Gene Variant Explains Differences in Blood Fatty Acid Levels
Epidemiological and experimental evidence suggest that unsaturated fatty acids may have favorable effects on lowering risk of cardiometabolic diseases like cardiovascular disease, type 2 diabetes and their mortalities. Replacing saturated fatty acids in the diet with polyunsaturated and monounsaturated fatty acids were shown to significantly reduce the total and LDL (low density lipoprotein) cholesterol levels. Therefore, unsaturated fatty acids are considered as “good fat”.
Alpha-linolenic acid and linoleic acid as essential polyunsaturated fatty acids are exclusively obtained from diet. The rest of unsaturated fatty acids can be obtained from dietary intake or synthesized through de novo lipogenesis (DNL) by the body. Therefore, the genetic variants that affect digestion, absorption and synthesis of unsaturated fatty acids may explain certain degree of variation for blood unsaturated fatty acid levels between individuals. Recent genome-wide association studies (GWAS) in European-ancestry populations have identified several gene loci that are associated with blood levels of unsaturated fatty acids including monounsaturated fatty acids (oleic acid, palmitoleciacid), and polyunsaturated fatty acids (arachidonic acid, eicosapentacnoic acid and eicosadienoic acid). However, it is unclear whether the loci identified in European populations exert similar effects in Chinese populations. Moreover, it remains to be clarified whether there are additional gene loci or the loci associated with other unsaturated fatty acids. Trans-ethnic genome-wide association study is a powerful approach for identifying additional novel fatty acid-associated loci and localizing the casual variants that drive association at each loci.
With genetic and fatty acid data from over 15,000 individuals of Chinese and European ancestry, a team of scientists, led by Professor LIN Xu, from Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, in collaboration with an international team of 28 scientists from the CHARGE (the Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium, recently conducted the genome-wide trans-ethnic genetic studies of blood PUFA (polyunsaturated fatty acid) and MUFA(monounsaturated fatty acid) levels.
The findings were published in Human Molecular Genetics entitled as “Genome-wide meta-analyses identify novel loci associated with n-3 and n-6 polyunsaturated fatty acid levels in Chinese and European-ancestry populations” and also in Journal of Lipid Research, respectively entitled as “Discovery and fine-mapping of loci associated with MUFAs through trans-ethnic meta-analysis in Chinese and European populations” The main findings of the two studies were as follows:
Four novel gene loci were identified with a significant association to blood PUFA levels. Of them, genetic variation in MYB (MYB proto-oncogene, transcription factor) and AGPAT4 (1-acylglycerol-3-phosphate O-acyltransferase 4) showed significant associations with docosatetraenoic acid concentration, while DGAT2 (diacylglycerol O-acyltransferase 2) and PPT2 (palmitoyl-protein thioesterase 2) were significantly associated with blood gamma-linolenic acid and docosapentaenoic acid levels, respectively. Notably, MYB-rs9399137 and AGPAT4-rs729986 showed significant heterogeneity in allelic effect between Chinese and European-ancestry populations.
Novel genome-wide significant associations were also observed for blood MUFA levels at loci: FADS1/2 (fatty acid desaturase 1/2 ) and PKD2L1 (polycystin 2 like 1, transient receptor potential cation channel) for vaccenic acid, and FADS1/2 and GCKR (glucokinase regulator ) for gondoic acid.
The previously reported associations in European population, namely, NTAN1(N-terminal asparagine amidase)-rs16966952 with linoleic acid and arachidonic acid, ELOVL2 (ELOVL fatty acid elongase 2)-rs3734398 with docosahexaenoic acid, GCKR-rs780094 with docosapentaenoic acid, as well as PKD2L1, FADS1/2, GCKR, and HIF1AN (hypoxia inducible factor 1 alpha subunit inhibitor ) with palmitoleic acid and FADS1/2 and LPCAT3 (lysophosphatidylcholine acyltransferase 3 ) with oleic acid were all confirmed in the Chinese populations.
Further trans-ethnic fine-mapping analysis suggests that a missense variant rs1260326 (P446L) is the causal variant that drives the association with GCKR variants, and improved fine-mapping resolutions were also observed at other loci including FADS1/2, GCKR, NTAN1, NRBF2 (nuclear receptor binding factor 2 ) and ELOVL2.
These findings provide not only novel insight into the genetic background of unsaturated fatty acids and their allelic heterogeneity between Chinese and European populations, but also provided scientific evidence for establishing the dietary guideline proper for Chinese and also for personalized nutrition.
The studies were funded by the Major Projects of the Ministry of Science and Technology of China and the National Natural Science Foundation of China.
Prof. LIN Xu
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
320 Yueyang Road, Shanghai 200031