:

-

Eskdale J, Keijsers V, Huizinga T, Gallagher G. Microsatellite alleles and single nucleotide polymorphisms (SNP) combine to form four major haplotype families at the human interleukin-

(IL-

) locus. Genes Immunity

;

:

-

Cataldo F, Lio D, Marino V, Scola L, Crivello A, Mulè AM, Corazza Cytokine genotyping (TNF and Il-

) in patients with celiac disease and selective I

deficiency. A

Gastroenterology(in press).

Wilson AG, di Giovine FS, Blakemore AI, Duff GW. Single base polymorphism in the human tumour necrosis factor alpha (TNF alpha) gene detectable by Nc

restriction of PCR product. Hu

o

enet

;

:

Westendorp RG, Langermans JA, Huizinga TW, Verweij CL, Sturk A. Genetic influence on cytokine production and fatal meningococcal disease. Lancet

;

:

-

Finally, we would like to stress that our study has a number of possible limitations. Since this study was performed with Italian centenarians, we do not know whether the results can be extended to populations of other ethnic origins. Notably, in a Finnish population, IL-10 and TNF-a promoter allele and haplotype frequencies were not different between nonagenar- ians and controls.47 Moreover, no significant association between polymorphisms of some cytokines and longevity has been found in the Sardinian population.48 On the whole, these findings suggest that cytokine/longevity associations might have a population specific component, being affected by the population specific gene pool as well as by gene-environment interaction. Another limitation of the study was the lack of data regarding plasma levels of IL-10 and TNF-a , but the functional relevance of the polymorphisms studied is well known (see above). Besides, it may be argued that a Bonferroni type adjustment should be performed to correct for the testing of multiple polymorphisms. If this correction is carried out, none of the polymorphisms would have been sig- nificantly associated. However, this correction is too stringent and has the potential to ignore important observations49 and, in any case, for studies on centenarians the number of cases is very hard to increase.

However, inflammatory markers predict disability and mor- tality in elderly cohorts and a persistent inflammatory state has been proposed to be involved in the causal pathway of cer- tain age related chronic conditions.1 3 50 Thus, it is intriguing that the possession of an “anti-inflammatory” genotype is significantly increased in male centenarians.

ACKNOWLEDGEMENTS

The “Gruppo di Studio sull’immunosenescenza” coordinated by Professor C Caruso is funded by grants from the Italian Ministry of Education,UniversityandResearch(MIUR)(ex40%,toCCandDL;ex 60% to CC, DL, GC, and GCR) and from the Italian Ministry of Health Projects “Immunological parameters age-related” and “Pharmacog- enomicsofAlzheimer’sdisease”.Thecollaborationbetweenthisgroup and the Istituto Nazionale di Riposo e Cura per Anziani was enhanced by a cooperation contract (Longevity and elderly disability biological markers) and by the EU thematic network programme ImAginE

characterisation of the distal flanking region of the human interleukin-

gene. Gene

mmunity

;

:

-

Crawley E, Kay R, Sillibourne J, Patel P, Hutchinson I, Woo P. Polymorphic haplotypes of the interleukin-

¢ flanking region determine variable interleukin-

transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis. Arthriti

heum

;

:

-

Turner D, Williams DM, Sankaran D, Lazarus M, Sinnott PJ, Hutchinson IV. An investigation of polymorphism in the interleukin-

promoter. Eu

Immunogenet

;

:

-

Eskdale J, Gallagher G, Verweij CL, Keijsers V, Westendorp RGJ, Huizinga TWJ. Interleukin

secretion in relation to human IL-

locus haplotypes. Pro

at

ca

c

SA

;

:

-

D’Alfonso S, Rampi M, Rolando V, Giordano M, Momigliano-Richiardi P. New polymorphisms in the IL-

promoter region. Gene

mmunity

;

:

-

Price P, Witt C, Allcock R, Sayer D, Garlepp M, Kok CC, French M, Mallal S, Christiansen F. The genetic basis for the association of the

ancestral haplotype (A

, B

, DR

) with multiple immunopathological diseases. Immuno

ev

;

:

-

Hajeer AH, Hutchinson IV. Influence of TNFalpha gene polymorphisms on TNFalpha production and disease. Hu

mmunol

;

:

-

D’Alfonso S, Rampi M, Bocchio D, Colombo G, Scorza-Smeraldi R, Momigliano-Richardi P. Systemic lupus erythematosus candidate genes in the Italian population: evidence for a significant association with interleukin-

Arthriti

heum

;

:

-

Helminen M, Lahdenpohja N, Hurme M. Polymorphism of the interleukin-

gene is associated with susceptibility to Epstein-Barr virus infection. JInfec

is

;

:

-

Wu MS, Huang SP, Chang YT, Shun CT, Chang MC, Lin MT, Wang HP, Lin JT. Tumor necrosis factor-alpha and interleukin-

promoter polymorphisms in Epstein-Barr virus-associated gastric carcinoma. JInfect Dis

;

:

-

Howell WM, Turner SJ, Bateman AC, Theaker JM. IL-

promoter polymorphisms influence tumour development in cutaneous malignant melanoma. Gene

mmunity

;

:

-

Hajeer AH, Lazarus M, Turner D, Mageed RA, Vencovsky J, Sinnott P, Hutchinson IV, Ollier WE. IL-

gene promoter polymorphisms in rheumatoid arthritis. Scan

Rheumatol

;

:

-

Tagore A, Gonsalkorale WM, Pravica V, Hajeer AH, M

ahon R, Whorwell PJ, Sinnott PJ, Hutchinson IV. Interleukin-

(IL-

) genotypes in inflammatory bowel disease. Tissu

ntigens

;

:

-

Huizinga TW, Keijsers V, Yanni G, Hall M, Ramage W, Lanchbury J, Pitzalis C, Drossaers-Bakker WK, Westendorp RG, Breedveld FC, Panayi G, Verweij CL. Are differences in interleukin

production associated with joint damage? Rheumatology

;

:

-

Girndt M, Kaul H, Sester U, Ulrich C, Sester M, Georg T, Kohler H. Anti-inflammatory interleukin-

genotype protects dialysis patients from cardiovascular events. Kidne

nt

;

:

-