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Abstract: PO1438

Association of TNIP1 Variants with Disease Severity and Progression and IP-10 Chemokine Levels in Lupus Nephritis Patients

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Powell, David W., University of Louisville School of Medicine, Division of Nephrology, Louisville, Kentucky, United States
  • Brady, Makayla, Department of Biochemistry and Molecular Genetics,University of Louisville., Louisville, Kentucky, United States
  • Barati, Michelle T., University of Louisville School of Medicine, Division of Nephrology, Louisville, Kentucky, United States
  • Caster, Dawn J., University of Louisville School of Medicine, Division of Nephrology, Louisville, Kentucky, United States
Background

African American SLE patients experience higher rates of LN, increased progression to ESKD, and higher mortality when compared with white patients, but etiology for this disparity in unclear. We reported that a TNIP1 polymorphism, rs4958881, is a risk variant for lupus nephritis (LN) in African American patients. TNIP1 encodes the protein ABIN1, which negatively regulates the transcription factor NF-κB. Transgenic mice with impaired ABIN1 function (ABIN1[D485N]) spontaneously develop autoimmunity and LN. IP-10 is a pro-inflammatory chemokine and NF-κB target. Increased tissue levels of IP-10 have been implicated in pathogenesis and as a diagnostic marker of LN, but the mechanism is unknown. The current project tested a hypothesis that LN severity and enhanced IP-10 levels are associated with the TNIP1 rs4958881 risk allele.

Methods

All endpoints were compared for LN patients w/wo TNIP1 variant rs4958881. LN pathology classifications were compared for 125 African American and 133 White American LN patients. Urine and serum IP-10 levels were measured in 33 LN patients using ELISA. Progression of disease was assessed and compared from follow up (mean = 3 yrs) for 33 LN patients. Urine, plasma, and kidney levels of IP-10 were compared in wildtype and ABIN1[D485N] mice.

Results

A higher percent of African Americans with Class IV LN had the TNIP1 variant (68%) versus 42% for Whites with Class IV and 93% of African American with Class V LN had the variant versus 38% for Whites with Class V. 26.3% of patients with the variant vs. 7.1% of patients without the variant reached the endpoint of doubling of creatinine or ESKD. Proteinuria at follow up was higher in variant (2800 mg/g) vs. non-variant (1175 mg/g) patients, suggesting refractory disease in variant patients. There were significantly higher levels of IP-10 in serum and urine from African American versus White LN patients and a trend for association in patients with the variant. Urine, plasma, and kidney levels of IP-10 were significantly enhanced in ABIN1[D485N] versus wildtype mice.

Conclusion

Our findings suggest that TNIP1 variant genotyping and IP-10 measurement could provide precision diagnostics for African American LN patients and that inhibition of NF-κB or neutralization of IP-10 is a promising personalized therapeutic direction for these patients.

Funding

  • NIDDK Support