Novel association of the obesity risk-allele near Fas Apoptotic Inhibitory Molecule 2 (FAIM2) gene with heart rate and study of its effects on myocardial infarction in diabetic participants of the PREDIMED trial

Abstract

BackgroundThe Fas apoptotic pathway has been implicated in type 2 diabetes and cardiovascular disease. Although a polymorphism (rs7138803; G > A) near the Fas apoptotic inhibitory molecule 2 (FAIM2) locus has been related to obesity, its association with other cardiovascular risk factors and disease remains uncertain.MethodsWe analyzed the association between the FAIM2-rs7138803 polymorphism and obesity, blood pressure and heart rate in 7,161 participants (48.3% with type 2 diabetes) in the PREDIMED study at baseline. We also explored gene-diet interactions with adherence to the Mediterranean diet (MedDiet) and examined the effects of the polymorphism on cardiovascular disease incidence per diabetes status after a median 4.8-year dietary intervention (MedDiet versus control group) follow-up.ResultsWe replicated the association between the FAIM2-rs7138803 polymorphism and greater obesity risk (OR: 1.08; 95% CI: 1.01-1.16; P = 0.011; per-A allele). Moreover, we detected novel associations of this polymorphism with higher diastolic blood pressure (DBP) and heart rate at baseline (B = 1.07; 95% CI: 0.97-1.28 bmp in AA vs G-carriers for the whole population), that remained statistically significant even after adjustment for body mass index (P = 0.012) and correction for multiple comparisons. This association was greater and statistically significant in type-2 diabetic subjects (B = 1.44: 95% CI: 0.23-2.56 bmp; P = 0.010 for AA versus G-carriers). Likewise, these findings were also observed longitudinally over 5-year follow-up. Nevertheless, we found no statistically significant gene-diet interactions with MedDiet for this trait. On analyzing myocardial infarction risk, we detected a nominally significant (P = 0.041) association in type-2 diabetic subjects (HR: 1.86; 95% CI:1.03-3.37 for AA versus G-carriers), although this association did not remain statistically significant following correction for multiple comparisons.ConclusionsWe confirmed the FAIM2-rs7138803 relationship with obesity and identified novel and consistent associations with heart rate in particular in type 2 diabetic subjects. Furthermore, our results suggest a possible association of this polymorphism with higher myocardial infarction risk in type-2 diabetic subjects, although this result needs to be replicated as it could represent a false positive.

Evaluation of pleiotropic effects among common genetic loci identified for cardio-metabolic traits in a Korean population

“…Recent studies suggested that pleiotropic effects on complex traits may be widespread. Genetic variants associated with two or more traits, such as rs7138803 on FAIM2 that related to obesity, T2D and myocardial infarction, rs8192673 on PGC - 1α and rs1801282 on PPAR - γ associated with waist circumference and T2D, were revealed by previous studies [ 32 – 34 ]. The increased use of genetic information in clinical practice, has underscored the importance of understanding pleiotropy and its implications for genetic testing and personal genomics.…”

MiR-3202 – Promoted H5V Cell Apoptosis by Directly Targeting Fas Apoptotic Inhibitory Molecule 2 (FAIM2) in High Glucose Condition

“…The FADD/Fas signal pathway plays a critical role in the apoptosis processes [ 25 ], it also plays an important role in vascular endothelial disease [ 26 ] and has been implicated in T2DM and cardiovascular disease [ 27 ]. It was suggested that sFas levels appeared to be associated with overweight, hyperlipedema, and clusters of metabolic risk factors among men [ 28 ].…”

Polymorphisms of the Peroxisome Proliferator-Activated Receptor-γ (rs1801282) and its coactivator-1 (rs8192673) are associated with obesity indexes in subjects with type 2 diabetes mellitus

“…Mutation in MC4R gene was found to be associated with morbid obesity in human beings [ 38 ]. Recently the association between the Fas apoptotic inhibitory molecule 2 (FAIM2)-rs7138803 polymorphism and greater obesity risk has been replicated [ 35 ]. Moreover, rs6232 of the proprotein convertase subtilisin/kexin-type 1 (PCSK1) was associated BMI [ 34 ].…”

“…Moreover, miRNA-dependent regulation of fat distribution by miR-196a2 and miR-1908-dependent regulation of lipid metabolism has recently been reported [ 36 ]. Additionally, according to the study of Corella and co-workers epigenetic factors may also be involved in the development of obesity [ 35 ].…”