Abstract 557: Gene Polymorphisms in IL-10, INF-γ and TGF-β are Associated with Early-Onset Coronary Artery Disease and Microvascular Function.

Abstract

The influence of genetics on atherosclerosis development remains unclear. Association of single-nucleotide polymorphisms (SNPs) with early-onset coronary artery disease (EOCAD), as well as with carotid intima-media thickness (CIMT), and systemic microvascular reactivity was examined in 52 patients with EOCAD (45 ±3 years old) and 35 age-matched controls. SNPs in ACE, TNF-α (-308G/A, -238 G/A), IFN-γ (+874 A/T), MMP-9 (-1562 C/T), IL-10 (-1082 A/G, -819 C/T, 592 C/A), NOS3 (894 G/T), ApoA1 (rs964184), and TGF-β (codon 10 T/C) genes were genotyped by automatic sequencing. CIMT was determined by ultrasound and capillary density by intravital video-microscopy. Microvascular reactivity was evaluated using laser speckle contrast imaging, cutaneous blood flow was assessed at rest and during post-occlusive reactive hyperemia (PORH), and acetylcholine (Ach) or sodium nitroprusside (SNP) iontophoresis. Genotype distribution was: ACE: 31 DD, 12 II, 43 DI; TNF-α: 56 GG, 20 GA, 3 AA at position -308, and 76 GG, 3 GA at position -238; IFN-γ: 8 subjects with high producer TT genotype; MMP-9: 62 CC, 23 CT; IL-10: 8 high producer haplotype, 35 intermediate, and 43 low; NOS3: 41 GG, 34 GT, 11 TT; ApoA1: 47 CC, 29 CG, 10 GG; TGF-β (cd 25): 75 GG, 10 GC; TGF-β (cd 10): 66 high producer genotype, 19 low producer. IFN-γ, IL-10 haplotype, and TGF-β were significantly related to EOCAD. CIMT was increased (0.93 ±0.02 mm, p<0.0001), while capillary density (87 ±3 capillaries/mm2, p=0.029) was reduced in EOCAD. CC genotype of TGF-β showed higher CIMT (p=0.004) and lower capillary density (p=0.019) than TT. High IL-10 haplotype reduced vasodilator response after PORH (0.32 APU/mmHg, p=0.0316), while high IFN-γ genotype reduced the response induced by both Ach (0.19 APU/mmHg) and SNP (0.13 APU/mmHg) in relation to low producer (0.44, 0.31, and 0.24 APU/mmHg, respectively). TT genotype of TGF-β showed lower vasodilator response after SNP than CC. In conclusion, IFN-γ, IL-10 and TGF-β genotypes were associated with EOCAD, as well as with systemic microvascular response, CIMT, and capillary rarefaction. The results suggest that IFN-γ, IL-10 and TGF-β genotypes could influence EOCAD, affecting microvascular reactivity through endothelium-dependent and -independent pathways.