Kim

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					Spine Surgical Research
at New England Baptist
Hospital
David H. Kim, MD
Chief of Medical Education
Spine Section, Dept of Orthopaedic Surgery
Iliac Crest Bone Graft
Harvest Related Pain
and Morbidity
David H. Kim, MD
Louis Jenis, MD
Robert Banco, MD
Sharon Koogler
Kelsey Miller
Scott Tromanhauser, MD
Introduction
   Frequently reported
    complications
     – chronic pain
     – numbness
     – cosmetic appearance
   No consensus regarding
    incidence of pain or functional
    significance
   Principal factor driving search for
    viable bone graft alternatives
   Few prospective studies of bone
    graft harvest site complications;
    no prospective study of
    functional disability
Comparative Use of Bone
Graft Alternative
Introduction

   Bone graft harvest site
    complications & fusion
    rates are two most
    important variables in
    cost-benefit
    calculations for high-
    priced technology such
    as recombinant growth
    factor
Purpose

   Prospectively study rates of ICBG
    harvest pain & morbidity
    – rates & severity of pain
    – numbness
    – cosmetic complaints
    – functional limitations
Study Design

   Prospective cohort
    study
   Study population
    – patients undergoing
      autologous ICBG
      harvest as part of
      elective spinal
      surgery
Study Population

   135 adult patients prospectively
    enrolled
   12 month postop f/u period
    – 5 patients failed f/u
    – 130 patients in final study group
        Female/male: 71/59
        Lumbar/cervical: 116/14
Outcome Measures
   Visual analogue scale (VAS) for pain from
    ICBG harvest site
   12 month f/u questionnaire regarding
    symptoms & effect on functional activities.
Methods

   Preoperative demographic data
   Postoperative VAS pain scores at 6 wk,
    6 mo, & 12 mo f/u
   12 mo f/u questionnaire
   Full-time research assistant
Results

   Mean harvest site VAS pain scores
    – 6 wks: 2.63 (S.D. 2.76)
    – 6 mos: 1.77 (S.D. 2.42)
    – 12 mos: 1.54 (S.D. 2.39)
 Harvest Site Pain

                      Total Population

100

 80

 60

 40

 20
            22.1              15.2          14.8
  0
          6Wk Graft         6 Mo Graft   12 Mo Graft

  N=129
 Harvest Site Pain by Primary
 Surgical Site

                      Non-WC


50
45
40                             LUMBAR
35
30                             CERVICAL
25
20        23.8
15   18
10               15
                        10.2    11
 5                                   3.7
 0
     6Wk Graft   6 Mo Graft    12 Mo Graft
     Harvest Site Pain by Age

                                   Non-WC Age

50                                                                    18-35 yo
45                                                                    36-50 yo
40                                                                    51-65 yo
35                                                                    66+
30
25            25.9
20                                        21.2
15                   16.4
                                                                    17.9
10                          12.4   12.6          11.8                            10.7
 5                                                                         8.8
       4.0                                              5.8   3.8
 0
             6Wk Graft                6 Mo Graft                12 Mo Graft
 Harvest Site Pain by Sex

                   Non-WC Gender

50
45
40                                        Male
35                                        Female
30
25          28.3
20
15
     15.4                   16.7
10                                        13.2
 5                   10.8          10.9
 0
     6Wk Graft       6 Mo Graft    12 Mo Graft
     Harvest Site Pain by
     Diagnosis

                     Non-WC Dx

50
45
40                                   DDD
35                                   Stenosis
30
25
20     22.1
15
              16.3    16
10                         13.6    13
 5                                       7.3
 0
       6Wk Graft     6 Mo Graft   12 Mo Graft
Results


   12 mo f/u:
    – 16.5% more severe pain from harvest
      site than primary surgical site
    – 3.9% bothered by scar appearance
    – 29.1% noticeable numbness
    – 11.3% bothersome numbness
Results

   Functional disability due to persistent
    harvest site pain:
    – 18.8% walking
    – 10.3% job
    – 19.0% recreational activity
    – 21.5% household chores
    – 10.8% sexual activity
    – 5.1% irritation from clothing
Conclusions
   High rate of persistent pain & morbidity
    from iliac crest bone graft harvest when
    associated with elective spine surgery
   Mean pain scores progressively decline over
    first postop year
   Harvest site pain remains functionally
    limiting in many patients one year following
    surgery
   Rates for functional limitation are higher
    than those previously reported
Polymorphic Variation of the GTP
Cyclohydrolase 1 Gene in Patients
Undergoing Surgical Treatment for
Lumbar Degenerative Disc Disease


David H. Kim, MD; Mitchell Max, PhD;
Inga Peter, PhD; Inna Belfer, PhD;
Robert Banco, MD; Scott Tromanhauser, MD;
Louis Jenis, MD; Carolyn Schwartz, ScD
New England Baptist Hospital, Boston, USA
National Institutes of Health, Bethesda, USA
Introduction

   Pain is genetically
    determined
   Genes that modulate pain
    sensitivity in humans
    – COMT    [Diatchenko et al, Hum Mol
      Genet 2005; Zubieta et al, Science
      2003]
    – Mc1r  [Mogil et al, Proc Natl Acad Sci
      USA 2003]
    – GCH1    [Tegeder et al, Nature Med
      2006]
     GCH1
   GTP cyclohydrolase (GCH1)
    – Rate-limiting enzyme in BH4 synthesis
    – BH4 essential cofactor for tyrosine,
      tryptophan, and phenylalanine
      hydroxylases, iNOS
    – Expression in brain, spinal cord, and
      peripheral nerve [Lentz & Kapatos,
      Neurochem Int 1996; Hwang et al, Synapse
      1998]
    – Loss of function mutation causes
      hereditary progressive dystonia with
      marked diurnal fluctuation (HPD) aka
      dopa responsive dystonia [Ichinose et al,
      Nature Gen 1994]
GCH1 and Pain Sensitivity
   15 single nucleotide
    polymorphisms
   Pain protective
    haplotype in 15.4%
   Distribution follows
    Hardy-Weinberg
    Equilibrium in general
    population
   Associated with less
    pain following lumbar
    discectomy
   Homozygotes reduced [Kim & Dionne, Mol Pain 2008]
    experimental pain
    sensitivity [Tegeder et al, Nature Med 2006]
Study Design
   Prospective cohort study
   100 patients undergoing surgical
    treatment for lumbar DDD
    – Moderate to severe LBP > 6 months
    – Failed nonoperative treatment
      (activity modification, NSAIDs, PT,
      injection)
    – MRI evidence of 1-2 level DDD
   Venous blood sample, DNA
    extraction, GCH1 DNA sequence
    analysis
Results
   15 single nucleotide polymorphisms (SNPs)
    in noncoding regions of GCH1 distributed
    evenly across gene
   14 of 15 loci informative in study population
     GCH1 Allele Frequencies
                      Standard                              Standard
Locus Allele   Frequency     Error   Locus  Allele   Frequency     Error
GCH1_1 C          0.7813   0.0264    GCH1_8 C           0.1389   0.0305
GCH1_1 G          0.2188   0.0264    GCH1_8 T           0.8611   0.0305
GCH1_2 A          0.2833   0.0352    GCH1_9 C           0.7857   0.0322
GCH1_2 C          0.7167   0.0352    GCH1_9 T           0.2143   0.0322
GCH1_3 C          0.7789   0.0265    GCH1_10 A          0.3187    0.0334
GCH1_3 T          0.2211   0.0265    GCH1_10 G          0.6813    0.0334
GCH1_4 C          0.2188   0.0264    GCH1_11 A          0.7865    0.0274
GCH1_4 T          0.7813   0.0264    GCH1_11 T          0.2135    0.0274
GCH1_5 C          0.3495   0.0321    GCH1_12 C          0.9194    0.0205
GCH1_5 T          0.6505   0.0321    GCH1_12 G          0.0806    0.0205
GCH1_6 A          0.3495   0.0330    GCH1_13 A          0.5852    0.0379
GCH1_6 G          0.6505   0.0330    GCH1_13 G          0.4148    0.0379
GCH1_7 G          0.0806   0.0205    GCH1_14 C          0.8000    0.0262
GCH1_7 T          0.9194   0.0205    GCH1_14 T          0.2000    0.0262
      GCH1 Genotype Frequencies
                            HWD      Standard                               HWD Standard
Locus Genotype   Frequency   Coeff      Error   Locus  Genotype   Frequency    Coeff    Error
GCH1_1 C/C        0.5729 -0.0374      0.0129    GCH1_8 C/C         0.0667 0.0474     0.0202
GCH1_1 C/G        0.4167 -0.0374      0.0129    GCH1_8 C/T         0.1444 0.0474     0.0202
GCH1_1 G/G        0.0104 -0.0374      0.0129    GCH1_8 T/T         0.7889 0.0474     0.0202
GCH1_2 A/A        0.1000 0.0197       0.0222    GCH1_9 C/C         0.6374 0.0200     0.0195
GCH1_2 A/C        0.3667 0.0197       0.0222    GCH1_9 C/T         0.2967 0.0200     0.0195
GCH1_2 C/C        0.5333 0.0197       0.0222    GCH1_9 T/T         0.0659 0.0200     0.0195
GCH1_3 C/C        0.5684 -0.0383      0.0131    GCH1_10 A/A        0.0879 -0.0136    0.0223
GCH1_3 C/T        0.4211 -0.0383      0.0131    GCH1_10 A/G        0.4615 -0.0136    0.0223
GCH1_3 T/T        0.0105 -0.0383      0.0131    GCH1_10 G/G         0.4505 -0.0136    0.0223
GCH1_4 C/C        0.0104 -0.0374      0.0129    GCH1_11 A/A        0.5843 -0.0343    0.0133
GCH1_4 C/T        0.4167 -0.0374      0.0129    GCH1_11 A/T        0.4045 -0.0343    0.0133
GCH1_4 T/T        0.5729 -0.0374      0.0129    GCH1_11 T/T        0.0112 -0.0343    0.0133
GCH1_5 C/C        0.0860 -0.0361      0.0225    GCH1_12 C/C        0.8495 0.0042     0.0095
GCH1_5 C/T        0.5269 -0.0361      0.0225    GCH1_12 C/G         0.1398 0.0042     0.0095
GCH1_5 T/T        0.3871 -0.0361      0.0225    GCH1_12 G/G         0.0108 0.0042     0.0095
GCH1_6 A/A        0.0968 -0.0253      0.0229    GCH1_13 A/A        0.3523 0.0098     0.0259
GCH1_6 A/G        0.5054 -0.0253      0.0229    GCH1_13 A/G        0.4659 0.0098     0.0259
GCH1_6 G/G        0.3978 -0.0253      0.0229    GCH1_13 G/G         0.1818 0.0098     0.0259
GCH1_7 G/G        0.0108 0.0042       0.0095    GCH1_14 C/C        0.6105 -0.0295     0.0122
GCH1_7 G/T        0.1398 0.0042       0.0095    GCH1_14 C/T        0.3789 -0.0295    0.0122
GCH1_7 T/T        0.8495 0.0042       0.0095    GCH1_14 T/T        0.0105 -0.0295    0.0122
Linkage disequilibrium
measure, δ
   δ := cov(I1, I2) = p1p2 – h12 = h11h22 –
    h12h21
    Where:
    – I1, I2 denote two loci
    – p1p2 denote allele frequencies
    – h12 denotes haplotype frequency


    – δ = 0 → linkage equilibrium
    – δ ≠ 0 → linkage disequilibrium
Linkage disequilibrium
measure, D
   D = x11 – p1q1


              A1          A2          Total
B1            x11=p1q1+   x21=p2q1-   q1
              D           D
B2            x12=p1q2-   x22=p2q2+   q2
              D           D
Total         p1          p2          1
Lewontin’s D'

   Extension for diploid cells
   D depends on allele frequency

   D' = D/Dmax when D ≥ 0
   D' = D/Dmin when D < 0
    Where: Dmax = lesser of p1q2 or p2q1
           Dmin = greater of (-)p1q1 or (-)p2q2
Correlation coefficient between loci
pairs

 r2   = D2/(p1p2q1q2)
Linkage disequilibrium of
GCH1 in patients with
lumbar DDD




   Haploview results with confidence interval method
    GCH1 allele procedure
    marker summary
                                        --------Test for HWE--------
                             Number Number
              of     of      Hetero- Allelic      Chi-         Pr >
Locus   Indiv Alleles   PIC zygosity Diversity     Square      DF ChiSq
GCH1_1      96      2 0.2834 0.4167     0.3418       4.6063      1 0.0319
GCH1_2      90      2 0.3236 0.3667     0.4061       0.8490      1 0.3568
GCH1_3      95      2 0.2851 0.4211     0.3444       4.7095      1 0.0300
GCH1_4      96      2 0.2834 0.4167     0.3418       4.6063      1 0.0319
GCH1_5      93      2 0.3513 0.5269     0.4547       2.3454      1 0.1257
GCH1_6      93      2 0.3513 0.5054     0.4547       1.1563      1 0.2822
GCH1_7      93      2 0.1373 0.1398     0.1483       0.3055      1 0.5805
GCH1_8      90      2 0.2106 0.1444     0.2392      14.1226      1 0.0002
GCH1_9      91      2 0.2800 0.2967     0.3367       1.2861      1 0.2568
GCH1_10      91     2 0.3400 0.4615     0.4342        0.3594     1 0.5488
GCH1_11     89      2 0.2794 0.4045     0.3358        3.7224     1 0.0537
GCH1_12      93     2 0.1373 0.1398     0.1483        0.3055     1 0.5805
GCH1_13      88      2 0.3676 0.4659    0.4855        0.1429     1 0.7054
GCH1_14      95     2 0.2688 0.3789     0.3200        3.2237     1 0.0726
Results

   Genotype ratios for 4 SNPs significantly
    divergent from Hardy-Weinberg Equilibrium
    – Underrepresented:
          rs10483639 (minor allele frequency, MAF 22%)
           p=0.0319
          rs752688 (MAF 22%); p=0.0300
          rs4411417 (MAF 22%); p=0.0319
    – Overrepresented:
          homozygous carriers of GCH1 rs12147422 (MAF 14%);
           p=0.0002
Conclusions

   As a group, patients presenting for surgical
    treatment of lumbar DDD demonstrate
    significant divergence from HWE and the
    general population for a set of
    polymorphisms in the pain-modulating gene
    GCH1
   Allelic variations in GCH1 may both
    predispose and protect patients from
    developing chronic pain associated with
    lumbar DDD
Thank you!

				
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posted:8/12/2012
language:English
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