Floyd Chilton,Ph.D, Mathias RA, Dutta R, Sergeant S, and Seeds MC

Professor of Physiology/Pharmacology and Cancer Biology, Wake Forest School of Medicine

Background. Numerous studies have shown associations between low levels of omega-3 (n-3) long chain (LC-) PUFAs and/or altered ratios of n-6 to n-3 LC-PUFAs and cognitive function as well as psychological disorders. However, systematic reviews/meta-analyses of n-3 LC-PUFA supplementation reveal inconsistent therapeutic results leading to consumer/clinician confusion and industry disappointment.

Methods. FADS SNP mapping and lipidomics analysis were carried out on the Diabetes Heart Study and GeneSTAR cohorts. The FADS genomic region was analyzed in individuals from HGDP and 1000 Genomes Project.

Results. Evidence reveals: 1) That dietary 18 carbon n-3 and n-6 PUFAs in the modern Western diet interact with common genetic variants in two desaturase genes (FADS1 and FADS2) to impact levels of n-3 and n-6 LC-PUFAs, their signaling metabolites, and clinical phenotypes; 2)  There are dramatic differences in the capacity of African, European, Asian and Native American ancestry populations to synthesize LC-PUFAs that are largely due to frequency differences of FADS variants; 3) Evolution within the FADS cluster in response to global PUFA environments gave rise to distinct ancestral variation; and 4) Modern gene-diet PUFA interactions lead to deficiencies of n-3 LC-PUFAs or altered n-3 LC-PUFA/n-6 LC-PUFA ratios in certain patient/populations that enhance the risk of brain functional disorders.

Conclusion. Our work provides a putative pathogenetic mechanism that underscores differences in risk and severity of inflammatory and brain disorders observed in diverse populations. Importantly, it also provides the basis for promising, new clinical applications for n-3 LC-PUFAs that take into consideration genetic heterogeneity of brain disorders patients.