Purine biosynthetic pathway genes and methotrexate response in rheumatoid arthritis patients among north Indians.
OBJECTIVE
Inter-individual variations to methotrexate (MTX) response among rheumatoid arthritis (RA) patients have been attributed to clinical heterogeneity and genetic variations influencing MTX pharmacology. In this study, we analyzed the association of polymorphisms in ATIC, AMPD1, ADA, and ADORA2A from the purine biosynthetic pathway with MTX response in RA patients from north India. We also assessed the cumulative contribution of these polymorphisms together with those from the receptor-metabolizer-transporter and folate pathway genes that we have previously investigated.


METHODS
RA patients recruited using the American College of Rheumatology criteria were grouped into good (n = 213) and poor (n = 68) responders to MTX, based on Disease Activity Score 28-3. Individual single nucleotide polymorphism association was tested using (chi)2 test, and cumulative contribution of all the single-nucleotide polymorphisms and cumulative contribution of all the SNPs and clinico-demographic factors were assessed using linear and logistic regression.


RESULTS
G allele of ADA rs244076 [P = 0.02, odds ratio (95% confidence interval): OR (95% CI) = 1.66 (1.01-2.75)]; and T allele of ADORA2A rs5751876 [P = 0.04, OR (95% CI) = 1.55 (1.01-2.37)] were associated with poor response, but did not stand Bonferroni correction. On regression analyses, FPGS rs1544105, TYMS rs2853539, DHFR rs7387, and ADA rs244076 were identified as putative predictors for MTX response. Carriers of the FPGS rs1544105 AA and AG genotypes [OR (95% CI) = 3.47 (1.19-10.12)] and TYMS rs2853539 AA genotype [OR (95% CI) = 2.76 (1.50-5.07)] were predictors of poor response in our patient population.


CONCLUSIONS
Genes from all the three pathways seem to contribute to MTX response in the Indian population. However, these observations need to be replicated in an independent sample set.
Sharma
Shruti
S
Department of Genetics, University of Delhi South Campus, New Delhi, India.
Das
Mitashree
M
Kumar
Ashok
A
Marwaha
Vishal
V
Shankar
Subramanian
S
Singh
Paramjeet
P
Raghu
Padmanabhan
P
Aneja
Ritu
R
Grover
Rahul
R
Arya
Vivek
V
Dhir
Varun
V
Gupta
Rajiva
R
Kumar
Uma
U
Juyal
Ramesh C
RC
K
Thelma B
TB
D000659:AMP Deaminase; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D014644:Genetic Variation; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases; D007194:India; D016015:Logistic Models; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D008875:Middle Aged; D009097:Multienzyme Complexes; D009709:Nucleotide Deaminases; D011110:Polymorphism, Genetic; D011687:Purines / Q000378:metabolism*
D009097:Multienzyme Complexes; D011687:Purines; C113120:inosine monophosphate synthase; D019877:Hydroxymethyl and Formyl Transferases; D009709:Nucleotide Deaminases; D000659:AMP Deaminase; C514117:AMPD1 protein, human; C030985:purine; D008727:Methotrexate