WASHINGTON, D.C.—The genotypes of patients with lupus nephritis (LN) may not predict response to mycophenolate mofetil (MMF), according to a new study presented at the American College of Rheumatology annual meeting.
“Mycophenolate mofetil is one of the first-line treatments of lupus nephritis,” said Noa Schwartz, MD, who was part of the New York University team that conducted the study under lead investigator Robert Clancy, MD. “However, not all patients respond similarly to this treatment, and as of yet, there are no known reliable response-prediction factors. Genetics is thought to play a major role in patients’ propensity to respond to MMF, and several single-nucleotide polymorphisms (SNPs) in the drug’s target enzyme, inosine monophosphate dehydrogenase (IMPDH), have been implicated in the renal transplant literature as affecting response to MMF therapy.”
Dr. Schwartz, who is now an intern in internal medicine at Montefiore Medical Center in New York, presented the study data. She said the Aspreva Lupus Management Study (ALMS) has previously shown that MMF is effective for both induction and maintenance in LN patients. These patients, however, demonstrate a wide range of responses to MMF. The team studied two SNPs with reported opposite effects: rs2278294 makes the disease more susceptible to MMF (patients with this variation respond better to MMF), while rs11706052 diminishes the effects of MMF.
Individuals carrying variant forms of IMPDH are also thought to have an attenuated ability to produce pathogenic nitric oxide (NO).
Researchers looked at 66 patients from the ALMS patients who had been randomized to MMF in induction and/or maintenance. The researchers obtained DNA and blood samples to evaluate genetic variation and serum NO levels.
The allele calling rate of 66 DNA samples was 98% for rs2278294 and 100% for rs11706052. Assignments were verified by PCR amplification and direct sequencing, and both rs11706052 (IMPDH2) and rs2278294 (IMPDH1) were tested by the researchers for departure from Hardy-Weinberg equilibrium (HWE) expectations.
The study showed that representation of the two candidate SNPs had no HWE deviation and the relatively frequent minor alleles were comparable to those in the dbSNP database and in agreement with allelic discrimination and direct sequencing. The researchers divided the patients into two groups. Group 1 included responders to MMF at induction and non-treatment failures at maintenance. Group 2 included non-responders at induction and treatment failures at maintenance.
Dr. Schwartz said for the IMPDH2 variant rs11706052, the distribution of variant alleles was similar for subjects in both groups (7.8% for Group 1 vs. 7.1% MAF for Groups 2). In addition, the results were similar when the analysis was restricted to Hispanics, which was the largest ethnic group. For the IMPDH1 variant rs2278294, the investigators found no association between groups (45.0% for Group 1 vs. 46.4% MAF for Group 2). With regard to NO, the researchers observed no association between genotypes at rs2278294 and levels (14.5% vs. 20.4%).
“The ALMS database provided an opportunity for us to investigate whether these previously identified SNP’s also confer a particular MMF response profile in lupus nephritis, as such a finding could have major implications on disease management decisions. Our results are preliminary, but do not demonstrate an association between lupus nephritis response to MMF and genetic variation in these previously identified SNPs,” Dr. Schwartz told Renal & Urology News. “Currently, more and more efforts are placed on identifying specific genetic profiles, and attributing much of inter-patient variation in disease and therapy to the genome. Within this context, our study makes an important point in that it demonstrates that perhaps other variables should be taken into account, beyond the patients’ genetic makeup.”
Study findings suggest that the effects of MMF in different disease contexts are influenced not only by the medication’s direct effects, but also by the pathogenesis and/or cellular micro-environments unique to each disease process, she said.