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Title: 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

Author
item CORELLA, DOLORES - University Of Valencia
item SORLI, JOSE - University Of Valencia
item GONZALEZ, JOSE - University Of Valencia
item ORTEGA, CAROLINA - University Of Valencia
item FITO, MONSTERRAT - Instituto De Salud Carlos Iii
item BULLO, MONICA - Instituto De Salud Carlos Iii
item MARTINEZ-GONZALEZ, MIGUEL ANGEL - Instituto De Salud Carlos Iii
item ROS, EMILIO - Instituto De Salud Carlos Iii
item AROS, FERNANDO - Instituto De Salud Carlos Iii
item LAPETRA, JOSE - Instituto De Salud Carlos Iii
item GOMEZ-GRACIA, ENRIQUE - Instituto De Salud Carlos Iii
item SERRA-MAJEM, LLUIS - University Of Las Palmas De Gran Canaria
item RUIZ-GUTIERREZ, VALENTINA - Instituto De Salud Carlos Iii
item FIOL, MIGUEL - Hospital Son Dureta
item COLTELL, OSCAR - University Jaume I Of Castellon
item VINYOLES, ERNEST - Catalan Institute Of Health
item PINTO, XAVIER - Hospital Universitario De Bellvitge
item MARTI, AMELIA - University Of Navarra
item SAIZ, CARMEN - University Of Valencia
item ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item ESTRUCH, RAMON - Instituto De Salud Carlos Iii

Submitted to: Cardiovascular Diabetology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/31/2013
Publication Date: 1/6/2014
Citation: Corella, D., Sorli, J.V., Gonzalez, J.I., Ortega, C., Fito, M., Bullo, M., Martinez-Gonzalez, M., Ros, E., Aros, F., Lapetra, J., Gomez-Gracia, E., Serra-Majem, L., Ruiz-Gutierrez, V., Fiol, M., Coltell, O., Vinyoles, E., Pinto, X., Marti, A., Saiz, C., Ordovas, J.M., Estruch, R. 2014. 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. Cardiovascular Diabetology. 5:1-13.

Interpretive Summary: Cardiovascular disease (CVD) results from the complex interactions of genetic and environmental factors. We, and others, have shown that the genetic components predisposing one to CVD consists of hundreds of genes; thus the importance of understanding the role of each of those genes in the development of the disease in order to get a more complete picture of an individual’s risk. One of the genes implicated is known as Fas apoptotic inhibitory molecule 2 (FAIM2). The metabolic processes involving the product of this gene have been connected with diabetes, obesity and CVD. A variant near the FAIM2 gene is known as rs7138803; G'>'A locus has been related to obesity. However, its association with other cardiovascular risk factors and disease remains uncertain. We analyzed the association between the FAIM2-rs7138803 polymorphism and obesity, blood pressure and heart rate in 7,161 subjects 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 CVD incidence according to diabetes status after a median 4.8-year dietary intervention follow-up. Our data validated the association between the FAIM2-rs7138803 polymorphism and greater obesity risk. Most important, we detected novel associations of this polymorphism with higher diastolic blood pressure (DBP) and heart rate at baseline. Moreover, this association was greater in type-2 diabetic subjects. Likewise, these findings were also observed longitudinally over a 5-year follow-up. Nevertheless, these effects were independent of diet. In summary, we have validated the relationship between the FAIM2-rs7138803 and obesity, and in addition, we have 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 heart attack risk in type-2 diabetic subjects.

Technical Abstract: The 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. We 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. We 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. We 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.