Genotype Determination

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Pharmacogenetics for Genes Pharmacogenetics for Genes Associated with Age-Related Associated with Age-Related Macular Degeneration in the Macular Degeneration in the

Comparison of AMD Treatments Comparison of AMD Treatments Trials (CATT)Trials (CATT)

Hagstrom SA, Ying G-S, Pauer GJT, Hagstrom SA, Ying G-S, Pauer GJT, Sturgill-Short GM, Sturgill-Short GM, Huang J, Callanan DG, Kim IK, Klein ML, Huang J, Callanan DG, Kim IK, Klein ML, Maguire MGMaguire MG,

Martin DF for the CATT Research Groupfor the CATT Research Group

Available through Available through http://www.med.upenn.edu/cpob/publications_main.shtml

Hagstrom SA, Ying G-S, Pauer GJT, Hagstrom SA, Ying G-S, Pauer GJT, Sturgill-Short GM, Sturgill-Short GM, Huang J, Callanan DG, Kim IK, Klein ML, Huang J, Callanan DG, Kim IK, Klein ML, Maguire MGMaguire MG,

Martin DF for the CATT Research Groupfor the CATT Research Group

Available through Available through http://www.med.upenn.edu/cpob/publications_main.shtmlSupported by Cooperative Agreements from the Supported by Cooperative Agreements from the

National Eye Institute, National Institutes of Health, National Eye Institute, National Institutes of Health, DHHSDHHS

http://www.med.upenn.edu/cpob/publications_main.shtml




Genotype Genotype DeterminationDetermination

Each patient was genotyped for Each patient was genotyped for CFHCFH, , ARMS2ARMS2, , HTRA1HTRA1, and , and C3C3..

Gene SNP ExonAmino Acid

CFH rs1061170

9 Y402H

ARMS2

rs10490924

1 A69S

HTRA1 rs11200638

promoter

-

C3 rs2230199

3 R80G

InflammationLipid Metabolism

Angiogenesis

Oxidative Stress

ECM StasisAMD

Biological PathwaysVEGFA

KDR

CFIBF

CFHC3C2

ARMS2ND2

HTRA1TIMP3

COL8A1FRK

APOELIPCCETP

LPLABCA1

Hagstrom et al. Pharmacogenetics of Anti-VEGF Therapy in CATT Ophthalmology 2013;120:593-599

Homozygous Allele 1

Homozygous Allele 2

Heterozygous

NegativeControls

Genotyping was performed using a custom made Genotyping was performed using a custom made TaqMan OpenArray loaded with TaqMan SNP genotyping TaqMan OpenArray loaded with TaqMan SNP genotyping

assays.assays.

Genotype Genotype DeterminationDetermination


Outcome VariablesOutcome Variables

All outcomes were determined following standardized All outcomes were determined following standardized protocols.protocols.

VA assessed using eETDRS VA assessed using eETDRS testingtesting

OCT outcomes determined by OCT outcomes determined by independent OCT Reading independent OCT Reading

Center Center

FA and photographic outcomes FA and photographic outcomes determined by independent determined by independent

Fundus Photographic Reading Fundus Photographic Reading CenterCenter


Comparison of baseline demographic and ocular Comparison of baseline demographic and ocular characteristics between participants and non-characteristics between participants and non-

participants in the genetic study (N=1149)participants in the genetic study (N=1149)


Baseline CharacteristicsSubjects in

genetic study

(N=834)

Alive subjects not in genetic

study

(N=315)

P Value

Age (years): Mean (SD) 78.5 (7.5) 80.9 (7.2) <0.0001

Female (%) 510 (61.2) 204 (64.8) 0.28

Former or current cigarette smoker (%) 483 (57.9) 169 (53.7) 0.36Presence of hypertension (%) 563 (67.5) 232 (73.7) 0.045Taking AREDS supplement (%) 536 (64.3) 189 (60.0) 0.21

Baseline VA (letters): Mean (SD) 61.3 (13.3) 58.8 (13.7) 0.005

Baseline area of CNV (DA): Mean (SD) 1.70 (1.69) 1.91 (1.90) 0.096Baseline total area of CNV lesion (DA):

Mean (SD)2.47 (2.55) 2.49 (2.54) 0.87

Presence of occult lesion (%) 505 (60.6) 169 (53.7) 0.04

Presence of RAP lesion (%) 80 (9.6) 41 (13.0) 0.12Total foveal thickness (microns): Mean

(SD)462 (190) 456 (180) 0.60

SD = standard deviation; AREDS = age-related eye disease study; VA = visual acuity; DA = disc area.

Visual Outcomes by Visual Outcomes by GenotypeGenotype

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GeneGene GenotypeGenotype nnMean VA Mean VA in lettersin letters

Mean VA Mean VA changechange

in lettersin letters

≥ ≥ 15 letters 15 letters increaseincrease

CFH

CC 270 70 7.9 28%

TC 391 68 8.2 29%

TT 173 69 8.6 34%

P-Value 0.30 0.61 0.22

ARMS2

TT 170 69 8.2 28%

GT 398 69 8.3 31%

GG 266 70 7.9 28%

P-Value 0.51 0.77 0.97

HTRA1

AA 162 69 8.4 29%

AG 398 69 8.2 31%

GG 274 69 7.9 29%

P-Value 0.68 0.69 0.99

C3

GG 56 71 8.1 28%

CG 318 70 8.9 31%

CC 460 68 7.6 29%

P-Value 0.03 0.34 0.72

# of Risk

Alleles

0-1 123 68 7.0 29%

2 141 69 9.1 33%

3 175 69 7.9 27%

4 170 69 8.1 31%

>=5 225 70 8.5 29%

P-Value 0.42 0.66 0.71

Genotypic Associations with Anatomic Genotypic Associations with Anatomic Outcome Measures on OCT at 1 Year Outcome Measures on OCT at 1 Year

(N=834)(N=834)

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GeneGene GenotypeGenotype nn

Retinal Retinal thinning thinning

<120 <120 µmµm

Retinal Retinal thicknethickness >212 ss >212

µmµm

Mean Mean change of change of

total foveal total foveal thickness thickness in micronsin microns

Dry Dry on on

OCTOCT

CFH

CC 270 17% 12% -142 27%

TC 391 22% 9% -188 29%

TT 173 21% 11% -174 33%

P-Value 0.62 0.03 0.18

ARMS2

TT 170 20% 10% -184 28%

GT 398 20% 9% -176 33%

GG 266 21% 13% -152 24%

P-Value 0.33 0.06 0.30

HTRA1

AA 162 21% 10% -178 28%

AG 398 20% 10% -179 33%

GG 274 20% 12% -152 25%

P-Value 0.64 0.10 0.23

C3

GG 56 20% 11% -182 35%

CG 318 22% 8% -161 32%

CC 460 19% 12% -174 27%

P-Value 0.51 0.67 0.07

# of Risk

Alleles

0-1 123 22% 15% -153 25%

2 141 18% 9% -157 24%

3 175 20% 12% -200 29%

4 170 24% 7% -174 37%

>=5 225 17% 11% -160 29%

P-Value 0.29 0.68 0.30 Hagstrom et al. Pharmacogenetics of Anti-VEGF Therapy in CATT Ophthalmology 2013;120:593-599

FA and Fundus Outcomes by Genotype FA and Fundus Outcomes by Genotype (N=834(N=834))

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GeneGene GenotypeGenotype nnDye leakage Dye leakage

on FAon FA

Mean change Mean change in lesion size in lesion size in disc areain disc area

CFH

CC 270 46% 0.2

TC 391 47% 0.2

TT 173 44% 0.4

P-Value 0.71 0.48

ARMS2

TT 170 49% 0.5

GT 398 44% 0.0

GG 266 48% 0.4

P-Value 0.89 0.80

HTRA1

AA 162 49% 0.5

AG 398 43% 0.1

GG 274 49% 0.3

P-Value 0.84 0.42

C3

GG 56 50% 0.0

CG 318 45% 0.1

CC 460 46% 0.3

P-Value 0.85 0.28

# of Risk

Alleles

0-1 123 55% 0.2

2 141 45% 0.5

3 175 38% 0.1

4 170 44% 0.0

>=5 225 50% 0.3

P-Value 0.93 0.80


Number of Injections by Number of Injections by GenotypeGenotype

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GeneGene GenotypeGenotype nn

Mean of Mean of total total

number of number of injections in injections in PRN Groups PRN Groups

CFH

CC 125 7.4

TC 166 7.4

TT 65 7.6

P-Value 0.72

ARMS2

TT 69 8.0

GT 170 7.2

GG 117 7.4

P-Value 0.35

HTRA1

AA 67 8.0

AG 170 7.3

GG 119 7.3

P-Value 0.25

C3

GG 27 7.0

CG 138 7.9

CC 191 7.2

P-Value 0.30

# of Risk

Alleles

0-1 51 7.6

2 59 7.0

3 80 7.2

4 65 7.3

>=5 101 7.9

P-Value 0.27Hagstrom et al. Pharmacogenetics of Anti-VEGF Therapy in CATT Ophthalmology 2013;120:593-599

ConclusionsConclusions

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Largest pharmacogenetic analysis exploring the Largest pharmacogenetic analysis exploring the relationship between genotypes and response to anti-relationship between genotypes and response to anti-VEGF therapy with >90% power to detect a 1 line VEGF therapy with >90% power to detect a 1 line difference between the highest risk and lowest risk difference between the highest risk and lowest risk groups.groups.

The relationship between genotype and response to The relationship between genotype and response to therapy did not vary by drug or dosing regimen.therapy did not vary by drug or dosing regimen.

Although specific risk alleles for Although specific risk alleles for CFHCFH, , ARMS2ARMS2, , HTRA1HTRA1 and and C3C3 may predict the development of AMD, they did may predict the development of AMD, they did not predict response to anti-VEGF therapy. not predict response to anti-VEGF therapy.

Further studies targeting SNPs in additional biological Further studies targeting SNPs in additional biological pathways are ongoing.pathways are ongoing.


Documents

Genotype Determination