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Genome-Wide Association Study for Serum Omega-3 and Omega-6 Polyunsaturated Fatty Acids: Exploratory Analysis of the Sex-Specific Effects and Dietary Modulation in Mediterranean Subjects with Metabolic Syndrome

1
Department of Computer Languages and Systems, Universitat Jaume I, 12071 Castellón, Spain
2
CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain
3
Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, 46010 Valencia, Spain
4
Area of Health Sciences, Valencian International University, 46002 Valencia, Spain
5
Red Temática de Investigación Cooperativa en Patología Ocular (OFTARED), Instituto de Salud Carlos III, 28029 Madrid, Spain
6
Ophthalmology Research Unit “Santiago Grisolia”, Dr. Peset University Hospital, 46017 Valencia, Spain
7
Department of Internal Medicine, Hospital Clinic, Institut d’Investigació Biomèdica August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain
8
Oncology Department, Sagunto Hospital, 46500 Sagunto, Spain
9
Assisted Reproduction Unit of the University Hospital of Valencia, 46010 Valencia, Spain
10
Nutrition and Genomics Laboratory, JM-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111 USA
11
Department of Cardiovascular Epidemiology and Population Genetics, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
12
IMDEA Alimentación, 28049 Madrid, Spain
*
Author to whom correspondence should be addressed.
Both authors contributed equally to this work as first authors.
Nutrients 2020, 12(2), 310; https://doi.org/10.3390/nu12020310
Received: 6 December 2019 / Revised: 13 January 2020 / Accepted: 21 January 2020 / Published: 24 January 2020
(This article belongs to the Special Issue Dietary Fat and Human Health)
Many early studies presented beneficial effects of polyunsaturated fatty acids (PUFA) on cardiovascular risk factors and disease. However, results from recent meta-analyses indicate that this effect would be very low or nil. One of the factors that may contribute to the inconsistency of the results is that, in most studies, genetic factors have not been taken into consideration. It is known that fatty acid desaturase (FADS) gene cluster in chromosome 11 is a very important determinant of plasma PUFA, and that the prevalence of the single nucleotide polymorphisms (SNPs) varies greatly between populations and may constitute a bias in meta-analyses. Previous genome-wide association studies (GWAS) have been carried out in other populations and none of them have investigated sex and Mediterranean dietary pattern interactions at the genome-wide level. Our aims were to undertake a GWAS to discover the genes most associated with serum PUFA concentrations (omega-3, omega-6, and some fatty acids) in a scarcely studied Mediterranean population with metabolic syndrome, and to explore sex and adherence to Mediterranean diet (MedDiet) interactions at the genome-wide level. Serum PUFA were determined by NMR spectroscopy. We found strong robust associations between various SNPs in the FADS cluster and omega-3 concentrations (top-ranked in the adjusted model: FADS1-rs174547, p = 3.34 × 10−14; FADS1-rs174550, p = 5.35 × 10−14; FADS2-rs1535, p = 5.85 × 10−14; FADS1-rs174546, p = 6.72 × 10−14; FADS2-rs174546, p = 9.75 × 10−14; FADS2-rs174576, p = 1.17 × 10−13; FADS2-rs174577, p = 1.12 × 10−12, among others). We also detected a genome-wide significant association with other genes in chromosome 11: MYRF (myelin regulatory factor)-rs174535, p = 1.49 × 10−12; TMEM258 (transmembrane protein 258)-rs102275, p = 2.43 × 10−12; FEN1 (flap structure-specific endonuclease 1)-rs174538, p = 1.96 × 10−11). Similar genome-wide statistically significant results were found for docosahexaenoic fatty acid (DHA). However, no such associations were detected for omega-6 PUFAs or linoleic acid (LA). For total PUFA, we observed a consistent gene*sex interaction with the DNTTIP2 (deoxynucleotidyl transferase terminal interacting protein 2)-rs3747965 p = 1.36 × 10−8. For adherence to MedDiet, we obtained a relevant interaction with the ME1 (malic enzyme 1) gene (a gene strongly regulated by fat) in determining serum omega-3. The top-ranked SNP for this interaction was ME1-rs3798890 (p = 2.15 × 10−7). In the regional-wide association study, specifically focused on the FADS1/FASD2/FADS3 and ELOVL (fatty acid elongase) 2/ELOVL 5 regions, we detected several statistically significant associations at p < 0.05. In conclusion, our results confirm a robust role of the FADS cluster on serum PUFA in this population, but the associations vary depending on the PUFA. Moreover, the detection of some sex and diet interactions underlines the need for these associations/interactions to be studied in all specific populations so as to better understand the complex metabolism of PUFA. View Full-Text
Keywords: polyunsaturated fatty acids; omega-3; omega-6; genetics; genome-wide association study; sex; Mediterranean population; heterogeneity; polymorphisms; metabolic syndrome polyunsaturated fatty acids; omega-3; omega-6; genetics; genome-wide association study; sex; Mediterranean population; heterogeneity; polymorphisms; metabolic syndrome
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Coltell, O.; Sorlí, J.V.; Asensio, E.M.; Barragán, R.; González, J.I.; Giménez-Alba, I.M.; Zanón-Moreno, V.; Estruch, R.; Ramírez-Sabio, J.B.; Pascual, E.C.; Ortega-Azorín, C.; Ordovas, J.M.; Corella, D. Genome-Wide Association Study for Serum Omega-3 and Omega-6 Polyunsaturated Fatty Acids: Exploratory Analysis of the Sex-Specific Effects and Dietary Modulation in Mediterranean Subjects with Metabolic Syndrome. Nutrients 2020, 12, 310.

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