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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 3 1705-1711
Copyright © 2005 by The Endocrine Society

Polymorphisms in the Fatty Acid-Binding Protein 2 and Apolipoprotein C-III Genes Are Associated with the Metabolic Syndrome and Dyslipidemia in a South Indian Population

Jean-Marc Guettier1, Angeliki Georgopoulos1, Michael Y. Tsai, Venkatesan Radha, Subramaniam Shanthirani, Raj Deepa, Myron Gross, Gundu Rao and Viswanathan Mohan

University of Minnesota (J.-M.G., A.G., M.Y.T., M.G., G.R.), and Endocrinology, Metabolism, and Nutrition Division (J.-M.G., A.G.), Department of Medicine, Veterans Affairs Medical Center, Minneapolis, Minnesota 55417; and Madras Diabetes Research Foundation (V.R., S.S., R.D., V.M.), Gopalapuram, Chennai, India 600086

Address all correspondence and requests for reprints to: Angeliki Georgopoulos, M.D., Division of Endocrinology, Metabolism, and Nutrition, One Veteran’s Drive, Mail Code 111G, VA Medical Center, Minneapolis, Minnesota 55417. E-mail: georg003{at}umn.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The Chennai Urban Population Study investigates a South Indian population with a high prevalence of cardiovascular disease associated with the metabolic syndrome (MS). The Ala54Thr polymorphism in the fatty acid-binding protein 2 (FABP2) gene as well as the T–455C and C–482T polymorphisms in the apolipoprotein C-III (APOC3) gene promoter have been associated with features of the MS in specific populations. This study evaluates in Asian-Indians the association between these polymorphisms with MS and dyslipidemia, defined according to National Cholesterol Education Program Adult Treatment Panel III. Allelic frequencies in 70 controls and 110 patients with diabetes from the Chennai Urban Population Study were 52.9% for FABP2 Thr54, 73.0% for APOC3 –482T, and 80.2% for APOC3 –455C. The polymorphisms were in agreement with Hardy-Weinberg equilibrium. Controls carrying FABP2 Thr54 were more likely to have MS than noncarriers (Fisher’s exact test P = 0.031; odds ratio = 6.9 with a 95% confidence interval of 1.1, 43.9). Those carrying at least one polymorphic allele in both genes had a higher likelihood of having MS than wild type (Fisher’s exact test P = 0.003; odds ratio = 12.1 with a 95% confidence interval of 1.88, 77.6). Dyslipidemia was associated with the polymorphism as well. The polymorphisms were not associated with MS in patients with diabetes. The association of the polymorphisms with MS and dyslipidemia could contribute to the high cardiovascular disease prevalence in this population.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
A HIGH CONCENTRATION of triglycerides and a low concentration of high-density lipoproteins (HDL) are two phenotypic characteristics of the metabolic syndrome that mark an increased risk toward cardiovascular disease (CVD). Populations with a high tendency to develop the metabolic syndrome have been scrutinized in an attempt to isolate genes that may predispose to its development. The fatty acid-binding protein-2 (FABP2) gene mapped to the long arm of chromosome 4 is one such candidate gene (1). This gene codes for a fatty acid-binding protein expressed in the villus tips of the small intestine and is thought to play a role in cytosolic fatty acid trafficking (reviewed in Ref. 2). A single-nucleotide polymorphism (G to A) at codon 54 results in the substitution of alanine for threonine (3). In vitro, Caco-2 cell line cultures expressing the Thr54/Thr54 genotype have a 2-fold higher affinity for long-chain fatty acids than cell lines expressing the wild-type genotype (4). Ex vivo, tissue from human jejunal explants with the Ala54/Thr54 and Thr54/Thr54 genotypes were associated with increased de novo triglyceride and apolipoprotein B secretion, resulting in increased chylomicron production (5). Caucasian men with diabetes carrying one or two polymorphic alleles were shown to have significantly higher levels of fasting and postprandial triglycerides when compared with wild types (6). An association between the Thr54 FABP2 allele and an abnormal postprandial lipemic response has also been reported in a population of obese Finns without diabetes (7). Viscerally obese Canadian men carrying the Thr54 allele did not exhibit postprandial lipid abnormalities but had triglyceride enrichment of both fasting and postprandial HDL (8). These studies suggest a link between the FABP2 codon 54 variant and the dyslipidemia associated with the metabolic syndrome.

Apolipoprotein C-III (apoC-III protein, APOC3 gene), a 79-amino-acid glycoprotein produced mostly in the liver, is believed to play an important role in the metabolism of circulating triglyceride-rich lipoprotein (TRL) through inhibition of lipoprotein lipase and interference with apoE-mediated TRL uptake by hepatic receptors. Animals transfected with the APOC3 gene overexpress apoC-III and develop marked hypertriglyceridemia (9). In humans with some forms of familial hypertriglyceridemia, elevation in serum levels of triglycerides was correlated with high plasma concentration of apoC-III (10). TRL and TRL-remnant-associated apoC-III accounted for the observed increase in plasma apoC-III concentration (10). The gene coding for apoC-III is found on the long arm of chromosome 11. Two polymorphic nucleotides located at positions –455 (T to C) and –482 (C to T) in the 5' APOC3 gene promoter region have been associated with elevated levels of serum triglyceride in a population of native Canadians and French women (11, 12). In an Italian population with and without features of the metabolic syndrome, carriers of the APOC3 T–455C variant were shown to have increased prevalence of coronary artery disease, increased serum apoC-III concentration, and increased serum triglycerides (13, 14). An insulin-responsive element (–490 to –449) has been identified in the promoter region of the APOC3 gene containing these two polymorphic alleles (15). Insulin is believed to exert its action by down-regulating gene expression. Mutations within the insulin-responsive element result in loss of this function (15, 16).

Asian-Indians have been shown to exhibit higher prevalence of CVD and excess CVD mortality when compared with other ethnic groups (17, 18, 19). Classic cardiac risk factors do not account for the observed differences in interethnic prevalence rates (20). Rather, the clustering of insulin resistance, central obesity, hypertension, and atherogenic dyslipidemia in migrants and native Asian-Indians is believed to predispose this specific population toward premature CVD (20, 21, 22, 23, 24). Although migration studies have documented the impact of environmental influences on the development of these traits, it is hypothesized that the high tendency of this population toward developing features of the metabolic syndrome is in part genetically determined. Significantly higher prevalence for the APOC3 promoter polymorphisms in populations of migrant Asian-Indians has been reported (25). These studies and others (26, 27) suggest an association between the two gene variants and features of the metabolic syndrome in Asian-Indians.

The present study is designed to examine the association between specific polymorphisms in the FABP2 and APOC3 genes and the metabolic syndrome, defined using the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP-III) (28) in a native Asian-Indian population with a high prevalence of CVD. The effect of these polymorphisms on the dyslipidemia component of the syndrome is also analyzed. A secondary goal of the study is to confirm the high prevalence of the –482 and –455 APOC3 promoter polymorphisms in native Asian-Indians as it has been the case in a population of migrant Asian-Indian (25).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
A total of 110 patients with diabetes and 70 control subjects from the Chennai Urban Population Study (CUPS), described elsewhere (29), were screened for the presence of polymorphisms in FABP2 and APOC3. Systemic random sampling of the entire Chennai population was used to select CUPS participants. The ethical committee of the Madras Diabetes Research Foundation (Chennai, India) approved the study. Informed consent was obtained from all the participants. Diagnosis of type 2 diabetes in this population was based on the World Health Organization study group criteria (30). DNA was extracted from blood samples obtained at the Madras Diabetes Research Foundation in Gopalapuram, Chennai, India, using a phenol-chloroform extraction technique. Labeled samples of extracted DNA were sent to the Veterans Affairs Medical Center, Minneapolis, MN, for detection of the presence of the polymorphisms.

Detection of the FABP2 polymorphism was carried out using an amplification and restriction enzyme digestion technique described initially by Baier et al. (3). Amplification of the FABP2 gene was carried using a PCR technique. Primers 5'-ACAGGTTAATATAGTGAAAAG-3' and 5'-TACCCTGAGTTCAGTTCCGTC-3' from exon 2 were used to isolate gene segments containing the FABP2 polymorphism and added to the PCR master mix containing 2.5 mmo/liter MgCl2, 0.2 mmol/liter of each deoxynucleotide triphosphate, 12.5 U of AmpliTaq DNA polymerase, PCR buffer II, and HPLC H2O. Temperature was cycled 32 times [30 cycles at 95 C for 1 min (denaturation), 55 C for 1 min (annealment), and 72 C for 2 min (elongation)]. The PCR product was digested using the HhaI restriction enzyme at 37 C overnight. Electrophoresis of the digested PCR product was carried out on a 3% agarose gel at 120 V for 40 min. The wild-type genotype is cleaved by HhaI into a 99-bp fragment and an 81-bp DNA fragment that migrate separately. The polymorphic genotype lacks the HhaI restriction site and migrates as one 180-bp DNA fragment.

Detection of the –455 and –482 APOC3 promoter polymorphisms was also carried out using an amplification and restriction enzyme digestion technique previously described (12, 31). PCR was used to amplify the APOC3 gene promoter region. Sense and antisense primers 5'-GGCTGTGAGAGCTCAGCCCT-3' and 5'-TCACACTGGAATTTCAGGCC-3' were added to the PCR master mix to isolate the APOC3 promoter region containing both polymorphisms. A 55 PE Biosystems (Applied Biosystems, Norwalk, CT) thermal cycler was used to amplify the gene segment. Temperature was cycled 35 times [33 cycles at 94 C for 1 min (denaturation), 58 C for 1 min (annealment), and 72 C for 1 min (elongation)]. PCR product digestion was carried out using the MspI restriction enzyme for APOC3C –482T polymorphism and using FokI for APOC3 T–455C at 37 C overnight. Electrophoresis of the digested PCR products was undertaken on a 3% agarose gel at 115 V for 60 min. The –482C (wild-type) variant is cleaved by MspI and appears as a single a 143-bp band on agarose gel. The –482T variant is also cleaved by MspI but appears as 159-bp band on electrophoresis. The –455T (wild-type) allele is cleaved by FokI and appears as two distinct bands on gel electrophoresis (133 and 129 bp). The –455C allele lacks the FokI restriction enzyme sequence and migrates as one 196-bp DNA fragment.

Historical, anthropometric, and laboratory data were collected at the Madras Diabetes Research Foundation as part of the previously reported Chennai Urban Population Study (31). Clinical data collected included age, gender, exercise level, body mass index (BMI), waist-to-hip ratio (WHR), systolic blood pressure, diastolic blood pressure, hemoglobin A1c (HbA1c), fasting blood glucose, and fasting lipid profile.

Statistical analysis of the data were undertaken using the Statistical Package for Social Sciences program (version 10.0, SPSS Inc., Chicago, IL). The data were analyzed using a dominant model for both genes. The metabolic syndrome and dyslipidemia were defined using the quantitative and sex-specific criteria described by the NCEP ATP-III (28). Therefore, the presence of any three of the following characteristics defines the metabolic syndrome: waist circumference of 102 cm (40 in.) in men, 88 cm (35 in.) in women; triglycerides at least 150 mg/dl (1.69 mmol/liter); HDL in men less than 40 mg/dl (1.03 mmol/liter), in women less than 50 mg/dl (1.29 mmol/liter); blood pressure at least 130 over at least 85 mm Hg; and fasting glucose at least 110 mg/dl (6.1 mmol/liter). {chi}2 goodness-of-fit was used to verify agreement of the observed genotype frequency with those expected ones (Hardy-Weinberg equilibrium). The statistical significance of possible associations between groups of categorical variables was assessed using Fisher’s exact test on the corresponding 2 x 2 tables. The odds ratio (OR) was calculated as follows: o' = (n11 + 0.5) (n22 + 0.5)/(n12 + 0.5) (n21 + 0.5) (32). Two multiple logistic regressions were performed as follows: the metabolic syndrome or dyslipidemia as dependent variables and age, smoking (categorical), gender (categorical), exercise, and BMI as independent variables.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Demographic and clinical characteristics of the population

The baseline characteristics for the population under study are summarized in Table 1Go. The two groups were of similar age. In the control group, the mean WHR was higher in men than in women. However, no difference in waist circumferences was noted between men and women. More men than women reported exercising regularly in both the control group and the group with diabetes. Smoking was more frequent among men than women in both the control group and the group with diabetes. Controls had lower mean waist circumferences, lower mean WHR, lower HbA1c, lower mean triglyceride concentration, and higher mean HDL concentration than subjects with diabetes. Hypertension and ischemic heart disease were the only two concurrent illnesses found in the control and diabetic groups; they were higher in the diabetic group: 20% vs. 27.3% for hypertension and 7.1% vs. 13.6% for ischemic heart disease. All controls were treated with ß-blockers for hypertension, and only one subject per drug category listed below was treated for ischemic heart disease with a ß-blocker, nitrates, aspirin, or calcium channel blocker. None was on lipid-lowering drugs.


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  		TABLE 1. Descriptive data for the study population

 
A fraction of the diabetic subjects were treated for hypertension (12.7%). They received ß-blockers (2.7%), calcium channel blockers (4.5%), and reserpine (2.7%), and three patients received one of the following drugs: hydrochlorothiazide, {alpha}-methyldopa, and angiotensin I-converting enzyme inhibitor. A fraction of diabetic patients (8.1%) received treatment for ischemic heart disease with a calcium channel blocker, nitrates, or aspirin alone or in combination with each other. Only one patient was on a ß-blocker, and none was on lipid-lowering drugs. Treatment for diabetes was by diet alone (10%), metformin alone (9%), sulfonylurea alone (33.6%), sulfonylurea plus metformin (35.5%), sulfonylurea plus metformin plus insulin (6.4%), or insulin and sulfonylurea (1.8%), and one patient was on insulin alone.

Allelic frequencies for each polymorphism studied

The frequency of at least one polymorphic allele for the two genes studied was 90/170 = 52.9% for FABP2 Thr54, 130/178 = 73.0% for APOC3 –482T, and 142/177 = 80.2% for APOC3 –455C. In controls, all three polymorphisms were in agreement with Hardy-Weinberg equilibrium. Allelic frequencies for the three polymorphisms in each study group are shown in Table 2Go.


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  		TABLE 2. Allelic frequencies for FABP2 Thr54, APOC3 –482T, and APOC3 –455C

 
Metabolic syndrome and FABP2 Thr54 and APOC3 –482T and –455C polymorphisms

The quantitative and sex-specific definitions from NCEP ATP-III (28) were used to identify the five determinants of the metabolic syndrome. Participants were defined as having the metabolic syndrome if they possessed at least three of these five markers (28). The prevalence of the metabolic syndrome was 16.1% in controls and 72.0% in those with diabetes. As seen in Table 3Go in controls, carriers of the FABP2 Thr54 allele were 6.9 [95% confidence interval (CI), 1.10–43.9] times more likely than noncarriers to have the metabolic syndrome [Fisher’s exact test (two-sided) P = 0.031]. The APOC3 –482T or –455C alleles, individually, were not associated with an increased likelihood of having the metabolic syndrome in the control group. In this same group, carriers of at least one polymorphic allele in both FABP2 and APOC3 genes were found to be 12.1 (95% CI = 1.9–77.6) times more likely to have the metabolic syndrome compared with carriers of the wild-type alleles. The differences in OR between FABP2 alone and the combination of FABP2/APOC3 illustrate an interaction between these genes on their association with the metabolic syndrome. Logistic regression analysis showed no confounding effect of age, smoking, gender, exercise, or BMI on the metabolic syndrome.


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  		TABLE 3. OR and 95% CI for the metabolic syndrome in participants carrying the FABP2 Thr-54, APOC3 –482T and APOC3 –455C alleles

 
Participants with diabetes that carried individual or combined polymorphic alleles were not more likely to have the metabolic syndrome (Table 3Go).

Dyslipidemia and FABP2 Thr54 and APOC3 –482T and –455C polymorphisms

The NCEP ATP-III (28) definition for dyslipidemia was used to define the presence or absence of dyslipidemia (serum [triglyceride] ≥ 150 mg/dl or 1.69 mmol/liter and serum [HDL] < 40 mg/dl or 1.03 mmol/liter for men and <50 mg/dl or 1.29 mmol/liter for women). Dyslipidemia was identified in 20.9% of controls and 40.9% of patients with diabetes in this population.

In the control group (Table 4Go), presence of one or more polymorphic FABP2 Thr54 alleles was associated with a significantly higher likelihood of having dyslipidemia [Fisher’s exact test (2-sided) P = 0.021]. The OR for dyslipidemia in carriers of the Thr54 allele was 4.35 (95% CI, 1.2–16.4). Controls carrying the APOC3 C–482T polymorphism were significantly more likely to have dyslipidemia than noncarriers [Fisher’s exact test (two-sided) P = 0.030; OR = 11.10 (95% CI, 0.59–209.6)]. Carriers of the APOC3 T–455C polymorphism were not more likely to have dyslipidemia when compared with carriers of the wild-type allele [Fisher’s exact test (two-sided) P = 0.055]. Dyslipidemia was absent in control subjects that carried two wild-type alleles in APOC3 at positions –455 and –482.


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  		TABLE 4. OR and 95% CI for dyslipidemia in participants carrying the FABP2 Thr-54, APOC3 –482T and APOC3 –455C alleles

 
FABP2 Thr54 carriers who also carried either APOC3 –482T or –455C were analyzed to evaluate the combined effect of the two genes on dyslipidemia. Presence of a polymorphic allele in both genes was associated with a highly significant [Fisher’s exact test (two-sided) P = 0.00073] increased likelihood of having dyslipidemia [OR = 10.03 (95% CI, 2.2–44.9)]. Logistic regression analysis showed no confounding effect of age, smoking, gender, exercise, or BMI on dyslipidemia. Neither FABP2 nor APOC3 polymorphisms were associated with dyslipidemia in the group with diabetes (Table 4Go).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study, for the first time, reports a high prevalence of the APOC3 promoter polymorphisms in a population of native Asian-Indians, supporting a previous observation describing a high prevalence for these polymorphisms in migrant Asian-Indians (14). The frequency of the codon 54 FABP2 polymorphism is similar to that previously reported in a population of Caucasian males with diabetes (6) and a population of Asian-Indian migrants from Guadeloupe (26). The frequency of the polymorphism varies in different ethnic populations (as summarized in Ref. 2). In Caucasian populations in the United States and in Europe, the frequency of the polymorphism is 24–31%. The corresponding numbers for the Pima American Indians, Oji-Cree American Indians, non-Indian Asians, and U.S. blacks are 31, 14, 23–43, and 22%, respectively.

More importantly, the study clearly establishes an association between polymorphisms within the FABP2 and APOC3 genes and presence of the metabolic syndrome in a population of Asian-Indian controls. The results were not affected by age (ANOVA), gender, or family history of diabetes ({chi}2). Our results support an interaction between FABP2 and APOC3 in contributing to the prevalence of the metabolic syndrome in this population. Indeed, participants who carried at least one polymorphic allele in both genes were more likely to have the syndrome than those who carried a polymorphic allele in FABP2 alone. The NCEP ATP-III definition for the metabolic syndrome was chosen because it is designed to identify prediabetic individuals at risk of developing CVD (28, 33). This definition has recently been shown to have good specificity but lacks sensitivity in detecting insulin resistance (34, 35). Nevertheless, individuals with the metabolic syndrome identified using NCEP criteria have a 3-fold higher risk of dying from CVD (33). The dyslipidemia component of the metabolic syndrome was further scrutinized because both in vitro and in vivo studies suggest direct effects for these polymorphisms on triglyceride metabolism. The NCEP ATP-III identifies high triglycerides and low HDL independently as CVD risk markers in its definition of the metabolic syndrome. In this study, these two markers were combined as dyslipidemia. Cluster analysis performed on a South Indian population identified abnormal lipid parameters together with markers of central adiposity as a cardiovascular risk cluster (24). The effect of the FABP2 and APOC3 polymorphisms on this specific cluster (defined using NCEP ATP-III criteria) was tested (data not shown). Only control subjects (without diabetes), who carried at least one polymorphic allele for both genes were at increased risk of having central adiposity and dyslipidemia [Fisher’s exact test (P = 0.019)]. Because Asian-Indians have been reported to exhibit excess cardiovascular risk at BMI and waist circumference considered normal for a Caucasian population (35, 36), Caucasian definitions of central adiposity may not appropriately reflect CVD risk in this population. Several studies have, however, underscored the importance of the metabolic lipoprotein phenotype in CVD development in Asian-Indians (18, 21, 22, 37, 38). Carotid intimal media thickness, a marker of atherosclerosis, is negatively correlated to a high apoA1/apoB ratio but not insulin resistance in South Indians without diabetes (39). The present study implicates both the codon 54 FABP2 and APOC3 promoter variants in the development of atherogenic dyslipidemia in Asian-Indians without overt diabetes, thereby potentially contributing to their high CVD prevalence.

The findings reported are not because of any confounding effects of age, gender, smoking, exercise, family history of diabetes, or BMI. They suggest a gene-gene interaction between FABP2 and APOC3 that results in an increased tendency toward atherogenic dyslipidemia. Indeed, controls carrying a polymorphic allele in both genes were 2.5 times more likely to have dyslipidemia compared with those who carried a polymorphic allele for FABP2 alone. From in vitro and in vivo experiments it is possible to speculate that these polymorphisms result in hypertriglyceridemia through their concerted action of increased chylomicron production and decreased lipolysis/clearance of TRL. The Thr54 polymorphism, in this specific population and environment, may lead to increased triglyceride synthesis by intestinal cells and result in increased chylomicron production. Polymorphisms within the APOC3 promoter, through loss of down-regulation by insulin, may cause overexpression of this apolipoprotein on TRL resulting in decreased lipolysis and delayed clearance of these lipoproteins. Triglyceride-enriched TRL may become cholesterol-enriched through exchanges with HDL via the cholesteryl ester transfer protein. These cholesterol-enriched TRL could promote atherosclerosis as suggested by McNamara et al. (40). Triglyceride enrichment of HDL may in turn change the size and/or promote the catabolism of HDL in a proatherogenic way. It is of interest that APOC3 is located in close proximity to the genes coding for apoA-I, apoA-IV, and apoA-V. An association and linkage between allelic variants within the APOA5 and APOC3 genes has been reported in northern Europeans with familial combined hyperlipidemia (41). Polymorphisms within the APOC3 promoter have also been shown to decrease the transcription of apoA-I, a major constituent of HDL (42). Therefore, genetic heterogeneity within the APOC3 promoter, through its effect on triglyceride and HDL metabolism, may contribute to the development of an atherogenic lipid profile. A polymorphism in the 3' untranslated region of exon 4 in APOC3 has been linked to hypertriglyceridemia in Asian-Indians (26). The findings in this study are consistent with the notion that the propensity toward development of an atherogenic lipid profile is partly inherited and at least oligogenic.

Studies in other populations have failed to show an association between the Thr54 allele and dyslipidemia. Two recent studies have proposed an ethnic-specific FABP2 protein effect on metabolic characteristics determined by variation in the FABP2 promoter region (43, 44). In Pima Indians, specific promoter polymorphisms that were in complete concordance with either the Ala54 allele or the Thr54 allele were shown to variably affect gene transcription (44). The authors of that study hypothesize that observed phenotypic differences between carriers of the Thr54 polymorphism across different ethnic groups may be explained by effects of promoter variants on gene expression and their concordance to the codon 54 polymorphic allele.

Gene-environment interactions may also have a role in accounting for some of the observed differences across populations. Dietary influences on lipid profile for both Thr54 FABP2 (2, 45) and APOC3 (46) promoter variants have been documented. Socioeconomic status in a population of South Indians has recently been reported to influence dyslipidemia (47) and supports the notion of a gene-environment interaction.

In this particular study, patients with diabetes who carried the FABP2 and APOC3 polymorphisms were not more likely than the wild type to have the metabolic syndrome or dyslipidemia. The effect of diabetes itself on lipid metabolism and other components of the syndrome may have contributed to confound the genetic effects. Alternatively, the study may have lacked sufficient power to detect differences in this group. Treatment of diabetes may have also influenced lipid metabolism and could have accounted for differences between controls and patients with diabetes. This finding differs from a previously reported study, which found significant differences between carriers of the Thr54 FABP2 polymorphism and levels of fasting and postprandial triglyceride levels in a population of obese Caucasian males with diabetes (6). The patients with diabetes in the current study were of different ethnic background, had lower glycosylated hemoglobin and lower BMI, and presumably followed a different diet from the population of Caucasian males previously described, which could have accounted for this difference. Finally, ethnic differences in the FABP2 promoter variant could have affected gene expression and accounted for this difference.

The following limitations apply to our study: The retrospective design of the study suggests an association but does not prove causality. It is possible to speculate that the effects of either genotype are not direct but result from linkage disequilibrium with other genes. The sample size was small, and larger studies are needed to confirm this association.

In conclusion, our data suggest that polymorphisms within the FABP2 and APOC3 genes seem to be associated with the metabolic syndrome and dyslipidemia, factors that have been associated with increased risk of CVD in other studies (18, 21, 22, 33, 37, 38). It is therefore possible that they may contribute to the high CVD prevalence in this South Indian population. Additional studies are needed to assess this possibility.


   Footnotes
 
This work was supported by a Minnesota Medical Foundation Account.

First Published Online December 14, 2004

1 J.-M.G. and A.G. contributed equally to the work. Back

Abbreviations: Apo, Apolipoprotein; APOC3, apolipoprotein C-III; BMI, body mass index; CI, confidence interval; CVD, cardiovascular disease; FABP2, fatty acid-binding protein 2; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; NCEP ATP-III, National Cholesterol Education Program Adult Treatment Panel III; OR, odds ratio; TRL, triglyceride-rich lipoprotein; WHR, waist-to-hip ratio.

Received July 9, 2004.

Accepted December 7, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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