susceptibility locus for type

diabetes. Nat Genet

;

:

–

Satoh MS, Lindahl T: Role of poly(ADP-ribose) forma- tion in DNA repair. Nature

;

:

–

The finding that the HUMTHO1 marker is asso- ciated with long life expectancy and that such an effect is sex-related gives rise to two questions. Could a tandem-repeat polymorphic region affect life expec- tancy? Why does such an effect occur in males but not in females? As to the first question, HUMTHO1 lies in intron 1. It was proposed7 that secondary structures of the first intron and between first and second introns could affect THO alternative splicings. We might speculate that the variability of HUMTHO1 may play a role in the efficient production of spliced mRNAs. Indeed recent data has shown that the biological role of VNTR alleles of different size may be different.29,30 On the other hand, since HUMTHO1 and INS-VNTR markers are in linkage-disequilibrium and INS-VNTR allele frequencies show a sex-specific age-related trend,31 it may also be that sex-specific age-related variations of the genotypic pool embrace the entire DNA region comprising both THO and INS loci. In our samples at present, we are analysing further markers occurring in the (11p15.5) DNA region in order to clarify this point. As to the second question, we must consider that the effect of a gene on a multifactorial trait depends on the physiological background in which the gene is expressed. Therefore, if the age-related physiological scenario changes in males and females differently, the effect of a certain gene on survival could vary between the sexes.

In conclusion, the data here reported shows that the genotypic pools at THO locus differ between male centenarians and male controls, the LL homozygous genotypes being very rare in centenarians. Further- more, the specificity of the positive association found at the THO locus is validated by the negative findings at REN, PARP and SOD2 loci.

Acknowledgements

The work was financed by Regione Calabria (Progetto Operativo Plurifondo 94-99) by the Italian Ministry of University and Scientific Research (40% and 60% MURST)

16 Satoh MS, Lindahl T: Role of poly(ADP-ribose) forma- tion in DNA repair. Nature 1992; 356: 356–358.

Gene/Longevity Studies

G De Benedictis et al

Burkle A, Grube K, Kupper JK: Poly(ADP) ribosylation: its role in inducible DNA amplification and its correlation with the longevity of mammalian species. Exp Clin Immunogenet

;

:

–

Grube K, Burkle A: Poly (ADP-ribose) polymerase activity in mononuclear leukocytes of

mammalian species correlates with species specific life span. Proc Natl Acad Sci USA

;

:

–

Burkle A, Muller M, Wolf I, Kupper JH: Poly (ADP- ribose) polimerase activity in intact or permeabilized leukocytes from mammalian species of different longevity. Mol Cell Biochem

;

:

–

Fougerousse F, Meloni R, Roudaut C, Beckmann JS: Dinucleotide repeat polymorphism at the human poly- (ADP-ribose) polymerase gene (PPOL). Nucleic Acids Res

;

:

Weisiger RA, Fridovich I: Mitochondrial superoxide dismutase: site of synthesis and intramitochondrial localiz- ation. J Biol Chem

;

:

–

Rosenblum JS, Gilula NB, Lerner RA: On signal sequence polymorphisms and disease of distribution. Proc Natl Acad Sci USA

;

:

–

Shimoda-Matsubayashi S, Matsumine H, Kobayashi T, Nakagawa-Hattori Y, Shimizu Y, Mizumo Y: Structural dimorphism in the mitochondrial targeting sequence in the human manganese superoxide dismutase gene. Bio- chem Biophys Res Comm

;

:

–

Weir BS: Genetic data analysis II. Sinauer Associates: Sunderland MA,

; pp

–

Sokal RR, Rohlf FJ: Biometry. Freeman WH & Co: New York,

; pp

–

Herskind AM, M

ue M, Holm NV, Sorensen TIA, Harvald B, Vaupel JW: The heritability of human longev- ity: a population based study of

Danish twin pairs born

–

Hum Genet

;

:

–

De Benedictis G, Falcone E, Rose G et al: DNA multiallelic systems reveal gene/longevity associations not detected by diallelic systems. The APOB locus. Hum Genet

;

:

–

Rothman KJ: No adjustments are needed for multiple comparisons. Epidemiology

;

:

–

Bennet ST, Lucassen AM, Gough SCL et al: Susceptibility to human type A diabetes at IDDM

is determined by tandem repeat variation at the insulin gene minisatellite locus. Nat Genet

;

:

–

O’Donovan MC, Craddock N, Guy C: Involvement of expanded trinucleotide repeats in common diseases. Lan- cet,

;

:

–

Tybjaerg-Hansen A, Gerdes LU, Overgaard K, Ingerslev J, Faergeman O, Nerup J: Polymorphism in

' flanking region of human Insulin gene.. Arteriosclerosis

;

:

–