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Letters to the Editor |
1 Service de Pédiatrie Générale & Laboratoire de Biochimie, and
2 Service de Cardiologie, Hôpital Antoine Béclère (AP–HP), Clamart, France
3 INSERM, UMR S 525, Université Pierre et Marie Curie-Paris, Paris, France
4 MONICA Register, Department of Epidemiology and Public Health, Queen’s University, Belfast, Ireland, UK
5 MONICA Register, Strasbourg, France
6 Unité Inserm U535, Hôpital Paul Brousse, Villejuif Cedex, France
aAddress correspondence to this author at: Service de Pédiatrie, Hôpital Antoine Béclère (AP HP), BP 405, 92141 Clamart cedex, France. Fax 33-1-4537-4020; e-mail philippe.labrune{at}abc.aphp.fr
In their recent paper in Clinical Chemistry, Bosma et al. (1) were unable to demonstrate a protective effect of the UGT1A1*28 allele against coronary heart disease (CHD). This was surprising because individuals homozygous for the UGT1A1*28 allele have higher serum bilirubin than do heterozygous or homozygous wild-type individuals and serum bilirubin concentration is inversely related to risk of CHD(2)(3).
We studied UGT1A1 bilirubin uridine diphosphate glucuronosyl transferase genotypes in the ECTIM case-control study of myocardial infarction (MI) (4). The study was conducted on a predefined subsample of the ECTIM Study population. DNA was available for 366 male cases and 314 male controls [from Strasbourg and Toulouse: 181 cases with mean (SD) age 53.7 (8.0) years and 159 controls, with mean (SD) age 52.7 (8.7) years; from Northern Ireland: 185 cases with mean (SD) age 54.8 (8.0), and 155 controls, with mean (SD) age 54.6 (7.8)]. The UGT1A1 genotype was determined for all samples. Body mass index, presence of diabetes mellitus, systolic blood pressure, LDL-cholesterol, and HDL-cholesterol were similar in the total ECTIM case population and the 366 cases selected for this study (data not shown). Serum bilirubin concentrations were not available.
Genomic DNA was extracted from peripheral leukocytes and TATA-box genotyping was performed as described (1).
Odds ratios for MI for the genotypes 6/7 and 7/7 were computed by logistic regression analysis, with the genotype 6/6 as the referent category. The overall UGT1A1*28 effect was tested assuming an additive effect of alleles by entering the genotypes coded as a continuous 0,1,2 variable in the model. A 2nd model was adjusted for country and for established cardiovascular risk factors (smoking habits, body mass index, LDL-cholesterol, HDL-cholesterol, diabetes mellitus, systolic blood pressure). All analyses were done with Stata 8.0 for Windows.
Because there was no significant heterogeneity between Northern Ireland and France with respect to the association between UGT1A1*28 allele and MI (P = 0.48 for interaction), data from the 2 countries were pooled for further analysis. UGT1A1 promoter genotype frequencies are presented in Table 1
. There was no significant deviation from Hardy–Weinberg equilibrium in controls (P = 0.33, 
2 test with 1 degree of freedom). Compared with genotype 6/6, the risks of MI were 1.4 (95% confidence interval, 1.0–2.0) for genotype 6/7 and 1.9 (1.1–3.4) for genotype 7/7, P for trend = 0.005. After adjustment for the risk factors above, the risk estimates were 1.5 (1.0–2.1) and 1.8 (0.9–3.5) for genotypes 6/7 and 7/7 respectively, P for trend = 0.017.
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On the basis of its frequency and its effect on serum bilirubin concentration, the UGT1A1*28 allele was considered a possible protective factor against CHD. Indeed, this allele encodes an enzyme with reduced activity and thus is associated with increased serum bilirubin concentration [although Bosma et al. (5) have demonstrated that genotype 7/7 is necessary but not sufficient to express the Gilbert phenotype with increased bilirubin]. Our results do not support the hypothesis that the UGTA1*28 allele is protective. We even observed an opposite result, because homozygous and heterozygous carriers of this allele appear to have an increased risk of MI. Moreover, serum bilirubin concentration depends not only on its degradation rate (catalyzed by UGT1A1), but also on its production rate. In connection with this, heme-oxygenase, the rate-limiting enzyme involved in bilirubin production(2), may also play an important role. It has been shown that a decreased activity of heme-oxygenase is associated with an increased risk of CHD in patients with coronary risks(6). It is also worth noting that heme-oxygenase induces the production of nitric oxide, a powerful and active vasodilator, likely to protect against atherosclerosis. Finally, as previously observed in other studies, it is possible that the lower serum bilirubin concentrations observed in patients with CHD simply reflect increased consumption of natural antioxidants as a result of increased oxidative capacity(7).
Our results on UGTA1*28 are in agreement with those of Bosma et al. (1). This does not rule out the potential protective role of bilirubin, but it means that other factors that result in mild hyperbilirubinemia, such as heme-oxygenase, may play important roles. Further studies should include measurements of serum bilirubin concentrations and liver functions tests to avoid confusing the results, as shown very recently by Ioannou et al.(8).
References
The following articles in journals at HighWire Press have cited this article:
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  B. Rantner, B. Kollerits, M. Anderwald-Stadler, P. Klein-Weigel, I. Gruber, A. Gehringer, M. Haak, M. Schnapka-Kopf, G. Fraedrich, and F. Kronenberg Association between the UGT1A1 TA-Repeat Polymorphism and Bilirubin Concentration in Patients with Intermittent Claudication: Results from the CAVASIC Study Clin. Chem., May 1, 2008; 54(5): 851 - 857. [Abstract] [Full Text] [PDF]
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