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TITLE: IL-6 AND TNF-a GENOTYPES PREDICTS ACUTE REJECTION AND LOWER SURVIVAL IN AFRICAN AMERICAN HEART TRANSPLANT RECIPIENTS

Bernice L. Coleman ¹, Lawrence S.C. Czer ¹, Stanley C. Jordan ¹, James Mirocka ³, Glenn Gillaspie ⁴, Carlos Blanche ¹, Anne Hickey ¹, Kathy E. Magliato ¹ and Dolly B. Tyan ².

¹Cardiothoracic Surgery, Cedars Sinai Medical Center, Los Angeles, California, United States; ²Medical Genetics, Cedars Sinai Medical Center, Los Angeles, California, United States; ³Cardiology, Cedars Sinai Medical Center, los Angeles, California, United States and ⁴Outcomes Management, Cedars Sinai Medical Center, Los Angeles, California, United States.

INTRODUCTION: Elevated levels of IL-6 and TNF-a have been detected in both heart failure and heart transplant rejection. Both cytokines play a role in T cell activation during acute allograft rejection. We explored the relationship of IL-6 and TNF-a gene polymorphism on acute rejection and survival after heart transplantation. METHODS: Pre-heart transplant patients (NYHA Class III-IV, idopathic 44.6%, ischemic 56.4%, African American (AA) N=31, Caucasian American (CA) N=200, were studied pre and post heart transplantation. Genomic deoxyribonucleic acid (DNA) was prepared from 231 available frozen monnuclear leukocyte samples. DNA extraction was done using the Qiagen DNA Extraction kit. Gene specific primer pairs for the polymorphisms of IL-6 GG high, -174g, and TNF-a GG low -308g, provided in the Cytokine Genotyping Tray (One Lamba) were used in prepartion for amplification by polymerase chain reaction-SSP technique. Results were visualized using ethidium bromide argarose gel. RESULTS: AA heart recipients (N=20) were predominately IL-6 GG high genotype (GG high 80%, GC high 20%) compared to CA heart recipients (N=71) (GG high 49%, GC high 51%; p= 0.002 FET). No difference was found in TNF-a or IL-6 CC low geneotypes between groups. AA heart recipients experienced earlier and greater acute rejection
(>=Ib) than CA heart recipients (p= 0.034 Chi Square). AA heart recipients with combined genotypes of IL-6 GG high and TNF-aGG low demonstrated lower survival compared to CA heart recipients at four years post transplant, AA recipients 61±2% and CA recipients 80 ±3% (p= 0.01). CONCLUSION: Cytokine genotypes of IL-6 GG high and TNF-a GG low are strong predictors of acute allograft rejection and lower allograft survival in AA heart transplant recipients. Pre-heart transplantation cytokine genotypes could help to predict the post transplant course and need for augmented immunosuppression.