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Letters to the Editor |
Glutamyltransferase: Results from the National Health and Examination Survey 1999–2002
1 Department of Preventive Medicine, and, Health Promotion Research Center, School of Medicine, Kyungpook National University, Daegu, Korea
2 Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis, MN
3 Department of Nutrition, University of Oslo, Oslo, Norway
aAddress correspondence to this author at: Department of Preventive Medicine, School of Medicine, Kyungpook University, 101 Dongin-dong, Jung-gu, Daegu, Korea 700–422. Fax 82-53-425-2447; e-mail lee_dh{at}knu.ac.kr.
We recently reported a relationship between serum concentrations of persistent organic pollutants (POPs) and diabetes mellitus in the general population(1). Furthermore, serum 
-glutamyltransferase (GGT) activity, even within its usual reference interval, strongly predicted type 2 diabetes in prospective studies through unclear mechanisms(2). Because exposure to high concentrations of POPs in occupational or accidental settings increased serum GGT(3), serum GGT may predict type 2 diabetes related to exposure to POPs. Thus, in the general population, low concentrations of POPs would be related to normal concentrations of serum GGT, and adjustment for POPs would attenuate the relationship of GGT and diabetes.
This hypothesis was tested in the National Health and Nutrition Examination Survey (NHANES) 1999–2002 public-use dataset in 2016 persons 
20 years of age. Serum concentrations of POPs and GGT activity were measured by highresolution gas chromatography/high-resolution mass spectrometry and by a Hitachi 737 analyzer, respectively. We selected the 6 POPs for which at least 80% of study participants had concentrations greater than the limit of detection, as listed in Table 1
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For each POP, persons with serum concentrations less than the limit of detection were assigned to the reference group, and those with detectable POPs concentrations were divided into categories with cut-points at the 25th, 50th, 75th, and 90th percentiles. To yield a cumulative measure of exposure to POPs, we summed the category ranking of the 5 POPs (SUMPOP5) that were positively associated with serum GGT, thus making a score from 0 to 25, and divided across the 25th, 50th, 75th, and 90th percentiles (omitting PCB153; 0 for nondetectable, 1 for detectable below the 25th percentile, and so on, up to 5 for above the 90th percentile). Adjustment for confounders was performed by general linear models; adjusting variables are provided in Table 1
. The association between serum GGT and prevalence of diabetes(1) was also examined after adjusting for POPs. All statistical analyses were performed with SAS 9.1 (SAS Institute) and SUDAAN 9.0 (Research Triangle Institute).
Serum concentrations of 5 of the POPs were positively associated with serum GGT. The associations were strengthened by additional adjustment for serum alanine aminotransferase (ALT), which was inversely associated with POPs. Adjusted geometric means of serum GGT by categories of SUMPOP5 were 20.5, 22.2, 23.6, 24.8, and 26.1 (P for trend <0.01). In these data, serum GGT was positively associated with the prevalence of diabetes, with the adjusted odds ratios of 1.0, 2.2, 2.1, 2.8, and 3.1 (P for trend <0.01), but further adjustment for POPs did not change the strength of this association.
POPs are known hepatotoxins(4). In humans, hepatic abnormalities, including abnormally increased serum GGT and ALT, have been observed after exposure to high concentrations of POPs(3). In this study, however, exposure to low concentrations of POPs was positively associated with serum GGT activities within the routine reference interval despite an inverse association with serum ALT, contradicting the interpretation of hepatotoxicity as the mechanism linking POPs to GGT. Similar to the current findings, patterns of association of serum antioxidant concentrations and C-reactive protein with serum ALT differed from those with GGT, both within their routine reference intervals(5)(6). Similarly, serum GGT within its routine reference interval was positively associated with low concentrations of blood lead or urinary cadmium in general population(7). As cellular GGT catalyzes the first step in the degradation of extracellular glutathione(8), all these findings suggest that serum GGT within its routine reference interval may be a biomarker reflecting the extent of exposure to environmental xenobiotics, especially biotransformed through conjugation of glutathione. Of further interest, the secular trend of serum GGT showed a strong increase among Koreans independent of changes in health behaviors including obesity(9); Korea is experiencing increasing exposure to various environmental pollutants, including POPs.
Although serum GGT was positively associated with the prevalence of diabetes, this association was not explained by POPs. Despite the generally positive associations between POPs and serum GGT, the associations of specific POPs with diabetes and serum GGT were inconsistent. For example, PCB153 was strongly associated with diabetes, but not with serum GGT. Thus, serum GGT may predict diabetes as a general marker of exposure to various environmental xenobiotics, including diabetes-related POPs and those unrelated to diabetes, such as lead or cadmium.
We recently proposed serum GGT within its routine reference interval as a marker of oxidative stress(8). Serum GGT may also be a marker of the combined exposure to various environmental xenobiotics. This further hypothesis does not contradict our assertion that serum GGT is a marker of oxidative stress because exposure to xenobiotics directly induces oxidative stress(10). Our hypothesis does add another dimension to the interpretation of serum GGT within its routine reference interval.
Acknowledgments
This study is partly funded by the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea. (A050349).
References
-glutamyltransferase and C-reactive protein. Atherosclerosis 2005;178:327-330.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]-glutamyltransferase inversely associated with serum antioxidants as a marker of oxidative stress?. Free Radic Biol Med 2004;37:1018-1023.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve] glutamyltransferase a marker of oxidative stress?. Free Radic Res 2004;38:535-539.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]-glutamyltransferase from 1996 to 2003 among South Korean men. Am J Epidemiol 2006;163:57-65.The following articles in journals at HighWire Press have cited this article:
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  D-H Lee and D R Jacobs Jr Serum {gamma}-glutamyltransferase: new insights about an old enzyme J Epidemiol Community Health, November 1, 2009; 63(11): 884 - 886. [Abstract] [Full Text] [PDF]
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 D. Janicki-Deverts, S. Cohen, K. A. Matthews, M. D. Gross, and D. R. Jacobs Jr Socioeconomic Status, Antioxidant Micronutrients, and Correlates of Oxidative Damage: The Coronary Artery Risk Development in Young Adults (CARDIA) Study Psychosom Med, June 1, 2009; 71(5): 541 - 548. [Abstract] [Full Text] [PDF]
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 A. M. Strasak, K. Rapp, L. J. Brant, W. Hilbe, M. Gregory, W. Oberaigner, E. Ruttmann, H. Concin, G. Diem, K. P. Pfeiffer, et al. Association of {gamma}-Glutamyltransferase and Risk of Cancer Incidence in Men: A Prospective Study Cancer Res., May 15, 2008; 68(10): 3970 - 3977. [Abstract] [Full Text] [PDF]
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 D.-H. Lee, M. D. Gross, M. W. Steffes, and D. R. Jacobs Jr Is Serum Gamma-Glutamyltransferase a Biomarker of Xenobiotics, Which Are Conjugated by Glutathione? Arterioscler Thromb Vasc Biol, April 1, 2008; 28(4): e26 - e28. [Full Text] [PDF]
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 D.-H. Lee, J.-S. Lim, and D. R. Jacobs Jr The authors of the article cited above respond: Clin. Chem., October 1, 2007; 53(10): 1869 - 1870. [Full Text] [PDF]
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J.-S. Lim, D.-H. Lee, J.-Y. Park, S.-H. Jin, and D. R. Jacobs Jr A Strong Interaction between Serum {gamma}-Glutamyltransferase and Obesity on the Risk of Prevalent Type 2 Diabetes: Results from the Third National Health and Nutrition Examination Survey Clin. Chem., June 1, 2007; 53(6): 1092 - 1098. [Abstract] [Full Text] [PDF]
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J. B. Whitfield Serum {gamma}-Glutamyltransferase and Risk of Disease Clin. Chem., January 1, 2007; 53(1): 1 - 2. [Full Text] [PDF]
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