Genome-wide association scan identifies candidate polymorphisms associated with differential response to anti-TNF treatment in rheumatoid arthritis.
The prediction of response (or non-response) to anti-TNF treatment for rheumatoid arthritis (RA) is a pressing clinical problem. We conducted a genome-wide association study using the Illumina HapMap300 SNP chip on 89 RA patients prospectively followed after beginning anti-TNF therapy as part of Autoimmune Biomarkers Collaborative Network (ABCoN [Autoimmune Bio-markers Collaborative Network]) patient cohort. Response to therapy was determined by the change in Disease Activity Score (DAS28) observed after 14 wks. We used a two-part analysis that treated the change in DAS28 as a continuous trait and then incorporated it into a dichotomous trait of "good responder" and "nonresponder" by European League Against Rheumatism (EULAR) criteria. We corrected for multiple tests by permutation, and adjusted for potential population stratification using EIGENSTRAT. Multiple single nucleotide polymorphism (SNP) markers showed significant associations near or within loci including: the v-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) gene on chromosome 20; the type I interferon gene IFNk on chromosome 9; and in a locus on chromosome 7 that includes the paraoxonase I (PON1) gene. An SNP in the IL10 promoter (rs1800896) that was previously reported as associated with anti-TNF response was weakly associated with response in this cohort. Replications of these results in independent and larger data sets clearly are required. We provide a reference list of candidate SNPs (P < 0.01) that can be investigated in future pharmacogenomic studies.
Liu
Chunyu
C
Biogen Idec Inc., Cambridge, Massachusetts, USA.
Batliwalla
Franak
F
Li
Wentian
W
Lee
Annette
A
Roubenoff
Ronenn
R
Beckman
Evan
E
Khalili
Houman
H
Damle
Aarti
A
Kern
Marlena
M
Furie
Richard
R
Dupuis
Josée
J
Plenge
Robert M
RM
Coenen
Marieke J H
MJ
Behrens
Timothy W
TW
Carulli
John P
JP
Gregersen
Peter K
PK
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000276:immunology / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000235:genetics*; D043303:Aryldialkylphosphatase / Q000235:genetics; D002874:Chromosome Mapping / Q000379:methods; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D007370:Interferon Type I / Q000235:genetics; D051258:MafB Transcription Factor / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D007370:Interferon Type I; C490407:MAFB protein, human; D051258:MafB Transcription Factor; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human