Subramanian Shankar

Publications (5)18.92 Total impact

• Article: Purine biosynthetic pathway genes and methotrexate response in rheumatoid arthritis patients among north Indians.

  Shruti Sharma, Mitashree Das, Ashok Kumar, Vishal Marwaha, Subramanian Shankar, Paramjeet Singh, Padmanabhan Raghu, Ritu Aneja, Rahul Grover, Vivek Arya, Varun Dhir, Rajiva Gupta, Uma Kumar, Ramesh C Juyal, Thelma B K
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  ABSTRACT: 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. 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. 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. 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.
  Pharmacogenetics and Genomics 10/2009; 19(10):823-8. · 3.48 Impact Factor
• Article: Preventing tuberculosis flare in patients with inflammatory rheumatic diseases receiving tumor necrosis factor-alpha inhibitors in India -- An audit report.

  Anand N Malaviya, Sanjiv Kapoor, Shriram Garg, Roopa Rawat, Subramanian Shankar, Savita Nagpal, Dinesh Khanna, Daniel E Furst
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  ABSTRACT: To test the efficacies of a strategy for preventing tuberculosis (TB) in Indian patients with inflammatory rheumatic diseases (IRD) treated with tumor necrosis factor-alpha (TNF-alpha) inhibitor. The screening strategy included tuberculosis skin test (TST), QuantiFERON-TB Gold (QTG) test, standard chest radiograph, and contrast enhanced-computerized tomography of the chest (CT). Among 53 patients screened, 17 (32%) had >or= 1 test positive, with 5 (9.4%) patients having TB infection (clinical, CT, biopsy). The remaining 12 patients showed latent TB; 1 additional patient with negative screening tests was diagnosed with latent TB retrospectively for he developed TB disease within a few weeks of receiving infliximab. The remaining 35 patients tested negative with all tests. The combination of 4 screening tests gave a sensitivity of 0.83, specificity of 0.74, positive predictive value (PPV) 0.29, and negative predictive value (NPV) 0.97. Only 22 patients could afford treatment with TNF-alpha inhibitors; 19 of them were negative in the screening tests. Three patients who were positive on TST and/or QTG received prophylactic treatment with TNF-alpha inhibitor. Since implementation of the screening strategy, only 1 of 22 (4.5%) patients given TNF-alpha inhibitor developed probable TB disease. With the use of these 4 TB screening tests in India, where TB is highly prevalent, TB could be excluded with a high degree of certainty (NPV 0.97). However, as even this combination of tests has only moderate sensitivity and specificity and poor PPV for detecting TB, vigilance may be advisable even if only one of the tests is positive.
  The Journal of Rheumatology 06/2009; 36(7):1414-20. · 3.69 Impact Factor
• Article: Interaction of genes from influx-metabolism-efflux pathway and their influence on methotrexate efficacy in rheumatoid arthritis patients among Indians.

  Shruti Sharma, Mitashree Das, Ashok Kumar, Vishal Marwaha, Subramanian Shankar, Ritu Aneja, Rahul Grover, Vivek Arya, Varun Dhir, Rajiva Gupta, Uma Kumar, Ramesh C Juyal, Thelma B K
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  ABSTRACT: Methotrexate (MTX) is the drug of choice for rheumatoid arthritis (RA) but is effective only in around 60% of treated patients. Bioavailability of MTX may be a major determinant of response status and this may be governed by variations in MTX receptor and transporter genes and genes responsible for polyglutamation and deconjugation. We investigated the contribution of single nucleotide polymorphisms (SNPs) in RFC, FOLR1, FPGS, GGH and MDR1 genes to MTX response in RA patients from North India. RA patients recruited using American College of Rheumatology criteria, were categorized into good and poor responders to MTX, based on disease activity score. A total of 17 SNPs from the above mentioned genes were genotyped and tested for association with MTX response using [chi]2 test; logistic regression along with clinical variables; and gene-gene interaction using multifactor dimensionality reduction (MDR). One novel synonymous SNP Ala324Ala (972 G > A) was identified in RFC gene. The CT genotype of C3435T in MDR1 gene conferred almost twice the risk of poor response [[chi]2 = 5.85, P = 0.01, odds ratio (95% confidence interval) = 1.97 (1.13-3.42)] and was retained in binary logistic regression [B = 0.66, P = 0.025, adjusted odds ratio (95% confidence interval) = 1.93(1.09-3.42)]. Significant interaction between SNPs in GGH and MDR1 genes seems promising. Interactions between genes coding for deconjugation and transporter seem to be important determinants of MTX response in RA but replication and functional studies would be confirmatory.
  Pharmacogenetics and Genomics 12/2008; 18(12):1041-9. · 3.48 Impact Factor
• Article: Bone mineral density in Indian women with rheumatoid arthritis.

  Subramanian Shankar, Rohini Handa, Ritu Aneja, Vishal Marwaha, A C Ammini, V Aprajita
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  ABSTRACT: Osteoporosis (OP) is being increasingly recognized in inflammatory rheumatic diseases like rheumatoid arthritis (RA). Ethnicity influences bone mineral density (BMD) and fracture risk. Due to paucity of data on this aspect of RA from Asian countries including India, we prospectively studied 84 premenopausal women with RA of at least 2 years duration and 247 healthy, age (within 5 years) and sex-matched controls. A significant difference in BMD between patients and controls was observed only at the femoral neck. As many as 22% patients with RA exhibited osteoporosis at least one site in contrast to 9% controls. Nearly 40% of patients exhibited osteopenia at all the three sites. Modified Sharp score, disease duration and DMARD naive period were found to correlate with low BMD. However, on multivariate analysis, only modified Sharp score was shown to be significantly associated with low BMD. Our study draws attention to the poor bone health in Asian Indian women with RA.
  Rheumatology International 10/2008; 29(4):377-81. · 1.88 Impact Factor
• Article: Biochemical assessment of Paget's disease of bone.

  Subramanian Shankar, David J Hosking
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  ABSTRACT: Biochemical measurements of bone turnover provide an objective assessment of disease activity and the response to treatment. Alkaline phosphatase is the best characterized of the bone turnover markers and reflects the extent and activity of Paget's disease. However, in addition to bone-specific alkaline phosphatase (Bone ALP), there is also osteocalcin (OC) and procollagen type 1 N-terminal propeptide (P1NP) as formation markers. A variety of telopeptides (C-terminal telopeptide of type I collagen, [CTX], N-telopeptide of type I collagen [NTX]) or cross-link breakdown products of type 1 collagen can be used to assess bone resorption. Total alkaline phosphatase (Total ALP), Bone ALP, and P1NP all perform similarly in diagnosis and in evaluating the response to treatment, but the general availability, low interassay variation, and inexpensiveness of Total ALP makes it the best test for routine use. Measurement of the biological variability of the different markers in stable, untreated Paget's disease indicates how great a change (critical difference) is needed to define a true alteration in disease activity. Bone ALP, P1NP, and NTX show the highest therapy induced change/critical difference ratio during antiresorptive treatment. Some of the resorption markers show more complex changes in response to treatment. Pyridinoline (PYD) or deoxypyridinoline (DPD) cross-links of type 1 collagen are excreted in urine either as free or as peptide bound moieties, but it is the latter which decrease by the greatest amount in response to bisphosphonate therapy. Newly formed type 1 collagen contains an aspartyl-glycine motif (alphaCTX), which undergoes spontaneous isoaspartyl formation to betaCTX as the bone ages. In untreated Paget's disease, the alphaCTX is raised proportionately more (16-fold) than betaCTX (3-fold) and decreases in response to bisphosphonate therapy to a greater extent than betaCTX (measured in the sCTX assay). As bisphosphonates have become more potent, the aim of treatment has shifted toward the achievement of a rate of bone turnover in the lower part of the reference range. This is important because the duration of remission of disease activity is strongly determined by the post treatment nadir bone turnover.
  Journal of Bone and Mineral Research 01/2007; 21 Suppl 2:P22-7. · 6.37 Impact Factor