Review
Gene–lifestyle interaction on risk of type 2 diabetes

https://doi.org/10.1016/j.numecd.2006.04.001Get rights and content

Abstract

The descriptive epidemiology of type 2 diabetes suggests that gene–lifestyle interactions are critical to the development of the condition. However, unravelling the molecular detail of these interactions is a complex task. The existing literature is based on small intervention studies or cross-sectional observational quantitative trait studies. Our systematic review of the literature identified some evidence of interactions, most notably for a common variant in the PPAR-gamma gene which appears to interact with the nature of dietary fat intake. Other interactions have been reported for adrenoceptors, uncoupling proteins, fatty acid binding proteins, apolipoproteins and lipoprotein lipase. There are, to date, no reports based on the ideal study design which is a case-control study nested within a cohort. To limit the likelihood of false discovery, such studies would need to be large and the search for interaction should be restricted to a priori biologically driven hypotheses. Additional study designs that examine differential response to lifestyle change or test interaction in the context of quantitative trait studies would complement the nested case-control approach, but the emphasis here should be on precision of measurement of both phenotype and lifestyle behaviour.

Introduction

The descriptive epidemiology of type 2 diabetes and its pattern of inheritance provide strong evidence that the disorder originates from an interaction between genetic and lifestyle risk factors [1]. It is not the intention of this article to review this evidence since it has been described previously in multiple papers. A much more challenging and complex task is to unravel the basis for these interactions and to identify which genes and which genetic variants are responsible for the interaction with lifestyle behaviour. Thus in this paper, we have set out to describe the current literature on specific gene–lifestyle interactions on the risk of type 2 diabetes. Our approach has been epidemiological and we have focused on observational and experimental studies in populations. We have put less emphasis on animal or molecular studies, but these obviously provide the justification for examining specific interactions or assist in the interpretation of the results, most particularly with respect to implications for causal inference, an issue to which we return in the discussion.

Section snippets

Epidemiological study designs for investigating gene–lifestyle interaction on type 2 diabetes risk

There is an accepted range of different study designs that can be used to assess gene–lifestyle interactions in population-based studies [1]. Some would argue that the strongest evidence comes from the examination of differential response to lifestyle intervention change in the context of a randomised controlled trial where individuals have been selected on the basis of a risk genotype. As this review will demonstrate, there are no studies of this type currently but this is an approach that

Systematic review

Our systematic review identified more than 100 epidemiological studies. Describing all of these studies is beyond the scope of this review. Therefore, we have restricted our discussion to the classes of genes that have been reported on at least three occasions. We conducted our literature review using the National Library of Medicine's medical publications database (PubMed), grey matter (e.g., PhD thesis bibliographies) and via ancestral searching of published and unpublished bibliographies. In

Peroxisome-proliferated activator receptor gamma (PPAR-gamma)

PPAR-gamma mRNA is expressed primarily in white adipocytes, placenta and macrophages. As is the case with other nuclear receptors, PPAR-gamma is constructed from a number of distinct functional domains. The transcription of PPAR-gamma is regulated largely through the availability and binding potential of specific ligands. The synthetic ligands of PPAR-gamma are the thiazolidinediones (TZDs), which are a powerful class of insulin sensitising drugs. The endogenous ligands are the prostaglandins,

β-Adrenergic receptors (ADRB)

β-Adrenergic receptors (ADRB) are expressed in white adipose tissue and bind the endogenous catecholamines epinephrine and norepinephrine. ADRBs signal to the interior of cells via the stimulatory guanine nucleotide-binding protein 309. Activation of all three ADRB isoforms (b1-, b2-, b3-) stimulates lipolysis, while inhibition of the ADRB2 reduces lipolysis. The ADRB2 gene contains a short open reading frame located 102 base pairs upstream of the receptor coding block in the 5′ leader cistron

Uncoupling proteins (UCP)

Uncoupling proteins (UCPs) comprise a complex of three homologous isoforms (UCP 1, 2, 3) that inhibit the synthesis of ATP following oxidative phosphorylation by dissipating energy as heat and by reducing the mitochondrial membrane potential. UCP1 is solely expressed in brown adipose tissue, which is of low abundance in humans, whereas UCP2 and UCP3 are expressed predominantly in skeletal muscle. Because of their role in thermogenesis, the UCP class of genes have been proposed as plausible

Lipid metabolism genes

Polymorphisms in numerous lipid metabolism genes have been related with variation in lipid and insulin levels. Because these genes do not fall into a specific class, the following section describes the epidemiological studies that pertain to gene–lifestyle interactions on lipid-related phenotypes (Table 4).

Hepatic lipase gene

The hepatic lipase gene (LIPC) encodes a liver-specific enzyme that controls lipoprotein metabolism in the liver. LIPC hydrolyses triglycerides and acts as a ligand facilitator for receptor-mediated uptake of lipoproteins. Because intra-hepatic lipids are associated with insulin resistance in humans [30], LIPC has been proposed as a candidate gene for type 2 diabetes and associated traits.

Several cross-sectional interaction studies have been reported for variants in LIPC (Table 4). In a study

Fatty acid binding protein 2

The fatty acid-binding protein 2 (FABP2) gene encodes the intestinal FABP protein, which is involved in fat absorption and transportation. A common amino-acid substitution (Ala54→Thr54) at codon 54 has been reported in several populations, with the frequency of the Thr54 allelic ranging between 20–40%. This is the only genotype at the FABP2 locus to have been repeatedly studied in the context of gene-nutrient interaction [37]. Functional studies have shown that the in vitro binding affinity of

Apolipoproteins

Apolipoprotein ApoC-III a very low density lipoprotein (VLDL) protein synthesized in liver and intestine, and consists of 79 amino acids. ApoCIII inhibits lipoprotein lipase and hepatic clearance of triglyceride-rich lipoproteins in vitro. Thus, elevations in ApoCIII result in increased triglyceride levels. Several common polymorphisms have been identified in the APOC3 gene promoter region, which are in high LD with variants in other APOC isoforms and which functionally affect intestinal

Lipoprotein lipase

Lipoprotein lipase (LPL) plays a role in the hydrolysis of triglyceride-rich lipoproteins, and is sensitive to changes in energy flux. Data in twins [55] indicate that the changes in adipose tissue LPL activity in response to acute exercise is more similar in monozygotic than in dizygotic twins, suggesting that the response is under the control of genetic factors. A number of polymorphisms have been described in the human LPL gene. Of these, the S447X (Ser447Ter) variant, located in exon 9 of

Discussion

This review has demonstrated that despite reasonably strong evidence that interactions between genetic and lifestyle factors underlie the distribution of type 2 diabetes in populations, the evidence base concerning the details of these interactions is extremely small. Our tables of published studies mostly include cross-sectional observational quantitative trait studies or various intervention study designs mostly involving small numbers of participants. The only intervention study to have

References (77)

  • L.J. Baier et al.

    A polymorphism in the human intestinal fatty acid binding protein alters fatty acid transport across Caco-2 cells

    J Biol Chem

    (1996)
  • R.E. Pratley et al.

    Effects of an Ala54Thr polymorphism in the intestinal fatty acid-binding protein on responses to dietary fat in humans

    J Lipid Res

    (2000)
  • P.D. Dworatzek et al.

    Postprandial lipemia in subjects with the threonine 54 variant of the fatty acid-binding protein 2 gene is dependent on the type of fat ingested

    Am J Clin Nutr

    (2004)
  • C. Marin et al.

    The Ala54Thr polymorphism of the fatty acid-binding protein 2 gene is associated with a change in insulin sensitivity after a change in the type of dietary fat

    Am J Clin Nutr

    (2005)
  • D.M. Waterworth et al.

    Variants in the APOC3 promoter insulin responsive element modulate insulin secretion and lipids in middle-aged men

    Biochim Biophys Acta

    (2003)
  • S. Brown et al.

    Interaction between the APOC3 gene promoter polymorphisms, saturated fat intake and plasma lipoproteins

    Atherosclerosis

    (2003)
  • J. Salas et al.

    The SstI polymorphism of the apolipoprotein C-III gene determines the insulin response to an oral-glucose-tolerance test after consumption of a diet rich in saturated fats

    Am J Clin Nutr

    (1998)
  • M.J. Artiga et al.

    Allelic polymorphisms in the transcriptional regulatory region of apolipoprotein E gene

    FEBS Lett

    (1998)
  • D. Corella et al.

    Environmental factors modulate the effect of the APOE genetic polymorphism on plasma lipid concentrations: ecogenetic studies in a Mediterranean Spanish population

    Metabolism

    (2001)
  • J.M. Hagberg et al.

    Apolipoprotein E genotype and exercise training-induced increases in plasma high-density lipoprotein (HDL)- and HDL2-cholesterol levels in overweight men

    Metabolism

    (1999)
  • C. Garenc et al.

    Linkage and association studies of the lipoprotein lipase gene with postheparin plasma lipase activities, body fat, and plasma lipid and lipoprotein concentrations: the HERITAGE Family Study

    Metabolism

    (2000)
  • R.M. Fisher et al.

    Common variation in the lipoprotein lipase gene: effects on plasma lipids and risk of atherosclerosis

    Atherosclerosis

    (1997)
  • V. Lindi et al.

    Impact of the Pro12Ala polymorphism of the PPAR-[gamma]2 gene on serum triacylglycerol response to n-3 fatty acid supplementation

    Mol Genet Metab

    (2003)
  • E.S. Tai et al.

    Polyunsaturated Fatty Acids Interact with the PPARA-L162V Polymorphism to Affect Plasma Triglyceride and Apolipoprotein C-III Concentrations in the Framingham Heart Study

    J. Nutr

    (2005)
  • A.-M. Paradis et al.

    The peroxisome proliferator-activated receptor {alpha} Leu162Val polymorphism influences the metabolic response to a dietary intervention altering fatty acid proportions in healthy men

    Am J Clin Nutr

    (2005)
  • G. Bos et al.

    Interactions of dietary fat intake and the hepatic lipase -480C→T polymorphism in determining hepatic lipase activity: the Hoorn Study

    Am J Clin Nutr

    (2005)
  • J.J. Agren et al.

    Postprandial responses of individual fatty acids in subjects homozygous for the threonine- or alanine-encoding allele in codon 54 of the intestinal fatty acid binding protein 2 gene

    Am J Clin Nutr

    (2001)
  • J.A. Moreno et al.

    The effect of dietary fat on LDL size is influenced by apolipoprotein E genotype in healthy subjects

    J. Nutr

    (2004)
  • J.A. Moreno et al.

    Apolipoprotein E gene promoter -219G→T polymorphism increases LDL-cholesterol concentrations and susceptibility to oxidation in response to a diet rich in saturated fat

    Am J Clin Nutr

    (2004)
  • J.A. Moreno et al.

    The apolipoprotein E gene promoter (-219G/T) polymorphism determines insulin sensitivity in response to dietary fat in healthy young adults

    J. Nutr

    (2005)
  • O. Poirier et al.

    The Pro12Ala polymorphism in the peroxisome proliferator-activated receptor gamma2 gene is not associated with postprandial responses to glucose or fat tolerance tests in young healthy subjects: the European Atherosclerosis Research Study II

    J Mol Med

    (2000)
  • D. Altshuler et al.

    The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes

    Nat Genet

    (2000)
  • A. Meirhaeghe et al.

    Association between peroxisome proliferator-activated receptor gamma haplotypes and the metabolic syndrome in French men and women

    Diabetes

    (2005)
  • J. Luan et al.

    Evidence for gene-nutrient interaction at the PPARgamma locus

    Diabetes

    (2001)
  • A. Memisoglu et al.

    Interaction between a peroxisome proliferator-activated receptor gamma gene polymorphism and dietary fat intake in relation to body mass

    Hum Mol Genet

    (2003)
  • J. Robitaille et al.

    The PPAR-gamma P12A polymorphism modulates the relationship between dietary fat intake and components of the metabolic syndrome: results from the Quebec Family Study

    Clin Genet

    (2003)
  • K.B. Adamo et al.

    Influence of Pro12Ala peroxisome proliferator-activated receptor gamma2 polymorphism on glucose response to exercise training in type 2 diabetes

    Diabetologia

    (2005)
  • V.I. Lindi et al.

    Association of the Pro12Ala polymorphism in the PPAR-gamma2 gene with 3-year incidence of type 2 diabetes and body weight change in the Finnish Diabetes Prevention Study

    Diabetes

    (2002)

    • Cited by (42)

    • Precision nutrition for prevention and management of type 2 diabetes

      2018, The Lancet Diabetes and Endocrinology
      Citation Excerpt :

      Earlier studies of gene–diet interactions for type 2 diabetes focused on candidate genetic variants.57 This approach did not generate robust evidence,58 as shown by Li and colleagues,59 who were unable to replicate eight published statistically significant interactions between single-gene variants and macronutrient intake in relation to type 2 diabetes in a large cohort from the EPIC-InterAct study. Since 2008, investigators have been using polygenic scores, which are combinations of multiple susceptibility loci identified by GWAS.

    • Interaction between genes and macronutrient intake on the risk of developing type 2 diabetes: Systematic review and findings from European Prospective Investigation into Cancer (EPIC)-InterAct

      2017, American Journal of Clinical Nutrition

    • DNA methylation in peripheral blood leukocytes for the association with glucose metabolism and invasive breast cancer

      2023, Clinical Epigenetics

    • The Glycemic Curve during the Oral Glucose Tolerance Test: Is It Only Indicative of Glycoregulation?

      2023, Biomedicines

    • Effect of TCF7L2 on the relationship between lifestyle factors and glycemic parameters: a systematic review

      2022, Nutrition Journal

    • Synergistic Effects of Genetic Variants of Glucose Homeostasis and Lifelong Exposures to Cigarette Smoking, Female Hormones, and Dietary Fat Intake on Primary Colorectal Cancer Development in African and Hispanic/Latino American Women

      2021, Frontiers in Oncology
    View all citing articles on Scopus
    View full text
    Copyright © 2006 Elsevier B.V. All rights reserved.