In this study, we investigated the relation of three PON1 polymorphisms, (cid:1)107C/T, 55M/L and 192Q/R, with survi- val in a large sample of Danish individuals aged 47–3 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 in 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,

Heinecke JW, Lusis AJ: Paraoxonase–gene polymorphisms associated with coronary heart disease: support for the oxidative damage hypothesis? Am J Hum Genet

;

:

–

Adkins S, Gan KN, Mody M, La Du BN: Molecular basis for the polymorphic forms of human serum paraoxonase/arylesterase: glutamine or arginine at position

, for the respective A or B allozymes. Am J Hum Genet

;

:

–

Leviev I, James RW: Promoter polymorphisms of human paraoxonase PON

gene and serum paraoxonase activities and concentrations. Arterioscler Thromb Vasc Biol

;

:

–

Mackness B, Mackness MI, Arrol S, Turkie W, Durrington PN: Effect of the human serum paraoxonase

and

genetic polymorphisms on the protection by high density lipoprotein against low density lipoprotein oxidative modification. FEBS Lett

;

:

–

Deakin S, Leviev I, Brulhart-Meynet MC, James RW: Paraoxonase-

promoter haplotypes and serum paraoxonase: a predominant role for polymorphic position (cid:

)

, implicating the Sp

transcription factor. Biochem J

;

(Part

):

–

Wheeler JG, Keavney BD, Watkins PH, Collins PR, Danesh PJ: Four paraoxonase gene polymorphisms in

cases of coronary heart disease and

controls: meta-analysis of

studies. Lancet

;

:

–

Heijmans BT, Westendorp RG, Lagaay AM et al: Common paraoxonase gene variants, mortality risk and fatal cardiovascular events in elderly subjects. Atherosclerosis

;

:

–

Bonafe M, Marchegiani F, Cardelli M et al: Genetic analysis of paraoxonase (PON

) locus reveals an increased frequency of Arg

allele in centenarians. Eur J Hum Genet

;

:

–

Nybo H, Gaist D, Jeune B et al: The Danish

cohort: a genetic–epidemiological nationwide survey. J Aging Health

;

:

–

Christensen K, Gaist D, Vaupel JW, M

ue M: Genetic contribution to rate of change in functional abilities among Danish twins aged

years or more. Am J Epidemiol

;

:

–

Skytthe A, Kyvik K, Holm NV, Vaupel JW, Christensen K: The Danish Twin Registry:

birth cohorts of twins. Twin Res

;

:

–

Gaist D, Bathum L, Skytthe A et al: Strength and anthropometric measures in identical and fraternal twins: no evidence of masculinization of females with male co-twins. Epidemiology

;

:

–

Bathum L, Christiansen L, Nybo H et al: Association of mutations in the hemochromatosis gene with shorter life expectancy. Arch Intern Med

;

:

–

Christiansen L, Bathum L, Andersen-Ranberg K, Jeune B, Christensen K: Modest implication of interleukin

promoter polymorphisms in longevity. Mech Ageing Dev

;

:

–

Sham PC, Curtis D: Monte Carlo tests for associations between disease and alleles at highly polymorphic loci. Ann Hum Genet

;

(Part

):

–

Chakravarti A, Buetow KH, Antonarakis SE et al: Nonuniform recombination within the human beta-globin gene cluster. Am J Hum Genet

;

:

–

Chen Q, Reis SE, Kammerer CM et al: Association between the severity of angiographic coronary artery disease and paraoxonase gene polymorphisms in the National Heart, Lung, and Blood Institute-sponsored Women’s Ischemia Syndrome Evaluation (WISE) study. Am J Hum Genet

;

:

–

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 associa- tion 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 caused mortality risks in 666 subjects age 85þ . 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. Further- more, this result was not replicated in the second sample. As we find some degree of pair-wise allelic association among all three polymorphisms (D¼0.23–0.42), 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 compar- ing 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).

References