 75-84   85+
                                                            Age group
Annual fracture incidence in Australia 1996-2051
          250
                                                               207.66
          200

                                                     150.74
          150                               125.86
   1000




                                  115.27
                        104.42
                93.75
          100


           50


            0
                2001     2006      2011      2016      2026     2051


           Projected annual number of all-limb fractures in Australia aged
           35+ (Sanders et al, MJA 1999)
Hip, vertebrae, and Colles fractures

  Fracture                 2006                 2051
  Hip                      20,700              60,000
  Vertebrae                14,500              31,700
  Colles                   11,900              23,000
  Humerus                  7,500               16,300
  Pelvis                   4,100                9,800

   Projected annual number of all-limb fractures in Australia aged
   35+(Sanders et al, MJA 1999)
Lifetime risk of some diseases - women

Any osteoporotic fracture                                            1/2
              Hip fracture             1/6
Clinical vertebral fracture                  1/4
        Cancer (any site)*                                2/5
           Breast cancer*            1/8
         Lung/bronchus*       1/16
 Coronary heart diseases                      1/4
        Diabetes Mellitus                           1/3

                          0    10      20      30         40    50   60    70
        *, from birth                Residual lifetime risk (%)
                                       (from the age of 50)
 Lifetime risk of some diseases - men

Any osteoporotic fracture                             1/3
              Hip fracture    1/16
Clinical vertebral fracture          1/8
        Cancer (any site)*                                       3/7
         Prostate cancer*          1/8
         Lung/bronchus*       1/16
 Coronary heart diseases                        1/3
        Diabetes Mellitus                                          1/2

                          0   10           20   30          40    50     60
        *, from birth
                                   Residual lifetime risk (%)
                                     (from the age of 50)
                                                            Survival probability in those
                                                             with and without fracture
                                        A   Women
                                                                                                                                           B   Men
                                  1.0
                                                                                                                                     1.0
                                  0.9
                                                                                                                                     0.9
Cummulative survival proportion




                                                                                                   Cummulative survival proportion
                                  0.8
                                                                                                                                     0.8
                                                                                   Non-fracture
                                  0.7
                                                                                                                                     0.7                                             Non-fracture
                                  0.6
                                                                                                                                     0.6
                                  0.5
                                                                                                                                     0.5
                                  0.4
                                                                                                                                     0.4
                                  0.3                                               Any fracture                                     0.3
                                  0.2
                                                                                                                                     0.2
                                  0.1
                                                                                                                                     0.1                                            Any fracture
                                  0.0
                                                                                                                                     0.0
                                        0   1   2   3   4   5   6   7   8   9 10 11 12 13 14 15
                                                                                                                                           0   1   2   3   4   5   6   7   8   9 10 11 12 13 14 15
                                                        Time to follow-up (year)
                                                                                                                                                           Time to follow-up (year)



                                                                                                                                                                       Nguyen et al, 2005
Risk factors of fracture
A model for predicting fracture
Bone mineral
Density (BMD)
                     Bone strength
Bone quality
(ultrasound ?)
                                        Fracture

     Fall
                  Trauma / mechanical

Force of impact
 Risk factors for low bone mass
                                           Smoker
                                           Age (per 5 years)
                                           Maternal history of fx
                                           Steroid use
                                           Caffeine intake
                   Activity score
                Age at menopause
                       Milk intake
                     Ever pregnant
               Surgical menopause
                    Waist/hip ratio
                           Weight
                       Grip strength
                            Height
                       Thiazide use
                      Oestrogen use


-8   -6   -4            -2             0            2               4   6   8
                        Effect on Bone Mass
             Risk factors for low BMD
Genetics          Race, Sex, Familial prevalence

Hormones          Menopause, Oophorectomy, Body composition

Nutrition         Low calcium intake, High caffeine intake,
                  High sodium intake, High animal protein intake

Lifestyles        Cigarette use, High alcoholic intake,
                  Low level of physical activity

Drug              Heparin, Anticonculsants, Immunosuppressants
                  Chemotherapy, Corticosteroids,
                  Thyroid hormone
                            Change in BMD with Age
                       Relationship between LSBMD and Age                                      Relationship between Femoral Neck BMD and Age




                                                                                    1.2
            1.4




                                                                                    1.0
            1.2




                                                                 Femoral neck BMD

                                                                                    0.8
BMD L2-L4

            1.0




                                                                                    0.6
            0.8




                                                                                    0.4
            0.6




                                                                                    0.2



                  10   20       30          40     50       60                            10        20        30          40     50       60

                                      Age                                                                           Age
                                                   Prevalence




                                                          10
                                                                12
                                                                      14
                                                                            16
                                                                                    18




                             0
                                 2
                                       4
                                             6
                                                    8
                   <0
                      .4
                        0
                   0.
                     40
                         -
                   0.
                     45
                   0. -
                     50
                         -
                   0.
                     55
                   0. -
                     60
                                                                                     T < 2.5




                         -
                   0.
                                                                                  osteoporosis




                     65
                         -
                   0.
                     70
                   0. -
                     75
                         -
                   0.
                     80
                         -
                   0.
                     85
                   0. -
                     90
                         -

Femoral neck BMD
                   0.
                     95
                   1. -
                     00
                         -
                   1.
                     05
                         -
                   1.
                     10
                         -
                             0
                                 0.1
                                       0.2
                                             0.3
                                                    0.4
                                                          0.5
                                                                0.6
                                                                      0.7
                                                                            0.8
                                                                                    0.9




                                             10-year Risk of Fx
                                                                                                 Bone mineral density and fracture
 Low BMD and fracture - women
                     1287women



      Osteoporosis               Non-osteop.
       345 (27%)                 942 (73%)



Fx = 137      No Fx =      Fx = 191        No Fx = 751
 (40%)       208 (60%)      (20%)            (80%)

               42%
Interaction between BMD and falls

                                                               n=56
                          60


                            50
                    on-years)
                       cture




                                                        n=11
                                40
       Rate of Hip fra
     (per 1000 pers




                                30
                                                                            n=17


                                20
                                                                                         n=3
                                                                      n=7
                                                  n=3




                                                                                                                  s
                                 10                                                                       3-5




                                                                                                               or
                                                                                                               ct
                                                                                   n=0




                                                                                                             fa
                                                                n=4
                                                                                                      2




                                                                                                          k
                                     0




                                                                                                          is
                                                                             n=0




                                                                                                        fr
                                         < -2.5




                                                                                                      ro
                                                                                               0-1




                                                                                                  be
                                                   -2.4 to -1.1
                                          FNBM            > -1.0


                                                                                                  m
                                              D (T-
                                                                                               Nu
                                                   scor
                                                       e)



                                         Nguyen et al, JBMR 2005
Genetics of Osteoporosis
    Heritability of femoral neck BMD
                               MZ                                                         DZ
         1.4                 r =0.75                                1.4                 r =0.45
         1.3                                                        1.3
         1.2                                                        1.2
         1.1                                                        1.1
          1
Twin 2




                                                           Twin 2
                                                                     1
         0.9                                                        0.9
         0.8                                                        0.8
         0.7                                                        0.7
         0.6                                                        0.6
         0.5                                                        0.5
               0.5 0.6 0.7 0.8 0.9 1 1.1 1.2 1.3 1.4                      0.5 0.6 0.7 0.8 0.9 1 1.1 1.2 1.3 1.4
                              Twin 1                                                     Twin 1


                                                       Nguyen et al, Am J Epidemiol 1998
         Genetics of fracture risk

   MZ twins have higher concordance in fracture
    rate than DZ twins (Kannus, BMJ 1999)

   Around 1/3 variance of fracture risk is due to
    genetic factors (Deng et al, JBMR 2000)
                  Gene search

   Genotype       Mathematical function
                                            Phenotype
Polymorphisms                             Fracture
Genetic markers                           Bone mineral density
SNPs                                      Quantitative ultrasound
         Strategies for gene search



   Linkage analysis          Genome-wide screen

   Association analysis      “Candidate gene”
      Linkage analysis – identical by
              descent (ibd)


 AB             AC     AB             CD     AB             CD




AB               AC   AC               AD   BC               BC

      IBD = 0               IBD = 1               IBD = 2
Linkage analysis: basic model

Squared
difference
in BMD
                o
among           o
                o
                o        o                  Regression line
siblings        o
                o
                o        o
                         o
                o        o
                o        o
                         o
                         o        o
                         o        o
                                  o
                         o        o
                                  o
                                  o
                                  o
                                  o
                                  o


               0        1           2
             Number of alleles shared IBD
Population-based association analysis


 Fracture

              AC AB AC BC AA AB BB AA AC     AB




No fracture

              AC BB BC BC CC AB BB CC   BC   BB
Family-based association analysis



AB        AA   AB        AC   BC        AA




     AB             BC             AB
Genome-wide vs candidate gene approach

   Genome-wide screen     Candidate gene analysis


 Complex                 Simple
 No prior knowledge of   Prior knowledge of
 mechanism               mechanism
 Expensive               Inexpensive
 No specific genes       Specific genes
Linkage vs association phenomena
                        Linkage   Association
Magnitude of “effect”     No         Yes
Transmission              Yes      No/Yes
Study design            Complex     Simple
complexity
Power                    Low         High
False +ve                High        High
    Some recent “osteoporosis genes”

   Vitamin D receptor gene (Morrison et al, Nature
    1994)

   Collagen I alpha 1 gene – COLIA1 (Grant et al,
    Nat Genet, 1996).

   LRP5 gene (Am J Hum Genet, 1998)
Candidate genes of osteoporosis
    Location   Name                            Symbol
    1q25       Osteocalcin                     BGLAP
    2q13       IL-1 Receptor Antagonist        CASR
    3q21-24    Calcium Sensing Receptor        CASR
    3q27       2HS Glycoprotein               AHSG
    4q11-13    Vitamin D binding protein       DBP/GCv
    4q21       Osteopontin                     SPP1
    5q31       Osteonectin                     SPOCK
    6q25.1     Estrogen receptor              ESR
    7p21       Interleukin-6                   IL-6
    7q21.3     Calcitonin receptor             CALCR
    7q22       Collagen type I2               COLIA2
    11p15      Parathyroid hormone             PTH
    12q13      Vitamin D receptor              VDR
    17q22      Collagen Type I1               COLIA1
    19q13      Transforming growth factor 1   TGF-1
    19q13      Apolipoprotein E                ApoE
Localization of genes for BMD
          VDR, COLIA1 and fracture

  Risk Genotype   Prevalence         Relative   Attributable Risk
                     (%)              Risk1       Fraction (%)
Taq-1 tt             15.4              2.6            19.8

Sp-1 ss              5.0               3.8            12.3

tt AND ss            1.0               3.0             2.0

tt OR ss             19.8              3.5            32.1



                     Nguyen et al, JCEM 2005
Poor replication of genetic associations

   600 positive associations between common gene
    variants and disease reported 1986-2000
       166 were studied 3+ times
            6 have been consistently replicated


     J N Hirschhorn et al. Genetics in Medicine 2002
Evolution of
the strength
of an
association as
more
information is
accumulated

Ioannidis et al,
Nat Genet 2001
    Problems of gene search – p-value

   “Traditional” model of inference
     Hypothesis H
     Collecting data D

     Computing p-value = Pr(D | H)
         If p-value < 0.05  reject H
         If p-value > 0.05  accept H
              The logic of P-value
   If Tuan has                    If there was truly no
    hypertension, he is             association, then the
    unlikely to have red hair       observation is unlikely

   Tuan has red hair              The observation occurred

   Tuan is unlikley to have
                                   The no-association
    hypertension
                                    hypothesis is unlikely
                   Diagnostic analogy
    Diagnosis       Has cancer    test +ve         OK
                    Has cancer    test –ve     ! (false -ve)
                    No cancer     test +ve     ! (false +ve)
                    No cancer     test –ve         OK

Genetic research
                   Association   Significant        Power
                   Association      NS
                   No assoc.     Significant       P-value
                   No assoc.        NS
What do we want to know?
              Clinical
         P(+ve | cancer), or
          P(cancer | +ve) ?

              Research
 P(Significant test | Association), or
  P(Association | Significant test) ?
      Breast cancer screening
Prevalence = 1%; Sensitivity = 90%; Specificity = 91%

                    Population



  Cancer (n=10)                No Cancer (n=990)



+ve               -ve            +ve               -ve
N=9              N=1             N=90            N=900


       P(Cancer| +ve result) = 9/(9+90) = 9%
 Probability of a true association
Prior prob. association = 0.05; Power = 90%; P-value = 5%

                        1000 SNPs



        True (n=50)                  False (n=950)



  +ve                 -ve           +ve               -ve
 N=45                 N=5           N=48             N=902


   P(True association| +ve result) = 45/(45+48) = 48%
         Risk factors for fracture

   Blonde hair               Drinking coffee
   Being tall                Drinking tea
   Wear trouser (women)
                              Coca cola
   High heel (women)
                              High protein intake
“Half of what doctors know is wrong.
Unfortunately we don’t know which half.”

Quoted from the Dean of Yale Medical School,
in “Medicine and Its Myths”, New York Times
Magazine, 16/3/2003
Can genes be used to predict
         fracture?
          Genetics in medicine: hope
   “within the next decade genetic testing will be used widely
    for predictive testing in healthy people and for diagnosis
    and management of patients. . . . The excitement in the
    field has shifted to the elucidation of the genetic basis of
    the common diseases.” (J Bell, BMJ 1998)

   “… new understanding of genetic contributions to human
    disease and the development of rational strategies for
    minimizing or preventing disease phenotypes altogether.”
    (F. S Collins NEJM 1999)
Positive predictive value as a function of
    gene frequency and relative risk
What is the probability that I will sustain a fracture if I have “high risk” genotype?

   Susceptibility             Relative        Relative       Relative       Relative
   genotype frequency        Risk =1.5       Risk =2.0      Risk =5.0       Risk =10


   0.1%                         15.0            20.0           49.8            99.1
   0.5%                         15.0            19.9           49.0            95.7
   1%                           14.9            19.8           48.1            91.7
   10%                          14.3            18.2           35.7            52.6
   20%                          13.6            16.7           27.8            35.7

        PPV (%) of susceptibility genotype for a disease with lifetime risk of 10%
Positive predictive value as a function of gene
  frequency and relative risk and co-factor

Frequency of    Frequency of   RR associated with     RR associated
co-factor       genotype        co-factor = 2.0     with co-factor = 5

Disregard co-                        19.8                 19.8
factor
1%              1%                   39.2                 95.2
                10%                  33.0                 55.0
5%              1%                   38.7                 91.6
                10%                  34.6                 68.0
10%             1%                   52.9                 87.4
                10%                  36.0                 64.9
  How many fractures are due to genes?
Population attributable risk fraction as a function of gene
frequency and relative risk
Susceptibility       RR=1.5   RR=2.0   RR=5.0     RR=10
genotype frequency


0.1%                  0.05     0.1       0.4        0.9
0.5%                  0.25     0.5       2.0        4.3
1%                    0.5      1.0       3.9        8.3
10%                   4.8      9.1       28.6      47.4
20%                   9.1      16.7      44.4      64.3
                    Summary

   Osteoporosis and fracture: serious public
    health problem

   Bone mineral density: primary predictor of
    fracture risk

   BMD is largely regulated by genetic factors
                        Summary

   BMD is largely regulated by genetic factors

   Finding genes for fracture: challenge
       Genetics, clinical medicine, statistics, bioinformatics


   Predictive value of genes in fracture
    prediction: consider environmental risk factors

				
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