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, Delphine Eberle, Simonetta Bacci, Yuan Yuan Zhang, David Nolan, Ernest V. Gervino, Michael T. Johnstone, Vincenzo Trischitta, Steven E. Shoelson, Alessandro Doria

Research output: Contribution to journalArticle

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 risk in type 2 diabetes. This effect is mediated by allelic differences in A20 expression.

Original languageEnglish
Pages (from-to)499-505
Number of pages7
JournalDiabetes
Volume56
Issue number2
DOIs
Publication statusPublished - Feb 2007

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Type 2 Diabetes Mellitus
Coronary Artery Disease
Tumor Necrosis Factor-alpha
Gene Expression
Odds Ratio
Proteins
Alleles
Homozygote
Single Nucleotide Polymorphism
Heterozygote
Italy
Blood Cells
Atherosclerosis
Polymerase Chain Reaction
Messenger RNA
Genes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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Tag polymorphisms at the A20 (TNFAIP3) locus are associated with lower gene expression and increased risk of coronary artery disease in type 2 diabetes. / Boonyasrisawat, Watip; Eberle, Delphine; Bacci, Simonetta; Zhang, Yuan Yuan; Nolan, David; Gervino, Ernest V.; Johnstone, Michael T.; Trischitta, Vincenzo; Shoelson, Steven E.; Doria, Alessandro.

In: Diabetes, Vol. 56, No. 2, 02.2007, p. 499-505.

Research output: Contribution to journalArticle

Boonyasrisawat, W, Eberle, D, Bacci, S, Zhang, YY, Nolan, D, Gervino, EV, Johnstone, MT, Trischitta, V, Shoelson, SE & Doria, A 2007, 'Tag polymorphisms at the A20 (TNFAIP3) locus are associated with lower gene expression and increased risk of coronary artery disease in type 2 diabetes', Diabetes, vol. 56, no. 2, pp. 499-505. https://doi.org/10.2337/db06-0946
Boonyasrisawat, Watip ; Eberle, Delphine ; Bacci, Simonetta ; Zhang, Yuan Yuan ; Nolan, David ; Gervino, Ernest V. ; Johnstone, Michael T. ; Trischitta, Vincenzo ; Shoelson, Steven E. ; Doria, Alessandro. / Tag polymorphisms at the A20 (TNFAIP3) locus are associated with lower gene expression and increased risk of coronary artery disease in type 2 diabetes. In: Diabetes. 2007 ; Vol. 56, No. 2. pp. 499-505.
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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 risk in type 2 diabetes. This effect is mediated by allelic differences in A20 expression.",
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AU - Boonyasrisawat, Watip

AU - Eberle, Delphine

AU - Bacci, Simonetta

AU - Zhang, Yuan Yuan

AU - Nolan, David

AU - Gervino, Ernest V.

AU - Johnstone, Michael T.

AU - Trischitta, Vincenzo

AU - Shoelson, Steven E.

AU - Doria, Alessandro

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N2 - 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 risk in type 2 diabetes. This effect is mediated by allelic differences in A20 expression.

AB - 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 risk in type 2 diabetes. This effect is mediated by allelic differences in A20 expression.

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