Genetic characterisation of delta-5 and delta-6 fatty acid desaturases and associations with fatty acid status in pregnant women of African descent

Abstract

Introduction and aim - Globally, dietary habits have shifted over the years from a traditional rural diet to a more Westernised diet. This has caused a drastic change in the intake ratio of n-6:n-3 polyunsaturated fatty acids (PUFA) from 1:1 to 20:1. Biosynthesis of long-chain polyunsaturated fatty acids (LCPUFA) is associated with genetic variation within the fatty acid desaturase (FADS) gene cluster. The FADS1/2 genes encode for the rate-limiting desaturation enzymes in the LCPUFA biosynthesis pathway. Thus far, genetic variations in the FADS1/2 gene cluster and their effect on LCPUFA metabolism have been investigated in the United States and in Europe, but limited research exists for the African population. The aim of this study was to characterise the genetic variations of the FADS1/2 genes and their effect on delta -5 and -6 desaturase (D5D and D6D) activity and study the associations with n-3 LCPUFA status at early pregnancy in women of African descent. Methods - In this cross-sectional study, a total of 250 apparently healthy pregnant women of African descent were enrolled and 243 of these women gave consent for genetic testing. Participants were divided into two groups depending on their n-6:n-3 LCPUFA ratio: a higher and lower n-3 LCPUFA status group. Nine variants, located in the FADS1/2 gene cluster, were investigated, and genotyping of these selected variants was done using the iPLEX® MassARRAY system from Agena Bioscience™. The genetic variants were investigated for association with D5D and D6D activity, estimating PUFA ratios and n-6:n-3 LCPUFA ratio. To determine D5D and D6D enzymatic activities, LCPUFA product to precursor ratios were determined. Univariate analyses were performed to assess differences between genotypes, adjusting for gestational age, age of the mother, and dietary FA intakes. Results - The alternative allele carriers of FADS1-rs174546(C/T) and FADS2-rs112425493(G/A) associated with both lower AA:DGLA and higher DGLA:LA ratios that are respectively indicative of lower D5D and higher D6D activities. Alternative allele carriers for FADS-rs174547(C/T), FADS1-rs174549(A/G), FADS1-rs174555(C/T) and FADS2-rs73489307(T/C), were all associated with higher DGLA:LA and therefore were associated with higher estimated D6D activity in comparison to the homozygous ancestral alleles. Alternative allele carriers of FADS2-rs78678033(G/A) were associated with higher AA:DGLA ratio, estimated D5D activity as well as lower DGLA:LA ratio and D6D activity. Alternative allele carriers of FADS2-

rs174606(T/G) and FADS2-rs174616(G/A) associated with both lower AA:LA and lower DGLA:LA ratios, lower combined D5D and D6D activity, and lower individual D6D activity. The carriers for the G allele for FADS2-rs112425493(G/A), T allele for FADS1-rs174546(C/T), T allele for FADS1-rs174547(C/T), and the G allele for FADS1-rs174549(A/G) all associated or tended to associate with a lower n-6:n-3 LCPUFA ratio and therefore with a higher n-3 LCPUFA status (P=0.033, P=0059, P=0.062 P=0.071, respectively). All associations were unaffected when adjusting for dietary intake of the individual n-6 or n-3 essential PUFA or LCPUFA. Conclusion - This mini-dissertation sheds light on the unique and noteworthy African genome and the importance of conducting genetic research in a population of African descent. The current study contributes to the investigation of the FADS1/2 gene cluster and the associations with LCPUFA metabolism in an African population. Nine genetic variants influenced estimated desaturase activities and four variants related to both increased desaturase activities and an improved n-3 LCPUFA status, and may thus be advantageous to improve n-3 LCPUFA status in pregnant women of African descent even in the context of low functional LCPUFA such as EPA and DHA dietary intake. This information may create an opportunity to alter the n-3 LCPUFA status of South Africans through dietary intervention which could in turn result in a decline in inflammatory diseases and an increase in optimal birth outcomes for the South