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A network approach to micronutrient genetics: interactions with lipid metabolism

Lietz, Georga,b; Hesketh, Johnb,c

Current Opinion in Lipidology: April 2009 - Volume 20 - Issue 2 - p 112–120
doi: 10.1097/MOL.0b013e3283295ecf
Genetics and molecular biology: Edited by Jose M. Ordovas and E. Shyong Tai

Purpose of review Although interactions between fat soluble micronutrients and lipid metabolism in relation to absorption, status and body composition have been well described, there is new evidence to suggest that key genes have profound effects on how micronutrients and lipids are handled in a range of cells and organs. This review highlights the importance of genetic variation in folate, selenium, zinc and carotenoid metabolism and the recent findings of micro–macro nutrient interactions.

Recent findings Although the methylenetetrahydrofolate reductase gene has been linked to CVD for some time, recent findings indicate that single-nucleotide polymorphisms (SNPs) in this gene are also linked to diabetes and may influence the pathogenesis of this disease through elevated alanine amino transferase concentrations. A recent selenium supplementation trial showed that SNPs can affect responses of GPx4, GPx1 and GPx3 protein expression or activity in response to Se supplementation or withdrawal. There is convincing evidence to suggest that the high variability of plasma carotenoids seen in human populations is at least partly caused by multiple genetic variations in genes involved in lipoprotein metabolism and lipid transfer. The most striking evidence of an interaction between carotenoid and lipid metabolism, however, comes from the observation that BCMO1−/− mice develop liver steatosis independent of the vitamin A content of the diet, and the discovery of common SNPs in this gene indicates that this interaction might be of clinical significance.

Summary Knowledge of genetic variants that affect micronutrient metabolism and responses to micronutrient supplementation were until recently largely limited to methylenetetrahydrofolate reductase. However, identification of novel functional SNPs in BCMO1, the critical enzyme of β-carotene metabolism, and in several key selenoproteins indicates the potential importance of micronutrient–gene interactions.

aSchool of Agriculture, Food and Rural Development, UK

bHuman Nutrition Research Centre, UK

cInstitute of Cell and Molecular Biosciences, Framlington Place, The Medical School, Newcastle University, Newcastle upon Tyne, UK

Correspondence to Professor John Hesketh, Institute of Cell and Molecular Biosciences, Newcastle University, Framlington Place, Newcastle upon Tyne, UK Tel: +44 191 222 8744; +44 191 222 6893; fax: +44 191 222 7424; +44 191 222 7811; e-mail:

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Knowledge of interindividual genetic variation is transforming the way that we think about nutritional requirements. Interindividual genetic variation can not only be a basis for investigating nutritional mechanisms but could also potentially be integral to ‘personalized’ nutritional advice tailored for individuals or population subgroups [1,2]. This is relevant not only to the major dietary macronutrients but also to the micronutrients such as vitamin A and related carotenoids, folates as well as trace elements such as selenium and zinc. So far, only a few single-nucleotide polymorphisms (SNPs) known to influence micronutrient metabolism have been described, such as the well known C677T gene variant in the methylene tetrahydrofolate reductase that affects folate and one-carbon metabolism [3]. Although the number of such functional SNPs is limited, a number of SNPs that affect Se, Zn, folate and carotenoid metabolism have been recently identified (see Tables 1 and 2). In order to study the genotype–health association, it is important to consider that genotype may confound purely nutritional studies due to their effects on serum levels and that SNPs in multiple genes within a metabolic network will give comparably more information about this association compared with SNPs in a single micronutrient-related gene.

Table 1

Table 1

Table 2

Table 2

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Functional genetic variants that influence micronutrient metabolism

The term micronutrients encompasses a wide range of vitamins and trace elements. For the purposes of this review, we will focus on genetic variants that affect folate, selenium, zinc and carotenoid metabolism.

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Hyperhomocysteinemia is now regarded as an independent risk factor in the development of cerebrovascular and coronary heart disease as well as venous thrombosis [4]. Methylenetetrahydrofolate reductase (MTHFR) is a key regulatory enzyme in folate and homocysteine metabolism, and the C677T (Ala222Val) variant has become recognized as the most common genetic factor associated with hyperhomocysteinemia and reduced folate concentrations [3,5•]. However, another common MTHFR variant, A1298C (Glu3Ala), also affects the enzyme activity and interacts with the C677T polymorphism [4]. Although MTHFR is certainly the best characterized candidate gene within the homocysteine-related metabolic pathway, more recent studies have also reported variants in methionine synthase (MTR; A2756G), MTR reductase (MTRR; A66G), cystathionine β-synthase (68 bp insertion at base 844) and transcobalamin (TCN2; C776G) [5•]. Combinations of genotypes can act together to increase the risk of disease, and in relation to blood levels of homocysteine, the presence of the MTRR 66 G allele has been reported to increase the effect of MTHFR 677 TT [5•]. It is reasonable to believe that other gene–gene interactions are involved in the regulation of serum homocysteine concentration; however, further large-scale studies are needed to investigate them [4,5•].

Recently, an association between folate and lipid metabolism has been indicated as both higher homocysteine levels and significantly higher oxidized LDL levels were found in diabetes mellitus patients compared with healthy individuals [6]. Furthermore, the same study indicated that homozygosity for the T allele of the MTHFR gene was more frequent in diabetic patients than in healthy individuals. The C677T variant has also been shown to impact on liver function in obese adolescents, as increased alanine amino transferase (ALT) concentrations and ALT/aspartate aminotransferase ratios were associated with the T allele [7]. As ALT steadily rises in individuals who develop type 2 diabetes [8], these two studies indicate for the first time that MTHFR may influence the pathogenesis of diabetes. A further indication of interactions with the metabolism comes from the observation that folate deficiency increases neuronal oxidative damage and the expression and activity of MTHFR during ApoE deficiency in response to folate deprivation [6]; in contrast, expression and activity of methionine synthase decreased following folate deprivation and ApoE deficiency. Folate deficiency, therefore, induces compensatory regulation of methionine cycle genes during ApoE deficiency in a gene-dosage manner [9].

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Selenium (Se) is incorporated as the amino-acid selenocysteine (SeCys) into approximately 25 selenoproteins including several glutathione peroxidases (GPx), the Se-transport protein in plasma, selenoprotein P (SEPP), and the thioredoxin reductases [10]. As illustrated in Fig. 1, SeCys incorporation occurs during translation by a mechanism that uses UGA, normally a stop codon, as the codon specifying SeCys and a specific RNA stem-loop structure selenocysteine insertion sequence (SECIS) in the 3′ untranslated region (3′UTR) of the mRNAs [11]. Thus, potentially SNPs in selenoprotein gene regions corresponding to 3′UTR sequences could affect expression [12].

Figure 1

Figure 1

It is well known that a SNP within the coding region of the gene encoding the selenoprotein glutathione peroxidase 1 leads to an amino-acid change (Pro to Leu) that leads to lower enzyme activity [13]. Although some disease association studies suggest that the Leu variant increases susceptibility to lung, breast and bladder cancer, possibly when combined with the influence of either a SNP in the gene encoding the antioxidant defense protein manganese superoxide dismutase or environmental factors such as alcohol consumption and smoking [14,15,16•], no direct demonstration of altered function in vivo has been demonstrated.

Recently, three SNPs in regulatory regions of selenoprotein genes have been shown to have functional consequences (see Table 1). In the promoter region of the GPx3 gene, there are eight linked variants in two haplotype groups, and gene reporter studies have suggested differences in promoter activity between the two haplotypes [17]. An SNP within the region of the GPx4 gene corresponding to the 3′UTR at position 718 (rs713041) was found in Caucasians a few years ago [18], but recently evidence has accumulated to indicate that this SNP is functionally significant. Reporter gene studies in transfected cells have shown that the C variant promotes reporter gene activity, presumably reflecting greater SeCys incorporation into the deiodinase reporter, and in-vitro studies show that transcripts corresponding to the T and C variants differ in their ability to form RNA–protein complexes [12,19•]. Furthermore, data from a Se supplementation trial showed that this SNP affected responses of GPx4, GPx1 and GPx3 protein expression or activity in response to Se supplementation or withdrawal [19•]. Two small disease association studies suggest that the T variant is associated with a lower risk of ulcerative colitis [20] and colon cancer [12], and results from a large association study suggest a link between genotype at this SNP and susceptibility to breast cancer [21].

SEPP contains multiple SeCys and is found in plasma in which it contributes the majority of functionally available Se [22]. As it is thought that SEPP plays a central role in Se transport throughout the body, potential variants in the SePP gene could have significant functional consequences. Three variants in the SePP gene appear to be functionally significant. First, a variant in a TC repeat sequence in the promoter region of the SePP gene has been reported to lower promoter activity in reporter gene constructs expressed in hepatoma cells [23]. Second, a G/A variant found in Caucasians in the coding region causes an amino-acid change from Ala to Thr at codon 234 (rs3877899) [24•]. Interestingly, the variant is not found in Chinese, indicating the added complexity of ethnicity in micronutrient–gene interaction studies. In a Se supplementation trial of prospectively genotyped volunteers, baseline plasma SEPP levels were found to be influenced by rs24731 [24•]. Third, a G/A variant is found within the 3′UTR at position 25 191 (rs7579), and this has been reported to affect plasma and lymphocyte glutathione peroxidise activities and plasma concentrations of SePP after supplementation [24•].

Two SNPs have been reported in the region of the Sep15 gene that corresponds to the 3′UTR of the mRNA [25], and reporter gene studies have shown that the combination of these two variants, a C/T substitution at position 811 (rs5845) and a G/A at position 1125 (rs5859), influences read-through at a UGA codon [25]. A G/A SNP at position −105 in the promoter of Selenoprotein S (rs34713741) appears functionally significant. It modulates the response to stressors of the endoplasmic reticulum and has been reported to influence markers of inflammation such as TNF-α and IL-1β [26•,27]. In summary, there is now evidence for several SNPs in selenoprotein genes being functional, but further work is required to define how they affect the overall Se metabolic pathway and its downstream targets (Fig. 1).

Several lines of work indicate links between Se, selenoproteins and lipid metabolism. Eicosapentaenoic and docosahexaenoic acids regulate both GPx1 and GPx4 expression and activity in human endothelial cells [28,29]. Furthermore, several studies have linked GPxs, particularly GPx4, and lipoxygenase activity in metabolism of arachidonic acid. GPx4 has been suggested to inhibit 5′-lipoxygenase activity in lymphocytes and basophils, and, recently, studies of a conditional GPx4 knockout mouse have suggested that GPx4 regulates generation of a 12/15-lipoxygenase-dependent proapoptotic signal in response to oxidative stress [30]. The value of considering such GPx4–lipoxygenase interactions in genetic studies is shown by the finding that individuals homozygous for C or T allele of the SNP in the 3′UTR of GPx4 show different levels of lipoxygenase metabolites in their lymphocytes [18]. Polyunsaturated fatty acid (PUFA) and Se metabolism should be considered together in relationship to identifying SNPs for experimental genotyping and choosing metabolic biomarkers for such studies. In addition, SePP appears linked to apolipoprotein metabolism. The low brain Se content and neurological symptoms found in SEPP knockout mice are similar to the phenotypic changes observed in knockout mice lacking the apolipoprotein receptor ApoER2 [31], and these changes could be overcome in both cases by feeding a diet supplemented with Se.

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The micronutrient zinc (Zn) plays a functional role in proteins and enzymes, but the evidence for functional SNPs in genes encoding Zn-related proteins is still limited. Two SNPs in metallothionein genes MT1A and MT2A appear related to a variety of clinical and immune parameters [32]. In addition, genome-wide association and tagged SNP studies have identified an association of a SNP in the zinc transporter SLC30A8 (rs13266634) with type 2 diabetes in individuals of European and Chinese ancestry [33•,34•]. A SNP in the promoter region of IL-6 gene (−174/G/C) has been found to influence both expression of metallothionein and zinc-regulated genes [35] and is likely to be due to IL-6-induced inflammation that in turn affects metallothionein expression and Zn availability.

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Dietary carotenoids follow the same absorptive pathways as dietary lipids and are transported in the bloodstream exclusively by lipoproteins, with the adipose tissue being their main storage site [36]. A high interindividual variability of carotenoid absorption and plasma status has been found [37,38], which could be caused by impaired intestinal absorption, impaired conversion to vitamin A, inefficient incorporation into chylomicrons or accelerated clearance due to atypical lipoprotein metabolism (Fig. 2). New evidence shows that a facilitated process involving the scavenger receptor-class B type I (SR-BI) is responsible for the uptake of carotenoids from the intestinal lumen [39,40–43]. Inhibition of SR-BI reduces β-carotene absorption by up to 60%, indicating the importance of this transporter [39]. A number of polymorphisms are known to be present in the gene coding for SR-BI, and three SNPs (in exons 1, 8 and intron 5) have been found to significantly alter fasting plasma carotenoid concentrations [44•]. Antibodies raised against SR-BI did not inhibit carotenoid uptake as much as the treatment with proteases, suggesting that other transporters may also be involved in carotenoid uptake [39,43]. SNPs in other genes involved in lipoprotein metabolism (apolipoprotein A-IV, apolipoprotein B and hepatic lipase) and intracellular transport of fatty acids (I-FABP) also modulate plasma concentrations of carotenoids, indicating that chylomicron assembly as well as lipoprotein clearance are important factors in determining carotenoid status [44•,45•]. Together with the recent discovery that the lipoprotein lipase (LPL) S447X polymorphism alters plasma concentrations of carotenoids [46•], there is now convincing evidence to suggest that the high variability of plasma carotenoids seen in human populations is at least partly caused by multiple genetic variations in genes involved in lipoprotein metabolism and lipid transfer.

Figure 2

Figure 2

The enzyme responsible for provitamin A conversion into retinal is β-carotene 15,15′-monoxygenase (BCMO1), and approximately 95% of retinoids arising from β-carotene are produced by this pathway in vivo[47]. Studies using BCMO1 knockout mice have provided evidence for the fundamental role of this enzyme in producing vitamin A from dietary β-carotene [48,49••,50]. Furthermore, altered tissue distribution and isomer patterns of lycopene were observed in the same mouse model after feeding lycopene in combination with low levels of vitamin A [50]. It is estimated that about 55–75% of absorbed β-carotene is cleaved with the rest being secreted as intact β-carotene [51]. However, variations in cleavage efficiency between different individuals vary considerably [52]. Our laboratory recently identified two common nonsynonymous SNPs (R267S; rs12934922 and A379V; rs7501331) in the BCMO1 gene with variant allele frequencies of 42 and 24%, respectively [53••]. Results of the functional analysis of these SNPs revealed that the recombinant 267S + 379V double mutant had a reduced catalytic activity of 57% in vitro, and assessment of the responsiveness to a pharmacological dose of β-carotene in female volunteers confirmed that carriers of both the 379V and 267S+379V variant alleles had a reduced ability to convert β-carotene by 32 and 69%, respectively [53••]. These results may provide an explanation for the molecular basis of the poor converter phenotype within the population.

BCMO1 and cellular retinol-binding protein (CRBP II) gene expression is regulated via long-chain fatty acids and PUFAs through PPAR/RXR heterodimers bound to the nuclear receptor response elements [54,55]. Perhaps, the most surprising interaction between the carotenoid and lipid metabolism comes from the observation that BCMO1−/− mice develop liver steatosis independent of the vitamin A content of the diet, suggesting that this condition is directly related to BCMO1 function and not to vitamin A status [49••]. Additionally, this mouse mutant displayed altered serum lipid levels with elevated serum unesterified fatty acids and was more susceptible to high-fat diet-induced impairments in fatty acid metabolism [49••]. In rodents, administration of retinal reduces body weight and body fat and increases insulin sensitivity, therefore identifying the BCMO1 product retinal as a distinct transcriptional regulator of the metabolic responses to a high-fat diet [56•]. Furthermore, the asymmetric cleavage product of β-carotene, β-apo-14′-carotenal, presents inhibitory properties on preadipocyte differentiation via suppression of PPARα, PPARγ and RXR-activation by their respective ligands [57]. It is, therefore, becoming clear that β-carotene breakdown products directly impact on lipid metabolism.

Several recent studies indicate that carotenoids have increased bioactivity dependent on genetic variation. For example, medium-to-high intakes of lycopene have been associated with reduced prostate cancer risk in men with the Arg/Arg genotype at codon 399 of the X-ray repair cross complementing group 1 (XRCC1) gene [58]; tomato juice intake reduced lipid peroxidation in healthy volunteers carrying the R-allele (Q/R substitution at position 192) of the paraoxonase gene, and increased serum carotenoid concentrations are associated with a reduced risk of lung cancer in volunteers with the Arg194Trp variant of XRCC1[59]. Thus, it is emerging that genetic variations in genes that regulate carotenoid uptake, tissue distribution and cleavage as well as in genes that are responsive to carotenoid status (see Table 2) could help to better understand the health benefits of these bioactive compounds.

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Summary and future perspectives

When considering micronutrient-related genes, the first challenge is to identify SNPs that alone, or in conjunction with other SNPs or nutritional factors, bring about functional changes in metabolism. Knowledge of genetic variants that affect micronutrient metabolism and responses to micronutrient supplementation was until recently largely limited to MTHFR. However, identification of novel functional SNPs in BCMO1[53••], the critical enzyme of β-carotene metabolism, and in several key selenoproteins [17,19•] indicates the potential importance of micronutrient–gene interactions in worldwide populations.

Nutrition is by nature an integrative discipline, and attention is now being directed at how nutrients affect not single enzymes but how they influence networks of biochemical pathways – ‘nutritional systems biology’. As illustrated schematically in Fig. 3, this integrative view emphasizes that in order to understand how genetics and micronutrient status could affect metabolism synergistically, functional knowledge of SNPs not in a single micronutrient-related gene, but at least in a physiological pathway and preferably in a wider physiological network including downstream targets is required [5•,60]. Despite the recent advances highlighted in this review, further research is needed to identify SNPs in other genes and to assess SNP functionality in terms of the whole functional pathway together with haplotype effects. The importance of such a pathway approach to nutrient–gene interaction studies is illustrated by reports that cancer risk is affected by the combination of two SNPs in different genes that both encode antioxidant enzymes, one in GPx1 and a second in manganese superoxide [14]. Recent studies with micronutrient-related SNPs also indicate that effects of genetic variants on response to micronutrients can be modulated by sex [19•,24•,53••], emphasizing the importance of considering such factors as age, ethnicity, sex and BMI when examining interactions of genes and micronutrients.

Figure 3

Figure 3

The well defined pathways of micronutrient function, the importance of micronutrient intake in relation to disease susceptibility and the increasing number of micronutrient-related SNPs together emphasize the need to have a fuller understanding of micronutrient –gene interactions. Building on the recent expansion in known functional SNPs that affect micronutrient metabolism and function, this need is being recognized by the new International Micronutrient Genetic Project (

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The work in the authors' laboratories has been supported by Food Standards Agency, BBSRC and NuGO, a EU-funded Network of Excellence.

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References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest

•• of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 142).

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carotenoids; folate; lipoprotein; selenium; single-nucleotide polymorphism; zinc

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