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Letters to the Editor |
2 Population Health Research Institute, Hamilton ON, Canada
3 McMaster University, Hamilton ON, Canada
4 Hamilton Health Sciences, Hamilton ON, Canada
5 Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, London, ON, Canada
6 Department of Medicine, University of Western Ontario, London, ON, Canada
7 Department of Nutritional Sciences, University of Toronto, Toronto ON, Canada
aAddress correspondence and reprint requests to this author at:, Population Health Research Institute, 4th floor, East Wing, Hamilton General Hospital, 237 Barton Street East, Hamilton, ON L8L 2X2, Canada, Fax 905-577-1490, E-mail anands{at}mcmaster.ca
To the Editor:
Fasting triglyceride concentrations and insulin resistance vary substantially according to patient ethnic origin(1)(2), but the role of genetic variants in these differences is not known. The fatty acid binding protein 2, intestinal (FABP2) gene encodes the intestinal fatty acid binding protein, which is involved in intestinal fatty acid uptake. Carriers of the T54 variant (c.163G>A;p.A54T) of FABP2 produce a modified, functional intestinal fatty acid binding protein that has high affinity for fatty acids. Thus carriers have higher triglyceride concentrations and insulin resistance than noncarriers(3). However, many of the studies in which this association was observed did not account for variations in health behaviors (e.g., physical activity and diet) and adiposity, which may also affect triglyceride concentrations and insulin resistance. Also, among individuals who consume a high-fat diet, T54 carriers may have higher lipids than noncarriers(4). We investigated the association of the FABP2 T54 variant with fasting triglyceride concentrations and insulin resistance in a multiethnic population, and by controlling for ethnicity, health behaviors, and adiposity we specifically focused on the explanatory power of this genetic variable. We also tested for interactions of the T54 variant with dietary variables.
Study participants were selected by stratified random sampling from 3 urban centers in Canada. The study population included a total of 972 persons of 3 ethnic origins, South Asian (n = 337), Chinese (n = 313), and European (n = 322).1 The mean (SD) age of this population was 49.6 (9.9) years; 51.5% were women (n = 501); 9.8% (n = 95) had confirmed type 2 diabetes; and 5.6% (n = 54) reported having had a cardiovascular disease episode (heart attack, stroke, or angina). Participants completed questionnaires on medical history, tobacco use, alcohol intake, physical activity, and diet. Study participants underwent an oral glucose tolerance test with a 75-g glucose load and provided blood samples for the analysis of fasting (8 h) triglycerides, glucose, and insulin. We used restriction isotyping to genotype all participants for the FABP2 T54 variant and the homeostasis model assessment for insulin resistance (HOMA-IR)(5). Multiple linear regression was used to measure the association of the T54 variant with triglycerides and insulin resistance after adjusting for age, sex, ethnicity, health behaviors (tobacco use, alcohol intake, physical activity, total fat intake, trans fat intake, protein intake, fiber intake, and total energy), and adiposity (body mass index and waist-to-hip ratio).
The T54 variant was present in 51.0% of all participants, and these individuals had significantly higher mean triglyceride concentrations than noncarriers (1.50 vs 1.42 mmol/L; P < 0.02). More T54 carriers than noncarriers were insulin resistant, although this difference was not statistically significant (HOMA-IR = 3.84 vs 3.41, P = 0.06). After adjustment for age, sex, and ethnicity, the T54 variant was not a significant determinant of triglyceride concentration or insulin resistance (Table 1
); however, after adjustment for health behaviors and adiposity measurements, the T54 variant was significantly associated with triglyceride concentrations. This association did not differ significantly in study participants who were healthy compared with those who were undergoing treatment for high lipids or diabetes. The percentage variance in triglyceride concentrations that was attributable to the T54 variant was small (0.5%) compared to the percentage variances attributable to ethnicity (1.7%), health behaviors (4.9%), and adiposity (12.6%). After multivariate adjustment of the data, we found that the T54 variant was not significantly associated with insulin resistance. We observed no significant interactions between the T54 variant and dietary factors.
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T54 prevalence, mean triglyceride concentrations, and insulin resistance were significantly higher in South Asians (60.2%, triglycerides = 1.58 mmol/L, HOMA-IR = 4.60) compared to Europeans (48.4%, triglycerides = 1.40 mmol/L, HOMA-IR = 3.08), and Chinese (43.8%, triglycerides = 1.39 mmol/L, HOMA-IR = 3.15). These differences were highly significant (overall P < 0.01; contrast P < 0.01), except for the difference between Europeans and Chinese (P > 0.29). Among South Asians, T54 carriers had significantly higher triglyceride concentrations than noncarriers (1.62 vs 1.52 mmol/L, P = 0.04) and tended to have higher insulin resistance (HOMA-IR = 4.85 vs 4.23, P = 0.18). Among Europeans, T54 carriers had higher triglyceride concentrations and insulin resistance than noncarriers, but the differences were not significant (1.43 vs 1.37 mmol/L, P = 0.31; HOMA-IR = 3.27 vs 2.91, P = 0.28). We did not observe this pattern in Chinese participants (1.39 vs 1.39 mmol/L, P = 0.38; HOMA-IR = 3.00 vs 3.27, P = 0.96). Adjustment for health behaviors and adiposity did not alter these associations.
Our investigation of a Canadian multiethnic population demonstrated that FABP2 T54 carriers had significantly higher triglyceride concentrations than noncarriers. Triglyceride concentrations were affected less by the T54 variant than by ethnicity, health behaviors, and adiposity. We found no evidence that the T54 variant was associated with insulin resistance or dietary interactions. Although ethnicity is probably associated with several factors that affect triglyceride concentrations (e.g., FABP2 T54, health behaviors, and adiposity), adjustment of our data for ethnicity alone was insufficient to control for confounding by these factors. Despite a higher prevalence of the T54 variant in individuals of South Asian origin, the T54 variant accounted for little variation in the high triglyceride concentrations and insulin resistance found in this ethnic group.
Acknowledgments
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.
Authors’ Disclosures of Potential Conflicts of Interest: Upon submission, all authors completed the Disclosures of Potential Conflict of Interest form. Potential conflicts of interest:
Employment or Leadership: None declared.
Consultant or Advisory Role: Robert A Hegele, Merck Schering, Pfizer, and Oryx.
Stock Ownership: None declared.
Honoraria: None declared.
Research Funding: This study (the Study of Health Assessment and Risk in Ethnic Groups) was supported by grants from the Medical Research Council of Canada and Merk Frosst. Genotyping was supported by the Canadian Institutes of Health Research (MOP-79533) and by Genome Canada through the Ontario Genomics Institute. L. de Koning is a recipient of a Canadian Institutes of Health Research Canada Graduate Scholarship Doctoral Award. A. Merchant is a recipient of the Hamilton Health Sciences Hirsh Research Career Award. S. Anand is a recipient of a Canadian Institutes of Health Research Clinician-Scientist Phase 2 Award. R. Hegele holds the Jacob Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Canada.
Expert Testimony: None declared.
Other: All participants in this study provided written informed consent. The study was approved by the ethics committees of McMaster University, the University of Toronto and the University of Alberta. Ethics approval for DNA analysis was obtained from the University of Western Ontario Institutional Review Board. R. Hegele has spoken on the genetic determinants of dyslipidemia and received payment from those funding the events (Merck Schering, Pfizer, and Oryx) in amounts less than $10 000.
Role of Sponsor: The funding organizations played no role in the design of study, choice of enrolled patients, review and interpretation of data, or preparation or approval of manuscript.
Acknowledgments: L. de Koning conducted the analysis, interpreted the data, and wrote the manuscript. A. Merchant contributed to the interpretation of the data and editing of the manuscript. R. Hegele performed DNA extraction and genotyping, and contributed to editing of the manuscript. C. Xie contributed to interpretation of the data. S. Yusuf contributed to the design and execution of the study, interpretation of the data, and editing of the manuscript. S. Anand contributed to the design and execution of the study, interpretation of the data, and editing of the manuscript. We thank S. Islam for database management and K. Stewart for administrative support.
Footnotes
1 The study population was sampled from 3 urban centers (Toronto, Hamilton, and Edmonton, Canada) from lists of South Asian and Chinese last names that were created manually, and merged with a software compilation of public telephone directories. From these lists, a household was randomly selected and mailed an introductory letter, followed by up to 12 telephone calls inviting the individual with the earliest date of birth from the household to participate in the study. Once a clinic visit was confirmed, the participant’s postal code was entered into a list. Individuals sharing the same postal code were presumed to be of European origin and were approached in the same manner. Ethnicity was confirmed in the clinic if both parents and grandparents shared the same ethnicity. 
References
The following articles in journals at HighWire Press have cited this article:
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  M. B. Lanktree, R. A. Hegele, S. Yusuf, and S. S. Anand Multi-Ethnic Genetic Association Study of Carotid Intima-Media Thickness Using a Targeted Cardiovascular SNP Microarray Stroke, October 1, 2009; 40(10): 3173 - 3179. [Abstract] [Full Text] [PDF]
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