Introduction:
Type 2 Diabetes Mellitus (T2DM) is a complex disorder caused by the interaction
between genetic predisposition and environmental factors. Genetics plays an important
role on lipid homeostasis. Many genes are involved in the lipid metabolism, such
as FABP-2 and PPAR-γ. Aim: To evaluate
the association between specific SNPs and haplotypes of the FABP-2 and PPAR-γ genes with T2DM and lipid profile in an
Argentinean population. Methods: The FABP-2 (rs1799883)
and PPAR-γ (rs1801282) polymorphisms were
genotyped and analyzed in association with lipid profile and T2DM, separately and
also combined in haplotypes. Results: The frequency of the rare Thr54 allele of
the FABP-2 polymorphism in control (0.33) was not different from the frequency in
T2DM (0.27), whereas the frequency of the rare Ala12 allele of the PPAR-γ polymorphism in control was different from
the frequency in T2DM (0.26 and 0.14, respectively; p = 0.0031). Frequencies of
haplotypes for these two single-nucleotide polymorphisms differed significantly
in control and T2DM. Haplotype association analysis showed the associations between
ThrPro haplotype and TG levels (OR = 2.520; 95% CI = 1.139 - 5.575; p = 0.027) and
between ThrPro haplotype and TC and LDL-c levels when compared to AlaPro haplotype
(difference = 0.175, 95% CI = 0068 - 0.499, p < 0.0001; difference = 0.052, 95%
CI = 0.017 - 0.158, p < 0.0001, respectively). Conclusions: These results from
a haplotype analysis show for the first time that genetic combinations of alleles
of the FABP-2 and PPAR-γ gene could play
a role in the susceptibility to develop dyslipemia in T2DM.
Cite this paper
Siewert, S. , Nicotra, M. F. O. , Gonzalez, I. I. , Fernandez, G. and Ojeda, M. S. (2014). FABP-2 and PPAR-γ Haplotype as Risk Factors for Dyslipidemia in a Type 2 Diabetes Mellitus Population of Santa Rosa del Conlara, San Luis, Argentina. Open Access Library Journal, 1, e967. doi: http://dx.doi.org/10.4236/oalib.1100967.
Slimel, M.R., Coppolillo, F.E., Masi, J.D., Mendoza, S.M. and Tannuri, J. (2010) Epidemiology of Diabetes in Argentina. Avances en Diabetología, 26, 101-106. http://dx.doi.org/10.1016/S1134-3230(10)62006-6
Gross, B. and Staels, B. (2007) PPAR Agonists: Multimodal Drugs for the Treatment of Type-2
Diabetes. Best Practice Research Clinical
Endocrinology Metabolism, 21, 687-710. http://dx.doi.org/10.1016/j.beem.2007.09.004
Gouda, H.N., Sagoo, G.S., Harding, A.H., Yates, J., Sandhu, M.S. and Higgins, J.P. (2010) The Association between the Peroxisome
Proliferator-Activated Receptor-Gamma 2 (PPARG2) Pro12Ala Gene Variant and Type 2 Diabetes Mellitus: A HuGE
Review and Meta-Analysis. American Journal of Epidemiology,
171, 645-655. http://dx.doi.org/10.1093/aje/kwp450
Cullen, P. (2000) Evidence That
Triglycerides Are an Independent Coronary Heart Disease Risk Factor.American Journal of Cardiology, 86, 943-949. http://dx.doi.org/10.1016/S0002-9149(00)01127-9
Chen, E.S., Mazzotti, D.R., Furuya, T.K., Cendoroglo, M.S., Ramos, L.R., Araujo, L.Q., Burbano, R.R. and Smith Mde, A. (2010) Association of PPARalpha
Gene Polymorphisms and Lipid Serum Levels in a Brazilian Elderly Population. Experimental and Molecular Pathology,88, 197-201. http://dx.doi.org/10.1016/j.yexmp.2009.10.001
Prieur, X., Coste, H. and Rodriguez, J.C. (2003) The Human Apolipoprotein AV Gene Is
Regulated by Peroxisome Proliferator-Activated Receptor-Alpha and Contains a
Novel Farnesoid X-Activated Receptor Response Element. The Journal of Biological
Chemistry, 278, 25468-25480. http://dx.doi.org/10.1074/jbc.M301302200
Yong, E.L., Li, J. and Liu, M.H. (2008) Single Gene Contributions: Genetic Variants of Peroxisome
Proliferator-Activated Receptor (Isoforms Alpha, Beta/Delta and Gamma) and Mechanisms
of Dyslipidemias. Current Opinion in
Lipidology, 19, 106-112. http://dx.doi.org/10.1097/MOL.0b013e3282f64542
Fajas, L.,
Debril, M.B. and Auwerx, J. (2001) PPAR Gamma: An Essential Role in Metabolic Control. Nutrition Metabolism and Cardiovascular
Diseases, 11, 64-69.
Deeb, S.S., Fajas, L., Nemoto, M.,
Pihlajamaki, J., Mykkanen, L., Kuusisto, J., Laakso, M., Fujimoto, W. and Auwerx, J.A. (1998) Pro12Ala Substitution in PPARgamma2 Associated with
Decreased Receptor Activity, Lower Body Mass Index and Improved Insulin
Sensitivity. Nature Genetics, 20,
284-287. http://dx.doi.org/10.1038/3099
Doney, A.S., Fischer, B., Cecil, J.E., Boylan, K., McGuigan, F.E., Ralston, S.H., Morris, A.D. and Palmer, C.N. (2004) Association
of the Pro12Ala and C1431T
Variants of PPARG and Their Haplotypes with Susceptibility to Type 2 Diabetes. Diabetologia, 47, 555-558. http://dx.doi.org/10.1007/s00125-003-1323-1
Meirhaeghe, A., Fajas, L., Helbecque, N., Cottel, D., Lebel, P.,
Dallongeville, J., Deeb, S., Auwerx, J. and Amouyel, P. (1998) A Genetic Polymorphism of the Peroxisome Proliferator-Activated
Receptor γ Gene Influences Plasma
Leptin Levels in Obese Humans. Human
Molecular Genetics, 7, 435-440. http://dx.doi.org/10.1093/hmg/7.3.435
Altshuler, D.,
Hirschhorn, J.N., Klannemark, M., Lindgren, C.M., Vohl, M.C., Nemesh, J., Lane, C.R., Schaffner, S.F., Bolk, S., Brewer, C., Tuomi, T., Gaudet, D., Hudson, T.J., Daly, M., Groop, L. and Lander, E.S. (2000) The Common PPARgamma Pro12Ala Polymorphism Is Associated
with Decreased Risk of Type 2 Diabetes. Nature
Genetics, 26, 76-80. http://dx.doi.org/10.1038/79216
Lohmueller, K.E., Pearce, C.L., Pike, M., Lander, E.S. and Hirschhorn, J.N. (2003) Meta-Analysis
of Genetic Association Studies Supports a Contribution of Common Variants to
Susceptibility to Common Disease. Nature
Genetics, 33, 177-182. http://dx.doi.org/10.1038/ng1071
Tonjes, A.,
Scholz, M., Loeffler, M. and Stumvoll, M. (2006) Association of Pro12Ala Polymorphism in Peroxisome Proliferator-Activated
Receptor Gamma with Pre-Diabetic Phenotypes: Meta-Analysis of 57 Studies on
Nondiabetic Individuals. Diabetes Care,
29, 2489-2497. http://dx.doi.org/10.2337/dc06-0513
Hegele, R.A. (1998) A Review of Intestinal Fatty Acid Binding Protein Gene Variation
and the Plasma Lipoprotein Response to Dietary Components. Clinical Biochemistry, 31, 609-612. http://dx.doi.org/10.1016/S0009-9120(98)00078-2
Baier, L.J.,
Sacchettini, J.C.,
Knowler, W.C., Eads, J.,
Paolisso, G., Tataranni, P.A., Mochizuki, H.,
Bennett, P.H., Bogardus, C. and Prochazka, M. (1995) 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. Journal of Clinical Investigation,95, 1281-1287. http://dx.doi.org/10.1172/JCI117778
Agren, J.J.,
Valve, R., Vidgren, H.,
Laakso, M. and Uusitupa, M.
(1998) Postprandial Lipemic Response Is Modified
by the Polymorphism at Codon 54 of the Fatty Acid-Binding Protein 2 Gene. Arteriosclerosis, Thrombosisand Vascular Biology, 18, 1606-1610. http://dx.doi.org/10.1161/01.ATV.18.10.1606
Agren, J.J., Vidgren, H.M., Valve, R.S., Laakso, M. and Uusitupa, M.I. (2001) Postprandial
Responses of Individual Fatty Acids in Subjects Homozygous for the Threonineor Alanine-Encoding Allele in Codon 54 of the Intestinal Fatty Acid Binding
Protein 2 Gene. The American Journal of
Clinical Nutrition, 73, 31-35.
Dworatzek, P.D., Hegele, R.A. and Wolever, T.M. (2004)
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. The American Journal of Clinical Nutrition,
79, 1110-1117.
Lefevre, M., Lovejoy, J.C., Smith, S.R., Delany, J.P., Champagne, C., Most, M.M., Denkins, Y., de
Jonge, L., Rood, J. and Bray, G.A.
(2005) Comparison of the Acute Response to Meals Enriched with Cis- or Trans-Fatty
Acids on Glucose and Lipids in
Overweight Individuals with Differing FABP2Genotypes. Metabolism,54, 1652-1658. http://dx.doi.org/10.1016/j.metabol.2005.06.015
Seino, Y., Nanjo, K., Tajima, N., Kadowaki, T., Kashiwagi, A., Araki, E., Ito, C.,
Inagaki, N., Iwamoto, Y., Kasuga, M., Hanafusa, T., Haneda, M. and Ueki, K. (2010)
Report of the Committee on the Classification and Diagnostic Criteria of Diabetes
Mellitus. Journal of Diabetes
Investigation, 1, 212-228. http://dx.doi.org/10.1111/j.2040-1124.2010.00074.x
Friedewald, W.T., Levy, R.I. and Fredrickson, D.S. (1972) Estimation of the Concentration of Low-Density Lipoprotein
Cholesterol in Plasma, without Use of the Preparative Ultracentrifuge. Clinical Chemistry, 18, 499-502.
Expert
Panel on Detection (2001) Expert Panel on Detection, Evaluation and Treatment
of High Blood Cholesterol in Adults: Executive Summary of the Third Report of the
National Cholesterol Education Program Expert Panel on Detection, Evaluation
and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel I II). Journal of the American Medical Association,285, 2486-2497. http://dx.doi.org/10.1001/jama.285.19.2486
Zhao, T.,
Nzekebaloudou, M. and Lv, J. (2010) Ala54Thr
Polymorphism of Fatty Acid-Binding Protein 2 Gene and Fasting Blood Lipids: A
Meta-Analysis. Atherosclerosis, 210,
461-467. http://dx.doi.org/10.1016/j.atherosclerosis.2009.11.049
Tahvanainen, E., Molin, M., Vainio, S., Tiret, L., Nicaud, V., Farinaro, E., Masana, L. and Ehnholm, C. (2000) Intestinal Fatty
Acid Binding Protein Polymorphism at Codon 54 Is Not Associated with Postprandial Responses to Fat and Glucose Tolerance Tests
in Healthy Young Europeans.
Results from EARS II Participants. Atherosclerosis, 152, 317- 325. http://dx.doi.org/10.1016/S0021-9150(99)00488-8
Gómez, L.C., Real, S.M., Ojeda, M.S., Gimenez, S., Mayorga, L.S. and Roqué, M. (2007) Polymorphism of
the FABP2 Gene: A Population Frequency Analysis and an Association Study with
Cardiovascular Risk Markers in Argentina. BMC Medical Genetics, 8, 39. http://dx.doi.org/10.1186/1471-2350-8-39
Almeida, J.C., Gross, J.L., Canani, L.H.,
Zelmanovitz, T., Perassolo, M.S. and Azevedo, M.J. (2010) The Ala54Thr Polymorphism of the FABP2Gene Influences the
Postprandial Fatty Acids in Patients with Type 2 Diabetes. The Journal of Clinical Endocrinology and
Metabolism, 95, 3909-3917. http://dx.doi.org/10.1210/jc.2009-2674
Canani, L.H., Capp, C., Ng, D.P., Choo, S.G., Maia, A.L., Nabinger, G.B., Santos, K.,
Crispim, D., Roisemberg, I.,
Krolewski, A.S. and Gross, J.L.
(2005) The Fatty Acid-Binding Protein-2 A54T
Polymorphism Is Associated with
Renal Disease in Patients with Type 2 Diabetes. Diabetes, 54, 3326-3330. http://dx.doi.org/10.2337/diabetes.54.11.3326
Albala, C., Santos, J.L., Cifuentes, M., Villarroel, A.C., Lera, L., Libermann, C., Angel, B. and Pérez-Bravo, F. (2004) Intestinal FABP2 A54T Polymorphism: Association
with Insulin-Resistance and Obesity in Women. Obesity Research, 12, 340-345. http://dx.doi.org/10.1038/oby.2004.42
Kim, C.H., Yun, S.K., Byun, D.W., Yoo, M.H., Lee, K.U. and Suh, K.I. (2001) 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, 50, 473-476. http://dx.doi.org/10.1053/meta.2001.21022
Yamada, K., Yuan, X., Ishiyama, S., Koyama, K., Ichikawa, F., Koyanagi, A., Koyama, W. and Nonaka, K. (1997) Association between
Ala54Thr Substitution of the Fatty Acid Binding Protein 2 Gene with Insulin
Resistance and Intra-Abdominal Fat Thickness in Japanese Men. Diabetologia, 40, 706-710. http://dx.doi.org/10.1007/s001250050737
Boullu-Sanchis, S., Lepretre, F., Hedelin, G., Donnet, J.P., Schaffer, P., Froguel, P. and Pinget, M. (1999) Type 2 Diabetes
Mellitus: Association Study of Five Candidate Genes in an Indian Population of
Guadeloupe, Genetic Contribution of FABP2
Polymorphism. Diabetes & Metabolism,
25, 150-156.
Chiu, K.C., Chuang, L.M. and Yoon, C. (2001) The A54T Polymorphism at the Intestinal Fatty Acid Binding
Protein 2 Is Associated with Insulin Resistance in Glucose Tolerant Caucasians. BMC Genetics, 2, 7-13. http://dx.doi.org/10.1186/1471-2156-2-7
Duarte, N.L., Colagiuri, S., Palu, T., Wang, X.L. and Wilcken, D.E. (2003) Obesity, Type II Diabetes and the Ala54Thr Polymorphism of
Fatty Acid Binding Protein 2 in the Tongan Population. Molecular Genetics and Metabolism, 79, 183-188. http://dx.doi.org/10.1016/S1096-7192(03)00088-X
Hegele, R.A., Harris, S.B., Hanley, A.J., Sadikian, S., Connelly, P.W. and Zinman, B. (1996) Genetic Variation of Intestinal Fatty Acid-Binding
Protein Associated with Variation in Body Mass in Aboriginal Canadians. The Journal of Clinical Endocrinology and
Metabolism, 81, 4334-4337.
Rissanen, J., Pihlajamaki, J., Heikkinen, S., Kekalainen, P., Kuusisto, J. and Laakso, M. (1997) The Ala54Thr Polymorphism
of the Fatty Acid Binding Protein 2 Gene Does Not Influence Insulin Sensitivity
in Finnish Nondiabetic and NIDDM Subjects. Diabetes,
46, 711-712. http://dx.doi.org/10.2337/diab.46.4.711
Ito, K., Nakatani, K., Fujii, M., Katsuki, A., Tsuchihashi, K., Murata, K., Goto, H., Yano, Y., Gabazza, E.C., Sumida, Y. and Adachi, Y. (1999) Codon
54 Polymorphism of the Fatty Acid Binding Protein Gene and Insulin Resistance
in the Japanese Population. Diabetic
Medicine, 16, 119-124. http://dx.doi.org/10.1046/j.1464-5491.1999.00034.x
Ishii, T., Hirose, H., Kawai, T., Hayashi, K., Maruyama, H., Saito, I. and Saruta, T. (2001) Effects of Intestinal
Fatty Acid-Binding Protein Gene Ala54Thr Polymorphism and Beta3-Adrenergic
Receptor Gene Trp64Arg Polymorphism on Insulin Resistance and Fasting Plasma
Glucose in Young to Older Japanese Men. Metabolism,50, 1301-1307. http://dx.doi.org/10.1053/meta.2001.27228
Xiang, K., Zheng, T., Jia, W., Sun, D., Ding, W., Lu, J. and Tang, J. (1999) The Impact of Codon 54
Variation in Intestinal Fatty Acid Binding Protein Gene on the Pathogenesis of
Diabetes Mellitus in Chinese. Chinese
Medical Journal (English Edition),
112, 99-102.
Lei, H.H., Coresh, J., Shuldiner, A.R.,
Boerwinkle, E. and Brancati, F.L. (1999) 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, 48, 1868-1872. http://dx.doi.org/10.2337/diabetes.48.9.1868
Zhao, T., Zhao, J., Lv, J. and Nzekebaloudou, M. (2011) Meta-Analysis on the Effect of the Ala54Thr Polymorphism
of the Fatty Acid-Binding Protein 2 Gene on Body Mass Index. Nutrition, Metabolism & Cardiovascular Disease, 21, 823-829. http://dx.doi.org/10.1016/j.numecd.2010.02.020
de Luis, D.A., Aller, R., Izaola, O., Sagrado, M.G. and Conde, R. (2006) Influence
of ALA54THR Polymorphism of Fatty Acid Binding Protein 2 on Lifestyle
Modification Response in Obese Subjects. Annals
of Nutrition and Metabolism, 50, 354-360. http://dx.doi.org/10.1159/000094299
Huguenin, G.V. and Rosa, G. (2010) The Ala Allele in the PPAR-Gamma 2 Gene Is Associated
with Reduced Risk of Type 2 Diabetes Mellitus in Caucasians and Improved
Insulin Sensitivity in Overweight Subjects. British
Journal of Nutrition, 104, 488-497. http://dx.doi.org/10.1017/S0007114510000851
Stumvoll, M. and Haring, H. (2002) The Peroxisome Proliferator-Activated Receptor-Gamma 2
Pro12Ala Polymorphism. Diabetes, 51,
2341-2347. http://dx.doi.org/10.2337/diabetes.51.8.2341
Lindi, V., Sivenius, K., Niskanen, L., Laakso, M. and Uusitupa, M. (2001) Effect of the Pro12Ala Polymorphism of the PPAR-Gamma 2 Gene on
Long-Term Weight Change in Finnish Non-Diabetic Subjects. Diabetologia, 44, 925-926. http://dx.doi.org/10.1007/s001250100558
Ludovico, O., Pellegrini, F., Di Paola, R., Minenna, A., Mastroianno, S., Cardellini, M., Marini, M.A., Andreozzi, F., Vaccaro, O., Sesti, G. and Trischitta, V. (2007) Heterogeneous
Effect of Peroxisome Proliferator-Activated Receptor Gamma 2 Ala12
Variant on Type 2 Diabetes Risk. Obesity,
15, 1076-1081. http://dx.doi.org/10.1038/oby.2007.617
Mori, H., Ikegami, H., Kawaguchi, Y., Seino, S., Yokoi, N., Takeda, J., Inoue, I., Seino, Y., Yasuda, K., Hanafusa, T., Yamagata, K., Awata, T., Kadowaki, T., Hara, K., Yamada, N., Gotoda, T., Iwasaki, N., Iwamoto, Y., Sanke, T., Nanjo, K., Oka, Y., Matsutani, A., Maeda, E. and Kasuga, M. (2001) The
Pro12Ala Substitution in PPAR-c Is Associated with Resistance
to Development of Diabetes in the General Population Possible Involvement in
Impairment of Insulin Secretion in Individuals with Type 2
Diabetes. Diabetes, 50, 891-894. http://dx.doi.org/10.2337/diabetes.50.4.891
Mancini, F.P., Vaccaro, O., Sabatino, L., Tufano, A., Rivellese, A.A., Riccardi, G. and Colantuoni, V. (1999) Pro12Ala Substitution
in the Peroxisome Proliferator-Activated Receptor-Gamma 2 Is Not
Associated with Type 2 Diabetes. Diabetes,
48, 1466-1468. http://dx.doi.org/10.2337/diabetes.48.7.1466
Masugi, J., Tamori, Y., Mori, H., Koike, T. and Kasuga, M. (2000) Inhibitory Effect of a Proline-to-Alanine Substitution at
Codon 12 of Peroxisome Proliferator-Activated Receptor-Gamma 2 on Thiazolidinedione-Induced
Adipogenesis. Biochemical and Biophysical Research
Communications, 268,
178-182. http://dx.doi.org/10.1006/bbrc.2000.2096
