Discussion

Although reports have been contradictory, several studies have suggested an association between PON1 polymorphisms and susceptibility to cardiovascular disease. As cardiovascular disease is one of the leading causes of death in middle-aged and elderly people, an impact of such polymorphisms on mortality could be expected. In this study, we investigated the relation of three PON1 polymorphisms, 107C/T, 55M/L and 192Q/R, with survival in a large sample of Danish individuals aged 47-93 years, using both a cross-sectional and a longitudinal study design. The cross-sectional study revealed no difference in genotype distribution in neither men nor women for either of the polymorphisms when comparing different age groups, nor was there any change in haplotype distribution. As our data indicate an effect on the mortality pattern of RR homozygotes in women, this implies that PON1 192RR homozygosity, rather than being a susceptibility factor for CHD, is associated with CHD severity and survival after CHD. If PON1 192RR homozygosity is associated with higher mortality immediately after myocardial infarction, the association with CHD in case-control studies will be weaker than the association with survival. In support of this hypothesis, Chen et al20 recently reported an association between the PON1 192R allele and coronary artery disease severity in white women when evaluating disease severity in terms of the number of diseased vessels.

Contrary to our findings, Heijmans et al10 found no significant effect of the Q192R and M55L polymorphisms on either cardiovascular or all-cause mortality risks in 666 subjects aged 85+. This apparent discrepancy may be caused by the fact that our study population has a much larger age range (47-93 years), as well as the larger sample size in our study, which may be necessary to detect a moderately increased mortality risk as the one reported in the present study.

We furthermore observed a significantly decreased mortality risk in 55M/L heterozygotes compared to 55MM homozygotes in women. The finding of a decreased risk for heterozygotes only is not compatible with either a recessive or a dominant effect of the 55L allele. Furthermore, this result was not replicated in the second sample. As we find some degree of pairwise allelic association among all three polymorphisms (D0.23-0.42), these deviating results for PON55 may merely reflect the partial linkage disequilibrium with PON192.

In conclusion, we found no substantial impact of PON1 polymorphisms or haplotypes on longevity when comparing elderly Danish subjects to younger individuals in neither men nor women. However, the follow-up analysis suggested that, in particular, women homozygous for PON1 192RR may have an increased mortality risk in the second half of life.

Acknowledgements

We thank Shuxia Li for technical assistance. This work was supported by research grants from the National Institute on Aging (Grant NIA-PO1-AG08761), the Danish Medical Research Council and the GENOMEUTWIN Project (European Union Contract No. QLG2-CT-2002-01254).

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