x = age group; y = PTPN22 genotype (PTPN22 C*/C* PTPN22*T carriers); z = sex

significant differences were reported (Table 3). We also carried out a comparison between the genotype frequencies of octogenarians-nona/centenarians and the pooled geno- type frequency of younger individuals; no significant result was found (octogenarians, O.R. for T* carriers = 1.037, 95% CI 0.693–1.551, P = 0.862; nona/centenarians, O.R. for T* carriers = 1.253, 95% CI 0.800–2.014, P = 0.351), further confirming the results obtained from our study population. Of note, this comparison had sufficient power (0.80) to detect an association with a genotypic relative risk (or odds ratio) B0.80 and/or C1.2, thus excluding a marginal effect of PTPN22 1858C[T SNP on human longevity.

Discussion

Ageing is characterized by a pro-inflammatory status, which could contribute to the onset of major age-related diseases. Indeed, genetic variations in pro- or anti-inflam- matory cytokines were found to influence successful ageing and longevity [24]. These polymorphisms might confer flexibility in the immune response by allowing differential production of cytokines. Cytokine gene polymorphisms have been shown to be involved in the susceptibility,

To further support our results, allele and genotype fre- quencies of younger group were compared with those reported in previously published studied carried out on control individuals with Italic ancestry (age \ 70 years), comprising the re-analysis of our previous data [23]. No

Table 1 Distribution of PTPN22 1858C[T (R620W) SNP in the population studied

Sex Age group PTPN22 1858C[T genotype Total HWEa OR (95% CI)b Pc C*/C* Carriers of T* Females Nona/centenarians (mean age: 93.3 ± 2.9) 119 (88.1%) 16 (11.9%) 135 v2 = 0.54, P = 0.462 1.08 (0.53–2.24) Octogenarians (mean age: 84.1 ± 2.8) 189 (90.4%) 20 (9.6%) 209 v2 = 0.53, P = 0.466 0.85 (0.43–1.69) Young (mean age: 48.4 ± 15.5) 129 (89.0%) 16 (11.0%) 145 v2 = 0.57, P = 0.450 Total 437 (89.4%) 52 (10.6%) 489 v2 = 0.15, P = 0.698 Males Nona/centenarians (mean age: 92.7 ± 2.9) 84 (93.3%) 6 (6.7%) 90 v2 = 0.11, P = 0.740 0.79 (0.29–2.15) Octogenarians (mean age: 83.6 ± 2.5) 168 (93.3%) 12 (6.7%) 180 v2 = 0.21, P = 0.647 0.79 (0.35–1.82) Young (mean age: 53.1 ± 14.4) 122 (91.7%) 11 (8.3) 133 v2 = 0.25, P = 0.617 Total 374 (92.8%) 29 (7.2%) 403 v2 = 0.56, P = 0.452

b Odds ratios expressed as carriers of PTPN22*T versus non-carriers considering young group as control group c Fisher’s exact test of odds ratios

Table 3 Allele and genotype frequencies of PTPN22 1858C[T (R620W) SNP observed in this study, compared to those reported in other control Italic populations

Study N M/F Allele frequency Genotype frequency P a P b HWEc 1 2 C* T* C*/C* C*/T* T*/T* Present study 278 133/145 528 (95.0%) 28 (5.0%) 251 (90.3%) 26 (9.4%) 1 (0.3%) – – v2 = 0.14, P = [34] 232 163/69 449 (96.8%) 15 (3.2%) 218 (94.0%) 13 (5.6%) 1 (0.4%) 0.163 0.282 v2 = 2.53, P = [35] 256 150/106 491 (96.0%) 21 (4.0%) 235 (91.8%) 21 (8.2%) 0 (0.0%) 0.469 0.563 v2 = 0.47, P = [36] 545 278/267 1039 (95.4%) 51 (4.6%) 496 (91.1%) 47 (8.6%) 2 (0.4%) 0.808 0.942 v2 = 0.6, P = [23] 360 245/115 679 (94.3%) 41 (5.7%) 338 (93.9%) 21 (5.8%) 1 (0.3%) 0.620 0.236 v2 = 1.16, P = Total 1671 969/702 3186 (95.3%) 156 (4.7%) 1538 (92.0%) 128 (7.7%) 5 (0.3%) – – v2 = 1.77, P =

a P-value of Fisher’s exact test between allelic frequencies b P-value of v2 test between genotypic frequencies c Hardy–Weinberg equilibrium

anti-inflammatory molecules not allow the induction of biological damage able to reduce the life span expectancy

severity and clinical outcome of several diseases [25]. In particular ‘high producer’ alleles of pro-inflammatory cytokines have been associated with inflammatory age- related diseases [26] and disability [27], and with a decreased probability to reach extreme longevity [28]. Consequently, it can be hypothesized that anti-inflamma- tory cytokines might be involved in successful ageing and longevity. As the PTPN22 gene product LYP is an impor- tant down-regulator of T lymphocyte activation and PTPN22-knockout mice showed selective dysregulation in the effector/memory T-cell compartment, with hyper-pro- liferation and early signaling responses in re-stimulated T cells [29], we wanted to test whether the PTPN22 1858C[T (R620W) polymorphism was associated with longevity.

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