Volume 30 Issue 1
Jan.  2017
Turn off MathJax
Article Contents

LI Xiang, GAN Zhen Wei, DING Zhen, WU Yi Xia, CHEN Xue Yan, TIAN Hui Min, LIU Guo Liang, YANG Ye Tong, XIE Lin. Genetic Variants in the ELOVL5 but not ELOVL2 Gene Associated with Polyunsaturated Fatty Acids in Han Chinese Breast Milk[J]. Biomedical and Environmental Sciences, 2017, 30(1): 64-67. doi: 10.3967/bes2017.008
Citation: LI Xiang, GAN Zhen Wei, DING Zhen, WU Yi Xia, CHEN Xue Yan, TIAN Hui Min, LIU Guo Liang, YANG Ye Tong, XIE Lin. Genetic Variants in the ELOVL5 but not ELOVL2 Gene Associated with Polyunsaturated Fatty Acids in Han Chinese Breast Milk[J]. Biomedical and Environmental Sciences, 2017, 30(1): 64-67. doi: 10.3967/bes2017.008

Genetic Variants in the ELOVL5 but not ELOVL2 Gene Associated with Polyunsaturated Fatty Acids in Han Chinese Breast Milk

doi: 10.3967/bes2017.008
Funds:

This work was supported by the National Natural Science Foundation of China No. 81102115

More Information
  • Author Bio:

    LI Xiang, female, born in 1990, Master of Medical Science, majoring in nutrition and health.

  • Corresponding author: XIE Lin, Professor, Tel: 15043068965. E-mail:xielin@jlu.edu.cn
  • Received Date: 2016-07-11
  • Accepted Date: 2016-12-29
  • 加载中
  • [1] Groen-Blokhuis MM, Franić S, van Beijsterveldt CE, et al. A prospective study of the effects of breastfeeding and FADS2 polymorphisms on cognition and hyperactivity/attention problems. Am J Med Genet B Neuropsychiatr Genet, 2013; 162, 457-65. doi:  10.1002/ajmg.b.v162.5
    [2] Puskas LG, Kitajka K. Nutrigenomic approaches to study the effects of n-3 PUFA diet in the central nervous system. Nutr Health, 2006; 18, 227-32. doi:  10.1177/026010600601800305
    [3] Morales E, Bustamante M, Gonzalez JR, et al. Genetic Variants of the FADS Gene Cluster and ELOVL Gene Family, Colostrums LC-PUFA Levels, Breastfeeding, and Child Cognition. PlosOne, 2011; 6, e17181. doi:  10.1371/journal.pone.0017181
    [4] Glaser C, Lattka E, Rzehak P, et al. Genetic variation in polyunsaturated fatty acid metabolism and its potential relevance for human development and health. Matern Child Nutr, 2011; 7, 27-40. https://www.researchgate.net/profile/Berthold_Koletzko/publication/50265875_Genetic_variation_in_polyunsaturated_fatty_acid_metabolism_and_its_potential_relevance_for_human_development_and_health/links/55aa775408ae481aa7fbc323.pdf?origin=publication_list
    [5] Chapkin RS, Kim W, Lupton JR, et al. Dietary docosahexaenoic and eicosapentaenoic acid:emerging mediators of inflammation. Prostaglandins LeukotEssent Fatty Acids, 2009; 81, 187-91. doi:  10.1016/j.plefa.2009.05.010
    [6] Schuchardt JP, Huss M, Stauss-Grabo M, et al. Significance of long chain polyunsaturated fatty acids (PUFAs) for the development and behaviour of children. Eur J Pediatr, 2010; 169, 149-64. doi:  10.1007/s00431-009-1035-8
    [7] Decsi T, Koletzko B. N-3 fatty acids and pregnancy outcomes. Curr Opin Clin Nutr Metab Care, 2005; 8, 161-6. doi:  10.1097/00075197-200503000-00009
    [8] Chisaguano AM, Montes R, Pérez-Berezo T, et al. Gene expression of desaturase (FADS1 and FADS2) and Elongase (ELOVL5) enzymes in peripheral blood:association with polyunsaturated fatty acid levels and atopic eczema in 4-year-old children. PLoS One, 2013; 8, e78245. doi:  10.1371/journal.pone.0078245
    [9] Lattka E, Illig T, Koletzko B, et al. Genetic variants of the FADS1 FADS2 gene cluster as related to essential fatty acid metabolism. Curr Opin Lipidol, 2010; 21, 64-9. doi:  10.1097/MOL.0b013e3283327ca8
    [10] Tanaka T, Shen J, Abecasis GR, et al. Genome-wide association study of plasma polyunsaturated fatty acids in the InCHIANTI Study. PLoS Genet, 2009; 5, e1000338. doi:  10.1371/journal.pgen.1000338
  • 加载中
通讯作者: 陈斌, bchen63@163.com
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索

Tables(3)

Article Metrics

Article views(1361) PDF downloads(87) Cited by()

Proportional views
Related

Genetic Variants in the ELOVL5 but not ELOVL2 Gene Associated with Polyunsaturated Fatty Acids in Han Chinese Breast Milk

doi: 10.3967/bes2017.008
Funds:

This work was supported by the National Natural Science Foundation of China No. 81102115

  • Author Bio:

  • Corresponding author: XIE Lin, Professor, Tel: 15043068965. E-mail:xielin@jlu.edu.cn
LI Xiang, GAN Zhen Wei, DING Zhen, WU Yi Xia, CHEN Xue Yan, TIAN Hui Min, LIU Guo Liang, YANG Ye Tong, XIE Lin. Genetic Variants in the ELOVL5 but not ELOVL2 Gene Associated with Polyunsaturated Fatty Acids in Han Chinese Breast Milk[J]. Biomedical and Environmental Sciences, 2017, 30(1): 64-67. doi: 10.3967/bes2017.008
Citation: LI Xiang, GAN Zhen Wei, DING Zhen, WU Yi Xia, CHEN Xue Yan, TIAN Hui Min, LIU Guo Liang, YANG Ye Tong, XIE Lin. Genetic Variants in the ELOVL5 but not ELOVL2 Gene Associated with Polyunsaturated Fatty Acids in Han Chinese Breast Milk[J]. Biomedical and Environmental Sciences, 2017, 30(1): 64-67. doi: 10.3967/bes2017.008
  • The present study was designed to examine the contributions of the fatty acid elongase (ELOVL) gene polymorphisms to the levels of polyunsaturated fatty acids (PUFAs) in breast milk. Two hundred and nine healthy Han Chinese mothers were included in the study. Carriers of minor alleles of SNPs (rs2397142 and rs9357760) in ELOVL5 were associated with higher levels of linoleic acid (LA), dihomo-γ-linolenic acid (DGLA), arachidonic acid (AA), docosatetraenoic acid (DTA), docosahexenoic acid (DHA), while in rs209512 of ELOVL5 the carriers of minor alleles had lower levels of DTA compared to major homozygote alleles (P ranged from 0.004-0.046), and genetically explained variability ranged from 3.2% for eicosapentaenoic acid (EPA) to 6.0% for LA. Our findings demonstrated that common variation in ELOVL5 gene encoding rate-limiting enzymes in the metabolism of PUFAs contribute to the PUFAs in breast milk.

    An adequate supply of long-chain Polyunsaturated fatty acids PUFAs (LC-PUFAs) during pregnancy is important for brain growth as well as visual and cognitive development of the fetus [1]. Breast milk is a major source of food for 0-6 month-old-infants, these PUFAs, which are transferred across the placenta and are present in human milk, are accumulated in the brain and retina during fetal and infant development, and insufficient LC-PUFAs intake may result in visual and cognitive impairment and disturbances in mental functions and could be the main reason for the increasing incidence of different mental disorders in humans [2]. ELOVL gene is the elongation of very long chain fatty acids family genes, ELOVL2 and ELOVL5 encode fatty acid elongase-2 and -5 elongases that catalyze the rate-limiting condensation reaction resulting in the synthesis of very long chain fatty acids [3]. The objective of this study was to investigate the association between the levels of PUFAs in breast milk and the common variants of the ELOVL2 and ELOVL5 genes.

    A total of 209 healthy participants from Shirentang House (a Postpartum Care Center, where mothers and babies were taken care after delivery) without any obstetrical complications were enrolled in this study, the age ranged from 22-39 years. They were non-smokers, with a pre-pregnancy BMI ranging from 17.60-26.30 kg/m2 and they gained weight (18.00 ± 6.90 kg) during pregnancy. Some (55.90%) were breastfed exclusively and the others chose mixed feeding; 68.3% had a caesarean delivery, gestational age was 39.00 ± 1.28 weeks, there are 114 boys and 95 girls, and their average weight was 3.3 kg, and most (56.7%) of the subjects came from middle-income families. There was no significant difference (P > 0.05) in the intake of dietary PUFAs between the carriers of minor alleles, compared to the major homozygote alleles. The intake data for each participant were estimated from a 24-h recall questionnaire (data not shown).

    The distributions of genotypes frequencies in the 209 subjects were in accordance with Hardy-Weinberg equilibrium. The selected SNPs are all in introns (Table 1), the prevalence of the minor alleles was relatively high and ranged from 11%-43% of the population. Hence, one would expect a considerable public health relevance of these genetic variants, which modulate the effects of environmental exposure on human health. To determine whether the ELOVL genotypes were associated with PUFAs, we evaluated the associations of the genotype of ten SNPs with eight levels of PUFAs by covariate ANOVA and the results are given in Table 2. Significant associations were observed between SNPs in ELOVL5 and the levels of PUFAs. Carriers of minor alleles of rs2397142 and rs9357760 in ELOVL5 had higher levels of linoleic acid (LA), dihomo-γ-linolenic acid (DGLA), arachidonic acid (AA), docosatetraenoic acid (DTA) and n-3 product docosahexaenoic acid (DHA) compared to major homozygote alleles (P changed from 0.004 to 0.046). However, there is an exception that the carrier of a minor allele of SNP rs209512 in ELOVL5 was associated significantly (P = 0.023) with lower levels of DTA in breast milk compared to major homozygote alleles.

    dbSNP Position (bp) * Function Alleles Genotype HWE# Genotyping Success Rate (%)
    M/m MM Mm mm
    ELOVL2
    rs2281591 10990260 Intron A/G 136 62 10 0.40 99.52
    rs12332786 10998735 Intron C/G 115 81 12 0.65 99.52
    rs3798713 11008389 Intron C/G 88 92 23 0.89 97.13
    rs3778166 11032931 Intron G/A 60 108 35 0.25 97.13
    rs9468304 11041932 Intron A/G 103 90 16 0.55 100.00
    ELOVL5
    rs2294867 53289156 Intron C/A 72 100 28 0.47 95.69
    rs9357760 53325336 Intron A/G 88 91 22 0.83 96.17
    rs2397142 53335501 Intron C/G 88 92 20 0.57 95.69
    rs209512 53338779 Intron A/G 59 109 39 0.36 99.04
    rs12207094 53339377 Intron A/T 166 39 4 0.35 100.00
    Note.* Position in basepairs was derived from dbSNP Build 126, based on NCBI Human Genome Build 36 of chromosome 6. M, major allele; m, minor allele. HWE, Hardy-Weinberg equilibrium.

    Table 1.  Characteristics of 10 Polymorphisms in the ELOVL Gene Cluster

    Gene SNP Genotype LA GLA DGLA AA DTA ALA EPA DHA
    ELOVL2 rs2281591 AA 0.363±0.233 0.194±0.070 0.224±0.077 0.078±0.059 0.128±0.045 0.145±0.083 0.088±0.032 0.211±0.072
    AG+GG 0.371±0.200 0.194±0.061 0.220±0.067 0.081±0.043 0.130±0.040 0.146±0.075 0.084±0.031 0.208±0.063
    P 0.783 0.945 0.722 0.658 0.813 0.978 0.348 0.796
    rs12332786 CC 0.365±0.194 0.192±0.062 0.221±0.069 0.078±0.041 0.128±0.040 0.147±0.079 0.086±0.030 0.207±0.067
    CG+GG 0.370±0.253 0.197±0.072 0.225±0.079 0.080±0.068 0.130±0.046 0.145±0.082 0.089±0.034 0.214±0.072
    P 0.888 0.553 0.717 0.785 0.737 0.888 0.539 0.480
    rs3798713 CC 0.379±0.198 0.191±0.057 0.220±0.067 0.081±0.041 0.130±0.039 0.150±0.079 0.085±0.030 0.209±0.065
    CG+GG 0.358±0.238 0.196±0.073 0.224±0.080 0.078±0.063 0.128±0.046 0.142±0.080 0.089±0.034 0.211±0.073
    P 0.516 0.641 0.753 0.707 0.689 0.476 0.444 0.863
    rs3778166 GG 0.365±0.199 0.192±0.065 0.216±0.071 0.077±0.041 0.126±0.041 0.146±0.077 0.084±0.031 0.208±0.071
    AG+AA 0.371±0.231 0.196±0.067 0.227±0.075 0.081±0.059 0.131±0.043 0.146±0.081 0.089±0.032 0.212±00.069
    P 0.865 0.697 0.351 0.602 0.426 1.000 0.391 0.701
    rs9468304 AA 0.355±0.249 0.190±0.070 0.220±0.080 0.077±0.065 0.128±0.047 0.143±0.088 0.087±0.033 0.208±0.073
    AG+GG 0.378±0.191 0.198±0.063 0.226±0.067 0.081±0.041 0.130±0.038 0.149±0.073 0.087±0.031 0.213±0.066
    P 0.449 0.409 0.614 0.612 0.739 0.639 0.955 0.563
    ELOVL5 rs2294867 CC 0.348±0.176 0.194±0.065 0.216±0.064 0.075±0.038 0.124±0.039 0.142±0.073 0.085±0.031 0.204±0.061
    AC+AA 0.378±0.248 0.195±0.068 0.228±0.079 0.083±0.063 0.132±0.046 0.150±0.086 0.089±0.033 0.215±0.075
    P 0.357 0.980 0.278 0.304 0.212 0.501 0.364 0.270
    rs9357760 AA 0.330±0.174 0.187±0.065 0.208±0.066 0.068±0.037 0.120±0.039 0.136±0.075 0.083±0.030 0.198±0.062
    AG+GG 0.405±0.249 0.203±0.067 0.236±0.078 0.089±0.064 0.137±0.044 0.157±0.083 0.091±0.032 0.222±0.073
    P 0.017 0.091 0.008 0.008 0.004 0.057 0.099 0.015
    rs2397142 CC 0.334±0.174 0.187±0.065 0.211±0.067 0.070±0.038 0.121±0.040 0.138±0.076 0.084±0.030 0.200±0.062
    CG+GG 0.397±0.251 0.200±0.067 0.233±0.079 0.087±0.063 0.136±0.045 0.155±0.084 0.089±0.032 0.219±0.074
    P 0.046 0.176 0.034 0.024 0.014 0.131 0.263 0.050
    rs209512 AA 0.394±0.276 0.199±0.062 0.235±0.087 0.090±0.079 0.140±0.049 0.157±0.087 0.090±0.032 0.224±0.072
    AG+GG 0.355±0.196 0.197±0.072 0.217±0.068 0.075±0.040 0.125±0.040 0.141±0.077 0.086±0.032 0.205±0.068
    P 0.253 0.475 0.109 0.067 0.023 0.175 0.365 0.082
    rs12207094 AA 0.367±0.233 0.192±0.066 0.222±0.078 0.079±0.058 0.129±0.046 0.145±0.084 0.087±0.033 0.209±0.072
    AT+TT 0.369±0.173 0.202±0.068 0.228±0.056 0.079±0.036 0.131±0.030 0.150±0.066 0.088±0.029 0.217±0.056
    P 0.954 0.399 0.595 0.996 0.731 0.733 0.885 0.522
    Note. SNP, single nucleotide polymorphism; LA, linoleic acid; GLA, γ-linoleic acid; DGLA, dihomo-γ-linolenic acid; AA, arachidonic acid; DTA, docosatetraenoic acid; ALA, a-linolenic acid; EPA, eicosapentaenoic acid; DHA, docosahexenoic acid; ELOVL, ELOVL fatty acid elongase. The data were normalized by square root transformation. Significance of genotype association with concentrations of PUFAs was tested by covariate ANOVA, All P values were adjusted by BMI and age.

    Table 2.  Relationship between the 10 SNPs in the ELOVL2 and ELOVL5 Gene Region and the Levels of PUFAs in Breast Milk (g/100 g, x±s)

    Linear regression analysis was used to investigate the associations of ELOVL gene polymorphisms with concentrations of PUFAs. The unadjusted R2 values, that reflected the variability of PUFA concentrations explained by the genetic variants, ranged from very low for eicosapentaenoic acid (EPA) (3.2%) or GLA (3.4%), to LA (6.0%). The variability of α-linolenic acid (ALA) amounts explained by the analyzed polymorphisms reached 7.4% in adjusted analyses, which included the effect of confounders (maternal age and pre-pregnancy BMI) (Table 3).

    Fatty Acids Unadjusted Adjusted*
    n-3
    ALA C18:3 5.5 7.4
    EPA C20:5 3.2 6.4
    DHA C22:6 4.8 6.4
    n-6
    LA C18:2 6.0 6.5
    GLA C18:3 3.4 3.8
    DGLA C20:3 4.5 5.5
    AA C20:4 5.9 6.0
    DTA C22:4 5.5 6.5
    Note.* All R2 were adjusted by BMI and age.

    Table 3.  R2Across the 10 Genetic Variants for Each Fatty Acid (%)

    The synthesis of LC-PUFAs from LA involves enzyme-mediated desaturation and elongation steps. Δ6-desaturase (D6D, encoded by the FADS2 gene) catalyzes the conversion of LA into GLA, which is then elongated into DGLA by elongase-5 (encoded by the ELOVL5 gene). Moreover, DGLA can be converted into AA by Δ5-desaturase (D5D, encoded by the FADS1 gene)(4). In the covariate ANOVA analyses, genetic variation in the elongase gene ELOVL5 (rs2397142 and rs9357760) was associated with higher levels of LA, DGLA, AA, DTA, and DHA compared to major homozygote alleles. Higher transcription of elongase-5 may increase the conversion of GLA to DGLA, and accumulated AA, which is the substrates for DTA. It may contribute to high efficient synthesis of AA to DTA. This is probably due to ELOVL5 gene variants that increased the conversion efficiency or contribute to a high enzyme activity.

    The biological effects of LC-PUFAs on brain function are assumed to be mediated by tissue contents of LC-PUFAs with > 20 carbon atoms and more than three double bonds, such as AA, EPA and DHA [5]. AA and DHA have important roles in synaptic transmission and plasticity during early brain development [6]. The intake of AA and DHA during pregnancy and lactation can improve the visual acuity, psychomotor development and mental performance [7]. Although infants are capable of synthesizing AA and DHA, the accumulation of LC-PUFAs in utero is predominantly via placental transfer. Based on the present results, maternal genetic variants influence levels of LC-PUFAs in breast milk and, thus, genetic polymorphisms in the lactating mothers are likely to have important influence on infant brain development.

    In addition, not all genetic variants were significantly associated with PUFA synthesis, we find only one n-3 PUFA (DHA) associated with SNP rs9357760 in ELOVL5, and the effect of gene variants on n-6 fatty acids was more obvious, compared with n-3 fatty acids, probably due to the low conversion of ALA to DHA (< 4%) [8]; Otherwise, limited sample size also affected the power of the findings.

    Associations of the ten SNPs and PUFAs were explained by linear regression. In the initial unadjusted analysis, the genetically explained variability of the amounts of fatty acids ranged from 3.2% for EPA to 6.0% for LA. Lattka et al. reported a genetically explained variability of 28.5% for AA [9] and Tanaka et al reported a variability of 18.6% [10]. In this study, the variability of the AA amounts explained by the ten genetic variants analyzed was 5.9%, which might be because the two earlier studies analyzed fatty acids in serum and plasma, whereas we analyzed fatty acids in breast milk. Our results suggest the amounts of fatty acids in breast milk are less influenced by ELOVL genotypes, compared to plasma or serum phospholipid fatty acids, but this is purely speculative. Nevertheless, all the associations remained stable despite adjustments for maternal age and preconception BMI confounders. By including these covariables into the analysis, we were able to explain ≤ 7.4% of the variance in the levels of fatty acids.

    Overall, the findings of this study show that the ELOVL5 gene polymorphisms might affect the levels of PUFAs in the breast milk, accordingly affecting children's growth and development in the future, and it also provides basic data for personalized nutritional intervention, but the underlying mechanism needs further investigation among different ethnic groups and with larger samples.

    Authors' contributions to manuscript The authors' responsibilities were as follows. LI Xiang performed the data analyses, and drafted the paper. GAN Zhen Wei, DING Zhen, and LIU Guo Liang aided with the fatty acids measurement. WU Yi Xia, CHEN Xue Yan, TIAN Hui Min, and YANG Ye Tong performed basic information questionnaire and dietary survey. XIE Lin conceived, designed and implemented the study. None of the authors reported a conflict of interest related to the study.

Reference (10)

Catalog

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return