Background/Purpose: The Aspreva Lupus Management Study (ALMS) demonstrated the efficacy of mycophenolate mofetil (MMF-a prodrug of MFA, mycophenolic acid) for both induction and maintenance of response in lupus nephritis.   However, response is not uniform and it remains unresolved whether this relates to genetic variation in inosine monophosphate dehydrogenase (IMPDH).  SNPs in IMPDH1 (rs2278294) and IMPDH2 (rs11706052) confer a higher risk of acute rejection in renal transplant recipients, and lymphocytes of mutant carriers (rs11706052) yield  an antiproliferative effect which is half that of subjects who are homozygous common. In addition, the ability of MMF to reduce pathogenic nitric oxide (NO) is attenuated in subjects carrying variant forms of IMPDH.   Accordingly, this study was initiated to determine whether the clinical response of MMF and phenotype (NO levels) in ALMS associates with variants of IMPDH. 

Methods: Subjects were 62 ALMS patients randomized to MMF in induction and/or maintenance.  DNA and blood samples were obtained for evaluation of genetic variation and serum NO levels (colorimetric method, NO = nitrite + nitrate).  Genotyping assignments were made based on a postread of the amplified genomic patient DNA by allelic discrimination and use of probes for IMPDH1 rs2278294 and IMPDH2 rs11706052 (Applied Biosystems).  The allele calling rate of 62 DNA samples was 98% for rs2278294 and 100% for rs11706052.  Assignments were verified by PCR amplification and direct sequencing.  Both rs11706052 (IMPDH2) and rs2278294 (IMPDH1) were tested for departure from Hardy-Weinberg equilibrium (HWE) expectations.

Results: Representation of the two candidate SNPs had no HWE deviation; the relatively frequent minor alleles were comparable to those in the dbSNP database and in agreement with allelic discrimination and direct sequencing.  Patients were stratified into two groups: Group I defined as responders to MMF at induction and non-treatment failures at maintenance, and Group 2 non-responders at induction and treatment failures at maintenance.  For the IMPDH2, rs11706052, the distribution of variant alleles was similar for subjects in both groups (10.5%  vs 13.9% MAF  for Groups 1 (N=18) and 2 (N=19), respectively).   Similar results were observed when the analysis was restricted to Hispanics (largest ethnic group). For the IMPDH1,  rs2278294, no association was observed between groups (44.4%  vs 44.7% MAF, Groups 1 vs Groups 2).  With regard to NO, there was no association between genotypes at rs2278294 and levels (14.5±2.6 uM vs 20.4±2.8, P=0.30, homozygous variant (N=9) versus heterozygous + homozygous common (N=33), respectively). 

Conclusion: In distinction to renal transplant, genetic variation at IMPDH1 and IMPDH2 does not account for variability in the clinical response to MMF or levels of NO.   These results should allay concerns regarding genetic testing of these alleles to predict efficacy of MMF in lupus.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/response-to-mmf-therapy-for-lupus-nephritis-is-independent-of-genetic-variation-of-inosine-monophosphate-dehydrogenase/