Association of Genetic polymorphism of PPARγ-2, ACE, MTHFR, FABP-2 and FTO genes in risk prediction of type 2 diabetes mellitus
Journal of Biomedical Science volume 20, Article number: 80 (2013)
Type 2 diabetes mellitus (T2DM) is a non-autoimmune, complex, heterogeneous and polygenic metabolic disease condition characterized by persistent elevated blood glucose levels (hyperglycemia). India as said to be the diabetic capital of the world is likely to experience the largest increase in T2DM and a greater number of diabetic individuals in the world by the year 2030. Identification of specific genetic variations in a particular ethnic group has a critical role in understanding the risk of developing T2DM in a much efficient way in future. These genetic variations include numerous types of polymorphisms among which single nucleotide polymorphisms (SNPs) is the most frequent. SNPs are basically located within the regulatory elements of several gene sequences. There are scores of genes interacting with various environmental factors affecting various pathways and sometimes even the whole signalling network that cause diseases like T2DM. This review discusses the biomarkers for early risk prediction of T2DM. Such predictions could be used in order to understand the pathogenesis of T2DM and to better diagnostics, treatment, and eventually prevention.
Overview of type 2 diabetes mellitus
T2DM is a chronic metabolic disorder with a rapidly increasing prevalence highlighting the importance of continued research and the need for novel methods to both prevent and treat this pandemic disease. In case of India, the disease burden is estimated to be 87 million around 2030 . The negative impacts of T2DM are considerable: as a lifelong disease, which increases morbidity and mortality, ultimately decreasing the quality of life . If diabetes is not efficiently controlled, then the patient has a significantly higher risk of developing complications such as, hypoglycemia, ketoacidosis, and non-ketotic hyperosmolar coma. Apart from these, long-standing complications could be cardiovascular disease, chronic kidney failure, retinal damage, nerve damage, poor healing of wounds, gangrene on the feet leading to amputation, and erectile dysfunction etc. The recent global epidemic of T2DM almost certainly indicates the importance of environmental triggers such as sedentary lifestyle and dietary changes over last several decades. Nevertheless T2DM is amongst those complex diseases for which genetic contribution is well accepted. Identification of genetic components of T2DM is the most important area of diabetes research because elucidation of the diabetes genes (alleles) will influence all efforts toward a mechanistic understanding of the disease, its complications, cure, treatment and prevention . Basically, many genes perform key regulatory functions in the development of T2DM, which is a polygenic disorder with multiple genes located on different chromosomes contributing to its susceptibility. The analysis of genetic factors associated with T2DM is further complicated by the fact that a variety of environmental factors interact with these genes to produce the disorder. Thus, identification and characterization of the gene variants among a particular ethnic group that play a significant role in T2DM, is one of the most important areas of diabetes research because it will influence all efforts toward a mechanistic understanding of the disease complications, treatment, cure and prevention.
Candidate genes for type 2 diabetes mellitus
Numerous reports have been published on the genetics of T2DM with most recent ones showcasing the effect of SNP’s in various genes corresponding to risk prediction of T2DM such as, gene variants of Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ) [4–6], Angiotensin Converting Enzyme (ACE) [7–9], Methylene Tetrahydrofolate Reductase (MTHFR) [10–14], Fatty Acid Binding Protein-2 (FABP2) [15–19] and Fat Mass and Obesity associated gene (FTO) [20, 21]. In this review, we will focus on candidate genes (PPAR-γ, ACE, MTHFR, FABP2 and FTO) in which the genetic variants have been well established to be functional and shown in more than one study for their association with T2DM, in various ethnic groups. Findings from Previously Conducted Meta-Analyses of different Gene Variant in T2DM are shown in Table 1.
Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ) gene
PPARs (isoforms α, δ, and γ) are ligand-activated transcription factors that heterodimerise with retinoid X receptor (RXR). It has been shown that agonists of PPAR possess antidiabetogenic, anti-inflammatory, and antioxidant effects. PPAR-γ gene, encoding the nuclear receptor PPAR-γ, was the first gene reproducibly associated with T2DM . PPAR-γ gene is located on chromosome 3p25 encodes a nuclear transcription factor involved in the expression of hundreds of genes. PPAR-γ gene contains 9 exons, spans more than 100 kilobases, because of alternative mRNA splicing results in the production of 2 protein isoforms: PPARγ-1 and PPARγ-2 . PPARs constitute a distinct sub-family of the nuclear receptors that are activated by naturally occurring fatty acids . The association between the substitution of alanine for proline at codon 12 of PPAR- γ and the risk for T2DM has been widely studied since Yen CJ, first reported this polymorphism . Within a unique domain of PPARγ-2 gene that enhances ligand independent activation, a common Pro12Ala polymorphism has been identified . This polymorphism has been reported to be associated with obesity. Using a family based design to control for population stratification, it was reported that Ala allele of this polymorphism was associated with a decreased risk of T2DM . A meta-analysis conducted by Ludovico found that the alanine polymorphism conferred significantly greater protection against T2DM among Asians than Caucasians , contradictory result have been reported within the same study elsewhere where Ala12 variant was associated with a reduced risk for the development of diabetes [5, 26, 42]. Soon, it became apparent that most negative studies had been underpowered and after combining the data from all published studies in a meta-analysis it became evident that Pro12Ala variant was associated with T2DM [5, 28, 43]. PPAR-γ plays a critical role in glucose homeostasis and serves as the molecular target for a class of insulin-sensitizing drugs called thiazolidinediones (TZDs). TZDs is PPARγ2 ligands and widely used for treatment of T2DM , they had very minimal activity toward PPAR-α or PPAR-β. Although PPAR- γ levels are 10–30 times higher in fat than in muscle or liver, this receptor is expressed in these latter tissues. Effects on insulin action in other tissues would then occur as a consequence of alterations in signalling molecules produced by fat, such as free fatty acids, TNF-α , leptin, or others (Perspectives in Diabetes PPAR- γ: Adipogenic Regulator and TZDs Receptor) . PPAR- γ activation controls one or more genes that regulate systemic insulin sensitivity like TNF-α and leptin.
Angiotensin Converting Enzyme (ACE) gene
Genetic studies have revealed that the genes of renin angiotensin are highly polymorphic, raising the possibility in addition to environmental factors. The genetic make-up of Renin Angiotensin System (RAS) affects the status of RAS in the individuals. The emerging picture of ACE function is that it is more than just a key enzyme that catalyses cleavage of angiotensin I to the potent vasoconstrictor peptide angiotensin II . ACE also hydrolyzes the inactive angiotensin (1–9) peptide into the vasodilator metabolite angiotensin (1–7) , and it is additionally thought to inactivate the vasodilator peptides bradykinin and kallidin . Among the various SNP’s associated with RAS, one of the examples is insertion (I)/deletion (D) polymorphism of ACE gene, which consists of 26 exons and span 21 kb on chromosome 17. The polymorphism exists within intron 16, consisting the presence or absence of 287 bp fragment . The II (Insertion-Insertion) genotype is reported to be protective against development and progression of diabetic and non-diabetic nephropathy to chronic kidney disease . Clinically, serum ACE level is useful for the evaluation of disease activity and follow-up in T2DM [31, 49–52]. All previous studies in non-diabetic and diabetic nephropathies have demonstrated that the deletion polymorphism of ACE gene, particularly the homozygote DD, is a risk factor for an accelerated loss of kidney function . Studies of ACE gene with T2DM have shown contradictory results, where some have shown association of ACE gene with T2DM [7, 9, 31–34] while others have shown no such association [8, 35]. Indian studies, reported a strong association of ACE gene polymorphisms with T2DM in Northern India . Vishwanathan and Bhavani established positive association of ACE polymorphism with T2DM in south India [54, 55]; while Prasad and Ajay Kumar reported no any relation between ACE gene and T2DM among North Indian population [56, 57].
Methylene Tetrahydrofolate reductase (MTHFR) gene
Methylenetetrahydrofolate reductase (MTHFR) has a major impact on regulating the folic acid pathway; it catalyzes the irreversible conversion of 5, 10‒methylenetretrahydrofolate, which is the methyl donor (for the conversion of dUMP to dTMP), into 5‒methyltetrahydrofolate. Genetic and environmental (e.g., dietary) factors play a key role in affecting the homocysteine levels . One of the most common genetic defects of homocysteine metabolism is a mutation in MTHFR gene. The gene encoding MTHFR is located at 1p36.3 . Studies have shown an association between homocysteine levels and diabetic complications such as macroangiopathy, retinopathy and nephropathy in T1DM, whereas no such association was seen among T2DM subjects . Numerous polymorphisms in MTHFR gene have been reported. Frosst et al. described a C677T substitution at of MTHFR gene that converts an alanine to a valine residue . In a few studies, no association was found between hyperhomocysteinemia, MTHFR gene C677T polymorphism, metabolic 6 syndromes and T2DM . Nevertheless, in another study a significant correlation between these polymorphisms and individuals with normal weight and increased risks of developing metabolic syndrome (normal weight obese syndrome) was observed . A high concentration of homocysteine was seen in patients with diabetes mellitus . The mutant homozygous genotype for MTHFR C677T showed high risk of diabetic retinopathy among the individuals with T2DM . Likewise, Ksaizek and co-workers have also found that MTHFR C677T mutation in MTHFR gene predisposes T2DM patients to the development of diabetic retinopathy . These common polymorphisms are also associated with hyper homocysteinemia that has been reported to be an increased risk factor for neural tube defects, diabetes and cardiovascular diseases.
Fatty acid binding protein 2 (FABP2) gene
FABP2 plays a key role in the absorption and intracellular transport of dietary long chain fatty acids. Since, glucose and fatty acid metabolism are inter-related phenomenons, FABP2 soon became an important candidate gene for T2DM. In the search for T2DM loci in Pima Indians, Prochazka and co-workers found linkage between insulin resistance and a region on chromosome 4q near the FABP2 locus . This finding is supported by a positive linkage between post challenge insulin levels and FABP2 in Mexican–Americans . Molecular scanning of FABP2 identified a missense mutation (Ala54Thr) responsible for insulin resistance . Carriers of the Thr54 allele in FABP2 have a twofold greater affinity for the absorption for the long-chain fatty acids than those with the Ala54-containing FABP2 . Genotypic/Phenotypic studies involving FABP2 have focussed on the Ala–›Thr (G–›A) substitution in exon-2 which is responsible for increased binding affinity, transport of long chain fatty acids and more efficient secretion of triglycerides in cells expressing Thr-encoding allele [69, 71]. In a study of Canadian Oji-Cree Indians, the Thr encoding allele was associated with increased BMI, percent body fat, and plasma triglycerides . FABP2 Ala54Thr variant has been associated with an increased fasting insulin concentration, increased rate of lipid oxidation, reduced insulin-stimulated glucose uptake and increased concentrations of fasting and postprandial triglyceride-rich lipoprotein [19, 70, 71, 73–75]. It has been suggested that the Ala54Thr polymorphism might associate with the risk for atherosclerosis because it causes a compositional change in LDL particles , an altered postprandial lipemia . Previous studies have found contradictory associations between FABP2 genotypes and the occurrence of T2DM, obesity or decreased insulin sensitivity [17, 70, 71, 77–79]. Contradictory to it, several studies have reported the association between the Ala54Thr polymorphism of FABP2 with insulin resistance and T2DM [17, 19, 69, 80–82]. In contrast, studies in other Japanese [83, 84], Caucasians [85, 86], and African-American  cohorts have not found an association of T2DM, insulin levels, or obesity with the Thr54 variant.
Fat Mass and Obesity associated gene (FTO)
Fat mass and obesity associated (FTO) gene was found in a genome-wide association (GWA) study for T2DM and showed to predispose individuals to diabetes through an effect on Body mass Index (BMI). The FTO gene, which is located on chromosome 16q12.2 consists nine exons and emerged 450 million years ago . FTO is primarily expressed in the hypothalamus and encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Sequence analysis suggested that FTO has homology with the AlkB family of DNA repair enzymes. Subsequent in vitro biochemical studies revealed FTO to be a member of the Fe (II) and 2-oxoglutarate (2OG) dependent oxygenase superfamily . In metazoans these enzymes are involved in diverse processes including oxygen sensing, DNA repair, fatty acid metabolism and post-translational modifications . A number of SNPs in tight linkage disequilibrium with rs9939609, and residing in the first intron of the FTO gene, had been associated with obesity in large populations of adults and children. Recently, part of a genome-wide association study found that SNPs of the FTO were strongly associated with obesity and T2DM [91, 92]. FTO gene encodes for a protein 2-oxoglutarate dependent nucleic acid demethylase involved in fatty acid metabolism, DNA repair and post- translational modifications . It may also play important roles in the management of energy homeostasis [88, 94], nucleic acid demethylation, and regulation of body fat masses by lipolysis . The hypothalamic expression of FTO suggests a potential role in the control of food intake and whole body metabolism wherein physical activity and food intake is unchanged but metabolic rate is increased. The association of FTO variants with T2DM and BMI has been independently identified in a number of white European populations  but the findings are somewhat inconsistent in Asians, which may be the result of varying study designs, inadequate sample sizes or ethnic differences [97–99]. A recent study in north Indian Sikhs demonstrated a strong association of FTO variants with type 2 diabetes, which did not seem to be mediated through BMI . This raises empirical probability that the association of FTO variants with BMI and T2DM might be different in Asian populations. FTO gene confers risk for T2DM in Europeans, with each A allele increasing BMI by approximately 0.4 kg/m2 . However, results have been variable for replication in other ethnic populations such as Hispanics , Asians, Oceanics  and Blacks .
Multiple genes are involved in pathogenesis of T2DM, each contributing a small amount to the overall risk making T2DM, a truly complex disorder. Our understanding of genetics of diseases gives a better prospective of biochemical and molecular mechanism of disease on the whole. The data could help to identify at-risk patients in early stages and may provide opportunities for early prevention. Our better understanding of such phenomena will throw new light on how common variants can alter disease susceptibility and it is necessary to understand the physiologic importance of the genetic associations those are uncovered. The utility of genetic approaches will depend on a holistic understanding of the interactions among the genes and also between genes and the environment. Combining these genetic variations with new developments in the fields of bioinformatics, genomics, and proteomics will lead to a greater understanding of the pathogenesis of T2DM and may present new information on diagnostics, treatment and eventual prevention of the disease. Additionally, inclusion of genetic studies in design and analysis of drug trials could lead to development of genetic biomarkers that predict treatment response. Prediction can be made on the basis of biomarkers in connection to the course of disease; treatment-response and possibilities of side-effects will be vastly appreciated. As a result of wide range of investigations over the last few years, a few biomarkers have been introduced into clinical practices. This requires a personalized medicine approach. This genetic information may also form the basis for development of new drug therapies such as individually specific or targeted pharmacotherapy. Thus, an understanding of common variants and of the genetic/non-genetic factors with which they interact can improve public health by focussing on genetic individuality in the diagnosis and treatment of disease.
Type 2 diabetes mellitus
Angiotensin converting enzyme
Peroxisome proliferator-activated receptor gamma
Methylene tetrahydrofolate reductase
Fat mass and obesity associated gene, type 2 diabetes mellitus
Fatty acid-binding proteins
Single nucleotide polymorphisms
Genome wide association
Body mass index.
Snehalatha , Ramachnadaran : Conference in Centre for Cellular and Molecular Biology. Insight into the Mechanism of Primary Prevention of Type 2 Diabetes: Improvement in Insulin Sensitivity and Beta cell function. “Genetic and Epigenetic Basis of Complex Diseases. 2009
Hoskote SS, Joshi SR: Are Indians destined to be diabetic. J Assoc Physicians India. 2008, 56: 225-226.
Das SK: Genetic epidemiology of adult onset type 2 diabetes in asian indian population: past, present and future. Int J Hum Genet. 2006, 6 (1): 1-13.
Barroso I, Gurnell M, Crowley VE, Agostini M, Schwabe JW, Soos MA, Maslen GL, Williams TD, Lewis H, Schafer AJ, Chatterjee VK, O'Rahilly S: Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature. 1999, 402 (6764): 880-3.
Altshuler D, Hirchhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J, Lane CR, Schaffner SF, Bolk S, Brewer C, Tuomi T, Gaudet D, Hudson TJ, Daly M, Groop L, Lander ES: The common PPAR Pro12Ala polymorphism in associated with decreased risk of type 2 diabetes. Nat Genet. 2000, 26: 76-80.
Agostini M, Schoenmakers E, Mitchell C, Szatmari I, Savage D, Smith A, Rajanayagam O, Semple R, Luan , Bath L, Zalin A, Labib M, Kumar S, Simpson H, Blom D, Marais D, Schwabe J, Barroso I, Trembath R, Wareham N, Nagy , Gurnell M, O'Rahilly S, Chatterjee Z: Non-DNA binding, dominant-negative, human PPARγ mutations cause lipodystrophic insulin resistance. Cell Metab. 2006, 6: 303-311.
Stephens JW, Dhamrait SS, Cooper JA, Acharya J, Miller GJ, Hurel SJ, Humphries SE: The D allele of the ACE I/D common gene variant is associated with type 2 diabetes mellitus in Caucasian subjects. Mol Genet Metab. 2005, 84 (1): 83-89.
Jayapalan JJ, Muniandy S, Chan SP: Null association between ACE gene I/D polymorphism and diabetic nephropathy among multiethnic Malaysian subjects. Indian J Hum Genet. 2010, 16 (2): 78-86.
Nikzamir A, Nakhjavani M, Golmohammadi T, Dibai L, Saffary R: Polymorphism in the angiotensin converting enzyme (ACE) gene and ACE activity in type 2 diabetic patients. Acta Med Iran. 2008, 46 (4): 277-282.
Yilmaz H, Agachan B, Ergen A, Karaalib ZE, Isbir T: Methylene tetrahydrofolate reductase C677T mutation and left ventricular hypertrophy in Turkish patients with type II diabetes mellitus. J Biochem Mol Biol. 2004, 37 (2): 234-8.
Mtiraoui N, Ezzidi I, Chaieb M: MTHFR C677T and A1298C gene polymorphism and hyperholnocysteinemia as risk factor of diabetic nephropathy in type 2 diabetes patients. Diabetes Res Clin Pract. 2006, 75: 99-106.
Errera FIV, Silva MER, Yeh E: Effect of polymorphism of the MTHFR and APOE gene on susceptibility to diabetes and severity of diabetic retinopathy in Brazilian population. Braz J Med Biol Res. 2006, 39: 883-888. 11
Jia-Zhong S, Yancheng X, Hongyun L: Polymorphism of the methylenetetrahydrofolate reductase gene association with homocysteine and ischemic stroke in Type 2 diabetes neurology. India. 2009, 57 (5): 589-593.
Barraz JT, Shojapoor M, Najem H: Methylenetetrahydrofolate reductase gene polymorphism in diabetes and obesity. Mol Biol Rep. 2009, 37: 105-109.
Vimaleswaran KS, Radha V, Mohan V: Thr54 allele carriers of The Ala54Thr variant of FABP2 gene have associations with metabolic syndrome and hypertriglyceridemia in urban South Indians. Metabolis. 2006, 55: 1222-1226.
Kim CH, Yun SK, Byun DW, Yoo MH, Lee KU, Suh KI: Codon 54 polymorphism of the fatty acid binding protein 2 gene is associated with increased fat oxidation and hyperinsulinemia but not with intestinal fatty acid absorption in Korean Men. Metabolism. 2001, 50: 473-476.
Carlsson M, Orho-Melander M, Hedenbro J, Almgren P, Groop LC: The T54 allele of the intestinal fatty acid-binding protein 2 is associated with a parental history of stroke. J Clin Endocrinol Metab. 2000, 85: 2801-2804.
Georgopoulos A, Aras O, Tsai MY: Codon-54 polymorphism of the fatty acid-binding protein 2 gene is associated with elevation of fasting and postprandial triglyceride in T2D. J Clin Endocrinol Metab. 2000, 85: 3155-3160.
Yamada K, Yuan X, Ishiyama S, Koyama K, Ichikawa F, Koyanagi A: Association between Ala54Thr substitution of the fatty acid binding protein 2 gene with insulin resistance and intra-abdominal fat thickness in Japanese men. Diabetologia. 1997, 40: 706-710.
Sanghera DK, Ortega L, Han S, Singh J, Ralhan SK, Wander GS, Mehra NK, Mulvihill JJ, Ferrell RE, Nath SK, Kamboh MI: Impact of nine common type 2 diabetes risk polymorphisms in Asian Indian Sikhs: PPARG2 (Pro12Ala), IGF2BP2, TCF7L2 and FTO variants confer a significant risk. BMC Med Genet. 2008, 9: 59-67.
Yajnik CS, Janipalli CS, Bhaskar S, Kulkarni SR, Freathy RM, Prakash S, Mani KR, Weedon MN, Kale SD, Deshpande J, Krishnaveni GV, Veena SR, Fall CHD, McCarthy MI, Frayling TM, Hattersley AT, Chandak GR: FTO gene variants are strongly associated with T2Din South Asian Indians. Diabetologia. 2009, 52: 247-252.
Fajas L, Auboeuf D, Raspe E, Schoonjans K, Lefebvre AM, Saladin R: The organization, promoter analysis, and expression of the human PPARc gene. J Biol Chem. 1997, 272 (30): 18779-18789.
Ludovico O, Pellegrini F, Di Paola R, Minenna A, Mastroianno S, Cardellini M, Marini MA, Andreozzi F, Vaccaro O, Sesti G, Trischitta V: Heterogeneous effect of peroxisome proliferator-activated receptor c2 Ala12 variant on type 2 diabetes risk. Obesity (Silver Spring). 2007, 15 (5): 1076-1081.
Florian B, Yasunori T, Evren C: Obesity, peroxisome proliferator-activated receptor, and atherosclerosis in type 2 diabetes. Arterioscler, Thromb, Vasc Biol. 2006, 26: 28-40.
Ek J, Urhammer SA, Sorensen TI, Andersen T: Homozygosity of the Pro12Ala variant of the peroxisomes proliferation-activated receptor- 2 (PPAR-γ2): divergent modulating effect on body mass index in Obese and lean Caucasian men. Diabetologia. 1999, 42: 892-895.
Mori H, Ikegami H, Kawaguchi Y: The Pro123Ala substitution in PPAR-g is associated with resistance to development of diabetes in the general population. Diabets. 2001, 50: 891-894.
Raza ST, Abbas S, Ahmed F, Fatima J, Zaidi ZH: Association of MTHFR and PPARγ2 genes polymorphism in relation to type 2 diabetes mellitus cases among north Indian population. GENE. 2012, 511: 375-379.
Tonjes A, Scholz M, Loeffler M, Stumvoll M: Association of Pro12Ala polymorphism in peroxisome proliferatoractivated receptor gamma with pre-diabetic phenotypes: meta-analysis of 57 studies on nondiabetic individuals. Diabetes Care. 2006, 29: 2489-97.
Raza ST, Fatima J, Ahmed F, Abbas S, Zaidi SH, Singh S, Mahdi F: Association of angiotensin converting enzyme (ACE) and fatty acid binding protein 2 (FABP2) genes polymorphism with type 2 diabetes mellitus in northern India. JRAAS. 2013, 14: 1-8.
Naresh VVS, Reddy ALK, Sivaramakrishna G, Sharama PVGK, Vardhan RV, Kumar SV: Angiotencin converting enzyme gene polymorphism in type 2 diabetics with nephropathy. Indian J Nephrol. 2010, 164 (100): 28.2-
Hsieh MC, Lin SR, Hsieh TJ, Hsu CH, Chen HC, Shin SJ, Tsai JH: Increased frequency of angiotensinconverting enzyme DD genotype in patients with type 2 diabetes in Taiwan. Nephrol Dial Transplant. 2000, 15 (7): 1008-1013.
Daimon M, Oizumi T, Saitoh T, Kameda W, Hirata A, Yamaguchi H, Ohnuma H, Igarashi M: The D allele of the angiotensin converting enzyme insertion/deletion (I/D) polymorphism is a risk factor for T2D in a population-based Japanese sample. Endocrine J. 2003, 50: 393-8.
Degirmenci I, Kebapci N, Basaran A, Efe B, Gunes HV: Frequency of angiotensin converting enzyme gene polymorphism in Turkish type 2 diabetic patients. Int J Clin Pract. 2005, 59: 1137-1142.12.
Grammer TB, Renner W, Von Karger S, Boehm BO, Winkelmann BR, Maerz W: The angiotensin-I converting enzyme I/D polymorphism is not associated with type 2diabetes in individual undergoing coronary angiography. (The Ludwigshafen risk and cardiovascular health study). Mol Genet Metab. 2006, 88: 378-383.
Arfa I, Abid A, Nouira S, Elloumi-Zghal H, Malouche D, Mannai I, Zorgati : Lack of association between the angiotensin converting enzyme gene (I/D) Polymorphism and diabatic nephropathy in Tunisian type 2 diabetic patients. J Renin Angiotensin aldosterone Syst. 2008, 9: 32-36.
Deeb SS, Fajas L, Nemoto M, Pihlajamaki J, Mykkanen L, Kuusisto J, Laakso M, Fujimoto W, Auwerx JA: Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet. 1998, 20: 284-7.
Pirie FJ, Motala AA, Pegoraro RJ, Paruk IM, Govender T, Rom L: Variants in PPARG, KCNJ11, TCF7L2, FTO, and HHEX genes in South African subjects of Zulu descent with type 2 diabetes. Afr J Diabetes Med. 2010, 1468-6570.
Ortega-Azorín C, Sorlí JV, Asensio AM, Coltell O, Martínez-González MA, Salas-Salvadó J, Covas MI, Arós F, Lapetra J, Serra-Majem L, Gómez-Gracia E, Fiol M, Sáez-Tormo G, Pintó X, Muñoz MA, Ros E, Ordovás JM, Estruch R, Corella D: Associations of the FTO rs9939609 and the MC4R rs17782313 polymorphisms with type 2 diabetes are modulated by diet, being higher when adherence to the Mediterranean diet pattern is low. Cardiovasc Diabetol. 2012, 11: 137-18
Doney ASF, Dannfald J, Kimber CH, Donnelly LA, Pearson E, Morris AD, Palmer CNA: The FTO gene is associated with an atherogenic lipid profile and myocardial infarction in patients with type 2 diabetes. CIRCGENETICS. 2009, 108: 822320-
Balasubramanyam M, Mohan V: Current concepts of PPARγ signaling in diabetes mellitus. Current Science. 2000, 79 (10): 1440-1445.
Yen CJ, Beamer BA, Negri C, Silver K, Brown KA, Yarnall DP, Burns DK, Roth J, Shuldiner AR: Molecular scanning of the human peroxisomes proliferator activated receptor gamma (hPPAR ) gene in diabetic cauccasian: identification of a Pro12Ala PPARγ2 missence mutation. Biochem Biophys Res Commun. 1997, 241: 270-274.
Ghoussaini M, Meyre D, Lobbens S, Charpentier G, Clément K, Charles MA, Tauber M, Weill J, Froguel P: Implication of the Pro12Ala polymorphism of the PPAR-gamma 2 gene in type 2 diabetes and obesity in the French population. BMC Med Genet. 2005, 6: 11-
Gouda HN, Sagoo GS, Harding AH, Yates J, Sandhu MS, Higgins JP: The association between the peroxisome proliferator-activated receptor-gamma2 (PPARG2) Pro12Ala gene variant and type 2 diabetes mellitus: a HuGE review and meta-analysis. Am J Epidemiol. 2010, 171: 645-55.
Spiegelman BM: P PA R - : adipogenic regulator and thiazolidinedione receptor. Diabetes. 1998, 47: 507-514.
Turner AJ, Hooper NM: The angiotensin-converting enzyme gene family: genomics an pharmacology. Trends Pharmacol Sci. 2002, 23: 177-183.
Sugaya T, Nishimatsu S, Tanimoto K, Takimoto E, Yamagishi T, Imamura K, Goto S, Imaizumi K, Hisada Y, Otsuka A: Angiotensin II type 1a receptor-deficient mice with hypotension and hyperreninemia. J Biol Chem. 1995, 270: 18719-18722.
Yoshida H, Kuriyama S, Alsumi Y: Angiotensin converting enzyme gene polymorphism in non insulin dependent diabetes mellitus. Kidney Int. 1996, 50: 657-64.
Ruggenenti P, Bettinaglio P, Pinares F, Remuzzi G: Angiotensin converting enzyme insertion/deletion polymorphism and renoprotection in diabetic and nondiabetic nephropathies. Clin J Am Soc Nephrol. 2008, 3: 1511-1525.
Bor MV, Elmali ES, Altan N: Serum antiotensin converting enzyme activity in streptozotocin-induced diabetic rats. Turk J Med Sci. 2000, 30: 311-313.
Ohno H, Kizaki T, Suzuki K, Hitomi Y, Nakano N, Sakurai T, Ogiwara R, Sakurai T, Izawa T, Noguchi I, Nagasawa J, Ohnuki Y, Takemasa T, Nukita M, Haga S: Is angiotensin I-converting enzyme I/D polymorphism associated with endurance performance and/or high altitude adaptation?. Adv Exerc Sports Physiol. 2005, 11 (2): 41-54.
Feng Y, Niu T, Xu X, Chen C, Li Q, Qian R, Wang G, Xu X: Insertion/deletion polymorphism of the ACE gene is associated with type 2 diabetes. Diabetes. 2002, 51 (6): 1986-1988.
Arzu Ergen H, Hatemi H, Agachan B, Camlica H, Isbir T: Angiotensin-I converting enzyme gene polymorphism in Turkish type 2 diabetic patients. Exp Mol Med. 2004, 36 (4): 345-350.
Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz LN: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. Engl J Med. 2001, 345: 851-860.
Vishwanathan V, Zhu Y, Bala K: Association between ACE gene polymorphism and diabetic nephropathy in South Indian patients. J Pancreas. 2001, 2: 83-7.
Bhavani BA, Padma T, Sastry BK: The insertion deletion polymorphism of angiotensin converting enzyme (ACE) gene increase the susceptibility to hypertention and/or diabetes. Int J Humen Genet. 2006, 5: 247-52.
Kumar A, Mahindra K, Sehajpal PK: Angiotensin 1 converting enzyme polymorphism and diabetic nephropathy in north india. Int J Hum Genet. 2005, 5: 279-83.
Prasad P, Tiwari AK, Kumar KM: Chronic renal insufficiency among Asian Indians with type 2 diabetes mellitus. BMC Med Genet. 2006, 7: 1-9.
Bostom AG, Shemin D, Yoburn D, Fisher DH, Nadeau MR, Selhub J: Hyperhomocysteinemia and traditional cardiovascular diseases risk factor in end stage renal desease patient on dialysis: a case- control study. A therosclerosis. 1995, 114: 93-103.
Outinen PA, Sood SK, Liaw PC, Sarge KD, Maeda N, Hirsh J, Ribau J, Podor TJ: Characterization of the stress-inducing effects of homocysteine. Biochem J. 1998, 332: 213-221.
Agullo Ortuno MT, Albaladejo MD, Parra S, Rodríguez-Manotas M, Fenollar M, Ruíz-Espejo F, Tebar J, Martínez P: Plasmatic homocysteine concentration and its relationship with complication associated to diabetes mellitus. Clin Chim Acta. 2002, 326: 105-12.
Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthew RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP: Candidate genetic risk factors for vascular disease: a common mutation in methylenetetrahydrofolate reductase: isolation of Cdna, mapping and mutation identification. Nat Genet. 1995, 10: 110-113.
Russo GT, Di Benedetto A, Alessi E, Corrado F, Di Cesare E, Alessi E, Nicocia G, D'Anna R, Cucinotta D: Mild hyperhomocysteinemia and the common C677T polymorphism of methylene tetrahydrofolate Reductase gene are not associated with the metabolic syndrome in type 2 diabetes. J Endocrinol Invest. 2006, 29: 201-207.
Di Renzo L, Bigioni M, Del Gobbo V, Premrov MG, Cianci R, De Lorenzo A: Interleukin-1 (IL-1) receptor antagonist gene polymorphism in normal weight obese syndrome: relationship to body composition and IL-1 alpha and beta plasma levels. Pharmacol Res. 2007, 55: 131-138.
Ozmen B, Ozmen D, Turgan N, Habif S, Mutaf I, Bayindir O: Association between homocysteinemia and renal function in patients with type 2 diabetes mellitus. Ann Clin Lab Sci. 2002, 32 (3): 279-86.
Maeda M, Yamamoto I, Fukuda M, Nishida M, Fujitsu J, Nonen S, Fujio Y, Kasayama S, Azuma J: MTHFR gene polymorphism as a risk factor for diabetic retinopathy in type 2 diabetic patients without serum creatinine elevation. Diabetes Care. 2003, 26: 547-8.
Ksiazek P, Bednarek-Skublewska A, Buraczynska M: The C677T methylenetetrahydrofolate reductase gene mutation and nephropathy in type 2 diabetes mellitus. Med Sci Monit. 2004, 10 (2): BR47-51.
Prochazka M, Lillioja S, Tait JF, Knowler WC, Mott DM, Spraul M, Bennett PH, Bogardus C: Linkage of chromosomal markers on 4q with a putative gene determining maximal insulin action in Pima Indians. Diabetes. 1993, 42: 514-
Mitchell BD, Kammerer CM, O’Connel P, Harrison CR, Manire M, Shipman P, Moyer MP, Stern MP, Frazier ML: Evidence for linkage of postchallenge insulin levels with intestinal fatty acidbinding protein (FABP2) in Mexican–Americans. Diabetes. 1995, 44: 1046-
Baier LJ, Sacchettini JC, Knowler WC, Eads J, Paolisso G, Tataranni PA, Mochizuki H, Bennett PH, Bogardus C, Prochazka M: An amino acid substitution in the human intestinal fatty acid binding protein is associated with increased fatty acid binding, increased fat oxidation, and insulin resistance. J Clin Invest. 1995, 95: 1281-
Agren JJ, Vidgren HM, Valve RS, Laakso M, Uusitupa M: Postprandial response 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, 73: 31-35. 19
Baier LJ, Bogardus C, Sacchettini JC: A polymorphism in the human intestinal fatty acid binding proteins alters fatty acid transport across Caco-2 cells. J Biol Chem. 1996, 271: 10892-10896.
Hegele RA, Harris SB, Hanley AJ, Sadikian S, Connelly PW, Zinman B: Genetic variation of intestinal fatty acid-binding protein associated with variation in body mass in aboriginal Canadians. J Clin Endocrinol Metab. 1996, 81 (12): 4334-4337.
Lefevre M, Lovejov JC, Smith SR, DeLany JP, Champagne C, Most MM: Comparison of the acute response to meals enriched with cis or trans fatty acids on glucose and lipids in overweight individuals with differing FABP2 genotypes. Metabolism. 2005, 54: 1652-1658.
Marin C, Pe’rez-Jime’nez F, Go’mez P, Delgado J, Paniagua JA, Lozano A: 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, 82: 196-200.
Berthier MT, Couillard C, Prud‘homme D, Nadeau A, Bergeron J, Tremblay A: Effects of the FABP2 A54T mutation on triglyceride metabolism of viscerally obese men. Obes. Res. 2001, 9: 668-675.
Pihlajamaki J, Rissanen J, Heikkinen S, Karjalainen L, Laakso M: Codon 54 polymorphism of the human intestinal fatty acid binding protein 2 gene is associated with dyslipidemias but not with insulin resistance in patients with familial combined hyperlipidemia. Arterioscler, Thromb, Vasc Biol. 1997, 17: 1039-
Brown MD, Shuldinger AR, Ferrell RE, Weiss EP, Korytkowski MT, Zmuda JM: FABP2 genotype is associated with insulin sensitivity in older women. Metabolism. 2001, 50: 1102-1105.
Galluzzi JR, Cupples LA, Meigs JB, Wilson PWF, Schaffer EJ, Ordovas JM: Association of the Ala54Thr polymorphism in the intestinal fatty acid-binding protein with 2 h postchallenge insulin levels in the Framingham offspring study. Diabetes Care. 2001, 24: 1161-1166.
Albala C, Santos JL, Cifuentes M, Villarroel AC, Lera L, Libermann C: Intestinal FABP2 A54T polymorphism: Asso- C. Albala et al. ciation with insulin-resistance and obesity in women. Obes Res. 2004, 12: 340-345.
Boullu-Sanchis S, Lepretre F, Hedelin G, Donnet JP, Schaffer P, Froguel P, Pinget M: Type 2 diabetes mellitus: association study of five candidate genes in an Indian population of Guadeloupe, genetic contribution of FABP2 polymorphism. Diabetes Metab. 1999, 25: 150-156.
Chiu KC, Chuang LM, Yoon C: The A54T polymorphismat the intestinal fatty acid binding protein 2 is associated with insulin resistance in glucose tolerant. Caucasians BMC. 2001, 2: 7-13.
Duarte NL, Colagiuri S, Palu T, Wang XL, Wilcken DE: Obesity, type II diabetes and the Ala54Thr polymorphism of fatty acid binding protein 2 in the Tongan population. Mol Genet Metab. 2003, 79: 183-188.
Hayakawa T, Nagai Y, Nohara E, Yamashita H, Takamura T, Abe T, Nomura G, Kobayashi K: Variation of the fatty acid binding protein 2 gene is not associated with obesity and insulin resistance in Japanese subjects. Metabolism. 1999, 48: 655-
Ito K, Nakatani K, Fujii M: Codon 54 polymorphism of the fatty acid binding protein gene and insulin resistance in the Japanese population. Diabet Med. 1999, 16: 119-
Sipilainen R, Uusitupa M, Heikkinen S, Rissanen A, Laakso M: Variants in the human intestinal fatty acid binding protein 2 gene in obese subjects. J Clin Endocrinol Metab. 1997, 82: 2629-
Rissanen J, Pihlajamaki J, Heikkinen S, Kekalaien P, Kumsisto J, Laakso M: The Ala54Thr polymorphism of the fatty acid binding protein 2 gene does not influence insulin sensitivity in Finnish nondiabetic and NIDDM subjects. Diabetes. 1997, 46: 711-
Lei HH, Coresh J, Shuldiner AR, Boerwinkle E, Brancati FL: Variants of the insulin receptor substrate-1 and fatty acid binding protein 2 genes and the risk of type 2 diabetes, obesity, and hyperinsulinemia in African-Americans: the atherosclerosis risk in communities study. Diabetes. 1868, 1999: 48-
Fredriksson R, Hagglund M, Olszewski PK, Stephansson O, Jacobsson JA, Olszewska AM, Levine AS, Lindblom J, Schioth HB: The obesity gene, FTO, is of ancient origin, up-regulated during food deprivation and expressed in neurons of feeding-related nuclei of the brain. Endocrinology. 2008, 149: 2062-2071.
Gerken T, Girard CA, Tung YC, Webby CJ, Saudek V: The obesity-associated FTO gene encodes a 2-oxoglutaratedependent nucleic acid demethylase. Science. 2007, 318: 1469-1472.
Clifton IJ, McDonough MA, Ehrismann D, Kershaw NJ, Granatino N: Structural studies on 2-oxoglutarate oxygenases and related doublestranded beta-helix fold proteins. J Inorg Biochem. 2007, 100: 644-669.
Hinney A: Genome wide association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants. PloS ONE. 2007, 2: e1361-
Scuteri A, Sanna S, Chen WM, Uda M, Albai G, Strait J, Najjar S, Nagaraja R, Orru M, Usala G, Dei M, Lai S, Maschio A, Busonero F, Mulas A, Ehret GB, Fink AA, Weder AB, Cooper RS, Galan P, Chakravarti A, Schlessinger D, Cao A, Lakatta E, Abecasis GR: Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. Plos Genet. 2007, 3: 1200-1210.
Clifton IJ, McDonough MA, Ehrismann D, Kershaw NJ, Granatino N, Schofield CJ: Structural studies on 2-oxoglutarate oxygenases and related double-stranded beta-helix fold proteins. J Inorg Biochem. 2006, 100: 644-69.
Stratigopoulos G, Padilla SL, Leduc CA, Watson E, Hattersley AT, McCarthy MI, Zeltser LM, Chung WK, Leibel RL: Regulation of Fto/Ftm gene expression in mice and humans. Am J Physiol Regul Integr Comp Physiol. 2008, 294: R1185-R1196.
Wahlen K, Sjolin E, Hoffstedt J: The common rs9939609 gene variant of the fat mass- and obesity-associated gene FTO is related to fat cell lipolysis. J Lipid Res. 2008, 49: 607-61.
Dina C, Meyre D, Gallina S, Durand E, Körner A, Jacobson P, Carlsson LM, Kiess W, Vatin V, Lecoeur C, Delplanque J, Vaillant E, Pattou F, Ruiz J, Weill J, Levy-Marchal C, Horber F, Potoczna N, Hercberg S, Le Stunff C, Bougnères P, Kovacs P, Marre M, Balkau B, Cauchi S, Chèvre JC, Froguel P: Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet. 2007, 39: 706-707.
Li H, Wu Y, Loos RJ Hu FB, Liu Y, Wang J, Yu Z, Lin X: Variants in the fat mass- and obesity-associated (FTO) gene are not associated with obesity in a Chinese Han population. Diabetes. 2008, 57: 264-268.
Hotta K, Nakata Y, Matsuo T, Kamohara S, Kotani K, Komatsu R, Itoh N, Mineo I, Wada J, Masuzaki H, Yoneda M, Nakajima A, Miyazaki S, Tokunaga K, Kawamoto M, Funahashi T, Hamaguchi K, Yamada K, Hanafusa T, Oikawa S, Yoshimatsu H, Nakao K, Sakata T, Matsuzawa Y, Tanaka K, Kamatani N, Nakamura Y: Variations in the FTO gene are associated with severe obesity in the Japanese. J Hum Genet. 2008, 53: 546-553.
Ng MC, Park KS, Tam CH OB, Cho YM, Shin HD, Lam VK, Ma RC, So WY, Cho YS, Kim HL, Lee HK, Chan JC, Cho NH: Implication of genetic variants near TCF7L2, SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2 and FTO in type 2 diabetes and obesity in 6719 Asians. Diabetes. 2008, 57: 2226-2233.
Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JR, Elliott KS, Lango H, Rayner NW, Shields B, Harries LW, Barrett JC, Ellard S, Groves CJ, Knight B, Patch AM, Ness AR, Ebrahim S, Lawlor DA, Ring SM, Ben-Shlomo Y, Jarvelin MR, Sovio U, Bennett AJ, Melzer D, Ferrucci L, Loos RJ, Barroso I, Wareham NJ: A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science (Wash DC). 2007, 316: 89-94.
Scuteri A, Sanna S, Chen WM, Uda M, Albai G, Strait J, Najjar S, Nagaraja R, Orrú M, Usala G, Dei M, Lai S, Maschio A, Busonero F, Mulas A, Ehret GB, Fink AA, Weder AB, Cooper RS, Galan P, Chakravarti A, Schlessinger D, Cao A, Lakatta E, Abecasis GR: Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet. 2007, 3: e115-
Chang YC, Liu PH, Lee WJ, Chang TJ, Jiang YD, Li HY, Kuo SS, Lee KC, Chuang LM: Common variation in the fat mass and obesity-associated (FTO) gene confers risk of obesity and modulates BMI in the Chinese population. Diabetes. 2008, 57: 2245-2252.
Bressler J, Kao WH, Pankow JS, Boerwinkle E: Risk of type 2 diabetes and obesity is differentially associated with variation in FTO in whites and African-Americans in the ARIC study. PLoS One. 2010, 5: e10521-
The authors declare that they have no competing interests.
SA and ST have done overall search and compilation of data. AA and SR help in the literature search and preparation of table. FA helps in the correction of grammatical and typological mistake. FM has done overall supervision. All authors read and approved the final manuscript.
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Abbas, S., Raza, S.T., Ahmed, F. et al. Association of Genetic polymorphism of PPARγ-2, ACE, MTHFR, FABP-2 and FTO genes in risk prediction of type 2 diabetes mellitus. J Biomed Sci 20, 80 (2013). https://doi.org/10.1186/1423-0127-20-80