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  • LOW-DENSITY LIPOPROTEIN-RELATED RECEPTOR 5 (LRP5) GENE

    POLYMORPHISMS AND AAA GENETIC SUSCEPTIBILITY

    Betti Giusti

    Department of Medical and Surgical Critical Care, University of Florence

    SOD Atherothrombotic Diseases, Careggi Hospital, Florence

    3rd International Meeting on Aortic Diseases - IMAD Liege, Belgium October 4-6 2012

  • COMMUNICATION AGENDA

    presentation of new data on the role of polymorphisms in the low density lipoprotein receptor-related protein 5 gene (LRP5) as genetic markers of abdominal aortic aneurysm (AAA) brief summary of ongoing and published data obtained by our group in the same cohort of AAA patients and controls on the identification of other AAA genetic susceptibility factors, in order to point out a future challenge

  • 91 genes differentially expressed

    (AAA patients vs controls)

    76 genes with increased expression

    15 genes with decreased expression

    Giusti B et al., Eur J Vasc Endovasc Surg 2009

    Gene expression profiling in whole peripheral blood

  • GO Term N n Geni P

    Oxigen Transport 9 4 HBA2(), HBD(),

    HBE1(), HBQ1()

  • LRP5 = low density

    lipoprotein receptor-

    related protein 5

    Giusti B et al.,

    Eur J Vasc Endovasc Surg 2009

    Lipid metabolic process

    Bone, lipid and

    glucose metabolism

    LRP5

  • Forest plot of standardized mean difference of circulating lipoprotein(a) concentrations between

    cases with abdominal aortic aneurysm (AAA) and controls without AAA.

    Takagi H et al. Interact CardioVasc Thorac Surg 2009;9:467-470

    Published by European Association for Cardio-Thoracic Surgery. All rights reserved.

    S.D., standard deviation; CI, confidence interval.

  • Lp(a)300 mg/L

    p=0.050

    B

    0.57

    (0.26-1.22)

    L R

    P 5

    f o

    ld c

    h an

    g e

    Relationship between LRP5 expression levels and Lp(a) levels in AAA patients

    A: Lp(a) levels in AAA patients and control subjects B: LRP5 expression levels according to Lp(a) levels in AAA patients (n=36).

    Giusti et al, Eur J Vasc Endovasc Surg 2009

  • Atherosclerotic lesions in apoE and apoE;LRP5 double knockout mice

    Magoori et al., J Biol Chem, 2003

  • To evaluate the role of single nucleotide polymorphisms

    (SNPs) in LRP5 gene in determining the genetic

    susceptibility to abdominal aortic aneurysm (AAA)

  • Demographic and clinical characteristics

    of AAA patients and controls

    Controls

    (N=423)

    AAA

    (N=423) p

    Age 72.0 (41-94) 73.5 (40-94) ns

    Sex (male) N (%) 366 (86.5) 376 (88.9) ns

    Smoking N (%) 267 (63.1) 366 (86.5)

  • SNP selection

    We studied 7 SNPs in LRP5 gene ( chromosome 11q13.4) according to literature data

    *minor allele frequency; ° synonimous

    SNP ID Nucleotide

    substitution MAF* Characterization

    rs312016 T/C T= 0.325 intron

    rs4988300 T/G T= 0.442 intron

    rs3781590 C/T T= 0.258 intron

    rs667126 C/T C= 0.239 intron

    rs3736228 C/T

    T= 0.138 Non syn

    (Ala1330Val)

    rs627174 C/T C= 0.177 intron

    rs556442 A/G G= 0.279 Syn°

    (Val1119Val)

    Taqman® technology

    obesity, BMI, bone mass and geometry

    bone density

    osteoarthritis

    bone density, hypercholester olemia

    bone density

    obesity

    bone density

  • Genotype distribution of polymorphisms of LRP5 gene in AAA patients (n=423) and control subjects (n=423)

    LRP5 rs3736228

    0

    20

    40

    60

    80

    CC CT TT

    Patients

    Control s

    LRP5 rs556442

    0

    20

    40

    60

    80

    GG GA AA

    Patients

    Controls

    %

    %

    65.3

    30.0

    4.7

    62.9

    31.4

    5.7

    11.6

    46.8 41.6

    9.7

    47.3 43.0

    Galora S et al, submitted

    Department of Medical and Surgical Critical Care, University of Florence, Italy

  • Genotype distribution of polymorphisms of LRP5 gene in AAA patients (n=423) and control subjects (n=423)

    Galora S et al, submitted

    Department of Medical and Surgical Critical Care, University of Florence, Italy

    LRP5 rs667126

    0

    20

    40

    60

    80

    CC CT TT

    Patients

    Controls

    LRP5 rs627174

    0

    20

    40

    60

    80

    CC CT TT

    Patients

    Controls

    %

    %

    LRP5 rs312016

    0

    20

    40

    60

    80

    CC CT TT

    Patients

    Controls%

    4.0

    27.7

    68.3

    3.8

    26.7

    69.5

    10.9

    42.3 46.8

    10.7

    47.0 42.3

    12.7

    42.1 45.2

    11.4

    43.0 45.6

  • p°= according to the additive model; p^= according to the dominant model

    LRP5 rs3781590

    33.5

    16,1

    50,4

    42.5 42,8

    14,6

    0

    20

    40

    60

    80

    CC CT TT

    Patients

    Controls

    LRP5 rs4988300

    48,2

    25,826

    18

    47,3

    34,7

    0

    20

    40

    60

    80

    GG GT TT

    Patients

    Control s

    Genotype distribution of polymorphisms of LRP5 gene in AAA patients (n=423) and control subjects (n=423)

    %

    LRP5 rs4988300

    74

    26

    65,3

    34,7

    0

    20

    40

    60

    80

    GG GT+TT

    Patients

    Controls

    LRP5 rs3781590

    66,5

    33.5

    57,5

    42.5

    0

    20

    40

    60

    80

    CC CT+TT

    Patients

    Controls

    P°=0.004

    P°=0.025

    P^=0.007

    P^=0.009

    % %

    %

    Galora S et al, submitted

    Intron 1

    Intron 7

  • Variables Univariable

    Analysis p

    Multivariable

    Analysis* p

    LRP5

    rs4988300

    T allele

    1.52

    (1.12-2.05) 0.007

    1.62

    (1.02-2.56) 0.040

    LRP5

    rs3781590

    T allele

    1.47

    (1.11-1.96) 0.008

    1.83

    (1.17-2.85) 0.008

    * adjusted for age, gender, hypertension, diabetes mellitus, dyslipidemia,

    smoking habit, COPD (chronic obstructive pulmonary disease).

    Odds ratio for the occurrence of AAA according to rs4988300 and rs3781580 LRP5

    polymorphisms

  • 200

    50

    150

    100

    108 (2-1394)

    180 (2-1773)

    Controls n=423

    AAA patients n=423

    L p

    (a )

    le v e

    ls (

    m g

    / L )

    Lp(a) levels in controls and AAA patients

    p

  • 40

    10

    30

    20

    30.8 %

    42.6 % P

  • Effect of rs4988300 and rs3781590 LRP5 polymorphisms on abdominal aortic diameters

    0

    2

    4

    6

    8

    10

    rs4988300 GG

    rs4988300 GT+TT

    0

    2

    4

    6

    8

    10

    0

    2

    4

    6

    8

    10

    0

    2

    4

    6

    8

    10

    0

    2

    4

    6

    8

    10

    0

    2

    4

    6

    8

    10

    Rs4988300 GG

    rs4988300 GT+TT

    rs3781590 CC

    Rs3781590 CT+TT

    Rs3781590 CC

    rs3781590 CT+TT

    cm cm

    cm cm

    5.0

    (3.2-9.8)

    5,0

    (3.1-9.1)

    5.0

    (3.1-9.1)

    5.0

    (3.2-9.8)

    AAA AAA

    Controls Controls

    1.8

    (1.2-4.3)

    1.9

    (1.2-4.7)

    1,9

    (1.2-4.7)

    1.9

    (1.2-3.1)

    P=0.953 P=0.862

    P=0.206 P=0.294

    Galora S et al, submitted

  • In conclusion, our data identified 2 LRP5 gene polymorphisms (rs4988300 and rs3781590) as independent genetic markers of AAA

    Present data suggest the need to confirm

    in larger populations the role of these two markers and of LRP5 gene in the aneurismal disease in order to improve the understanding of its pathophysiology and pathogenesis

    LRP5 AAA ASSOCIATION STUDY CONCLUSIONS

  • presentation of data on the role of polymorphisms in the low density lipoprotein receptor-related protein 5 gene (LRP5) as independent genetic markers of abdominal aortic aneurysm (AAA) brief summary of ongoing and published data obtained by our group in the same cohort of AAA patients and controls on the identification of other AAA genetic susceptibility factors, in order to point out a future challenge

    COMMUNICATION AGENDA

  • Bown et al. Am J Hum Genet

    2011

    Abdominal Aortic Aneurysm Is Associated with a

    Variant (rs1456535) in Low-Density Lipoprotein

    Receptor-Related Protein 1

    Genome wide