Epidemiology and Population Health

The combined effects of FADS gene variation and dietary fats in obesity-related traits in a population from the far north of Sweden: the GLACIER Study



Recent analyses in Greenlandic Inuit identified six genetic polymorphisms (rs74771917, rs3168072, rs12577276, rs7115739, rs174602 and rs174570) in the fatty acid desaturase gene cluster (FADS1-FADS2-FADS3) that are associated with multiple metabolic and anthropometric traits. Our objectives were to systematically assess whether dietary polyunsaturated fatty acid (PUFA) intake modifies the associations between genetic variants in the FADS gene cluster and cardiometabolic traits, and to functionally annotate top-ranking candidates to estimate their regulatory potential.


Data analyses consisted of the following: interaction analyses between the 6 candidate genetic variants and dietary PUFA intake; gene-centric joint analyses to detect interaction signals in the FADS region; haplotype-centric joint tests across 30 haplotype blocks in the FADS region to refine interaction signals; and functional annotation of top-ranking loci from the previous steps. These analyses were undertaken in Swedish adults from the GLACIER Study (N = 5,160); data on genetic variation and eight cardiometabolic traits were used.


Interactions were observed between rs174570 and n-6 PUFA intake on fasting glucose (Pint = 0.005) and between rs174602 and n-3 PUFA intake on total cholesterol (Pint = 0.001). Gene-centric analyses demonstrated a statistically significant interaction effect for FADS and n-3 PUFA on triglycerides (Pint = 0.005) considering genetic main effects as random. Haplotype analyses revealed three blocks (Pint < 0.011) that could drive the interaction between FADS and n-3 PUFA on triglycerides; functional annotation of these regions showed that each block harbours a number of highly functional regulatory variants; FADS2 rs5792235 demonstrated the highest functionality score.


The association between FADS variants and triglycerides may be modified by PUFA intake. The intronic FADS2 rs5792235 variant is a potential causal variant in the region, having the highest regulatory potential. However, our results suggest that multiple haplotypes may harbour functional variants in a region, rather than a single causal variant.

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This research was undertaken as part of a research program supported by the European Commission (CoG-2015_681742_NASCENT), Swedish Research Council (Vetenskapsrådet, Distinguished Young Researchers Award in Medicine, 542-2014-3529), Swedish Heart-Lung Foundation (Hjärt-Lungfonden, 20140776), and the Novo Nordisk Foundation (NNF17OC0026828), all grants to PWF. MK is funded by German Research Foundation (Deutsche Forschungsgemeinschaft) research fellowship (KE 2182/1-1). TVV is supported by the Novo Nordisk Foundation Postdoctoral Fellowship within Endocrinology/Metabolism at International Elite Research Environments via NNF16OC0020698. This study was supported by the Swedish Research Council, Strategic Research Area Exodiab, Dnr 2009-1039, the Swedish Foundation for Strategic Research Dnr IRC15-0067 and the Swedish Research Council, Linnaeus grant, Dnr 349-2006-237. We thank the participants, health professionals and data managers involved in the Västerbotten Intervention Project. We are also grateful to the staff of the Northern Sweden Biobank for preparing materials, and to K. Enqvist and T. Johansson (Västerbottens County Council, Umeå, Sweden) for DNA preparation. We thank Dr. Inês Barroso and colleagues at the Wellcome Trust Sanger Institute (Hinxton) for their work on genotyping the GLACIER cohort.

Author contibutions

YC, AK, PWF and TVV designed the study. YC and TVV performed the statistical analyses. ACE, MK and JDR undertook the functional annotations. AP and TVV conducted the literature review of the 3D interacting genes. YC, PWF and TVV drafted the manuscript. All authors critically revised and approved the manuscript. PWF and TVV have primary responsibility for final content.

Author information

Correspondence to Paul W. Franks or Tibor V. Varga.

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Conflict of interest

PWF has been a paid consultant in the design of a personalized nutrition trial (PREDICT) as part of a private–public partnership at Kings College London, UK, and has received research support from several pharmaceutical companies as part of European Union Innovative Medicines Initiative (IMI) projects. All other authors declare that they have no conflict of interest.

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