Tag Polymorphisms at the A20 (TNFAIP3) Locus Are Associated With Lower Gene Expression and Increased Risk of Coronary Artery Disease in Type 2 Diabetes

Tag Polymorphisms at the A20 ( TNFAIP3 ) Locus Are Associated With Lower Gene Expression and Increased Risk of Coronary Artery Disease in Type 2 Diabetes Watip Boonyasrisawat 1 2 , Delphine Eberle 1 2 , Simonetta Bacci 3 , Yuan-Yuan Zhang 1 2 , David Nolan 1 , Ernest V. Gervino 2 4 , Michael T. Johnstone 2 4 , Vincenzo Trischitta 3 5 , Steven E. Shoelson 1 2 and Alessandro Doria 1 2 1 Research Division, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 2 Department of Medicine, Harvard Medical School, Boston, Massachusetts 3 Diabetes and Endocrine Unit, Scientific Institute Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy 4 Cardiology Division, Beth Israel Deaconess Medical Center, Boston, Massachusetts 5 Department of Clinical Sciences, University La Sapienza, Rome, Italy Address correspondence and reprint requests to Alessandro Doria, MD, PhD, MPH, Section on Genetics and Epidemiology, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail: alessandro.doria{at}joslin.harvard.edu Abstract A20 or tumor necrosis factor (TNF)-induced protein 3 ( TNFAIP3 ) is a negative regulator of nuclear factor-κB (NF-κB). We have investigated whether polymorphisms in this gene are associated with increased atherosclerosis in diabetic patients. Five tag single nucleotide polymorphisms (SNPs) were typed in 479 type 2 diabetic patients from Boston, including 239 coronary artery disease (CAD)-positive case subjects and 240 CAD-negative control subjects. Two tag SNPs (rs5029930 and rs610604) were independently associated with CAD; adjusted odds ratios (ORs) for minor allele carriers were 2.3 (95% CI 1.4–3.8, P = 0.001) and 2.0 (1.3–2.9, P = 0.0008), respectively. The association with rs610604 was dependent on glycemic control, with ORs of 3.9 among subjects with A1C ≤7.0% and 1.2 for those with A1C >7.0% ( P for interaction = 0.015). A similar interaction pattern was found among 231 CAD-positive and 332 CAD-negative type 2 diabetic patients from Italy (OR 2.2, P = 0.05 vs. OR 0.9, P = 0.63 in the low vs. high A1C strata, P for interaction = 0.05). Quantitative RT-PCR in blood mononuclear cells from 83 nondiabetic subjects showed that rs610604 and rs5029930 minor allele homozygotes have 30–45% lower levels of A20 mRNA than major allele homozygotes, and heterozygotes have intermediate levels ( P = 0.04 and 0.028, respectively). These findings point to variability in the A20 / TNFAIP3 gene as a modulator of CAD ri