SLORTNO ROp)IC %59( ROp)IC %59( ROslortnoCsesaCllarevOredneGPNS 29.04251.0)58.1–19.0( 03.19561.0)08.1–09.0(72.181.022.02.0M2096849sr 25.03550.0)10.1–54.0( 76.04360.0)20.1–74.0( 96.072.012.032.0F 44.26200.0)30.2–61.1( 35.1300.0)89.1–51.1( 15.134.035.094.0M8822082sr 57.04304.0)12.1–26.0( 78.05793.0)12.1–26.0( 68.05.074.084.0F 65.140.0)14.2–20.1( 75.11.041.021.0M15099401sr 23.04748.0)16.1–65.0( 59.07948.0)06.1–75.0( 59.021.011.021.0F 85.22200.0)01.2–71.1( 75.18200.0)30.2–61.1( 35.114.015.074.0Mb,a2922082sr 08.03561.0)01.1–65.0( 97.02861.0)11.1–365.0( 97.022.081.02.0M01802231sr 21.11744.0)87.1–87.0( 71.12844.0)77.1–87.0( 71.12.032.022.0F 99.17220.0)68.1–50.1( 04.17620.0)18.1–40.1( 73.163.034.04.0Mb4624672sr 30.13556.0)13.1–56.0( 29.05756.0)03.1–66.0( 39.024.04.014.0F 41.22154.0)46.1–08.0( 51.14634.0)76.1–08.0( 61.151.071.071.0M3321437sr 16.30701.0)94.2–29.0( 15.17401.0)84.2–29.0( 15.121.061.041.0F 27.17328.0)05.1–27.0( 40.12718.0)35.1–17.0( 50.151.051.051.0M74789571sr 97.21191.0)34.2–48.0( 34.15281.0)64.2–48.0( 44.11.031.021.0F 67.14501.0)09.1–49.0( 43.14721.0)08.1–39.0( 92.12.042.022.0M7935829sr 17.07360.0)20.1–74.0( 96.09960.0)30.1–94.0( 17.013.042.062.0F 47.19747.0)35.1–47.0( 60.1937.0)65.1–37.0( 70.151.051.051.0M90220221sr 97.21191.0)34.2–48.0( 34.15281.0)64.2–48.0( 44.11.031.021.0F 17.11881.0)08.1–98.0( 72.1602.0)57.1 78.0( 42.191.022.012.0M6680849sr 15.00730.0)79.0–44.0( 56.02140.0)99.0–64.0( 76.092.012.042.0F 27.19287.0)25.1–37.0( 50.11577.0)45.1 27.0( 60.151.051.051.0M86870221sr 77.22991.0)14.2–38.0( 24.15091.0)44.2–48.0( 34.11.031.021.0F 03.29510.0)549.1–70.1( 44.16710.0)09.1–60.1( 24.13.083.053.0Mb,a59771231sr 78.11250.0)87.1–1( 33.18750.0)47.1 99.0( 13.143.014.083.0M0693512sr 38.09792.0)81.1–95.0( 38.09003.0)81.1–95.0( 38.024.083.04.0F 56.12611.0)86.1–49.0( 62.17811.0)76.1 49.0( 52.133.083.063.0M9220083sr 57.00132.0)51.1–75.0( 18.05822.0)41.1–75.0( 18.014.063.083.0F 56.13411.0)86.1–59.0( 62.1811.0)76.1 49.0( 52.133.083.063.0M9495391sr 77.02222.0)41.1–75.0( 18.00022.0)41.1–75.0( 18.014.063.083.0F .sPNS detupmIa .la te xoclliW yb derolpxe sPNSb FAM ;snairanetnec ni ycneuqerf elella ronim ,sesac FAM ;elpmas elohw no desab ycneuqerf elella ronim ,llarevo FAM ;)selamef ,F;selam ,M( sisylana cificeps-redneG ,redneG

SLORTNO CDNASLAUDIVIDN IGNIVI L-GNO LNISUCO LA3OXOF.2ELBA T

15 16Block 3 (11 kb)4BLLIZE LSE898202218)9980868!60zz0zz1 81L6ES8768!2PLB6S2581eeezbeelss~~ orgozzerssT6Z7OBTS!}S066r01S1 20698684 

FIG. 2. Pattern of LD of FOXO3A region displayed using D with HaploView. LD displays were generated using the D  thins)<]   4<1 color scheme. The different shades of gray indicate different D values (0 D 1). Haplotype blocks were generated us- ing the Four Gamete Rule as implemented in HaploView software. Boxed in light gray is rs2802288, boxed in dark gray are the SNPs explored by Willcox et al.

Discussion

ent cellular functions, such as differentiation, metabolism, proliferation, and survival.11,36,37

Research into aging has been rejuvenated by the recent discovery of SNPs in candidate genes that can extend the lifespan of laboratory model organisms. Thus, these poly- morphisms can also delay, ameliorate, or even abolish the impact of many aging-related diseases, including cardiovas- cular disease, neurodegeneration, and cancer. FOXO tran- scription factors have been implicated in regulating differ-

In this respect, in the Leiden Prospective Study the over- all and individual haplotype frequencies were not different between the elderly and young control group for the FOXO3A locus.21 However, possible limitations of the study are in the absence of gender stratification. In fact, due to the profound effect of this pathway on the reproductive/hor- monal system, which differs between males and females, it

TABLE 3. HAPLOTYPE ASSOCIATION TEST OF BLOCK 1 USING HAPLOVIEW

Frequency Frequency Block 1 Gender Frequency for cases for controls p value CGA M 0.51 0.48 0.57 0.003 F 0.51 0.53 0.49 0.3683 TAA M 0.2 0.21 0.17 0.1588 F 0.23 0.21 0.27 0.0634 CAA M 0.17 0.18 0.16 0.4968 F 0.13 0.15 0.11 0.2556 CAG M 0.12 0.14 0.09 0.0381 F 0.12 0.11 0.12 0.8689

    Block 1, haplotypes in block 1, Gender, gender-specific analysis (M males, F females); Frequency, haply- type frequency based on whole sample; Frequency for cases, haplotype frequency in centenarians, Frequency for controls, haplotype frequency in the control population; p-vaule, haplotypic association test p-value.

Homozygous OR and 95% ClCurrent Study 2.68 (1.42-4.70) |Willcox et al 2.75 (1.61-6.02) !Random effects 2.66 (1.74-4.07) ;Fixed effects 2.66 (1.74-4.07) i 0406 08 1 12 14 16 18 2 22 24 26 28 3 32 34 36 38 4 42 44 46 48 5

FIG. 3. Meta-analysis of rs2802292 variant in the current investigation and in Willcox et al. study. Each study is repre- sented by the estimate of the homozygous minor versus homozygous major alleles OR and its 95% CI (circle). Summary effects by random effects (diamond) and fixed effects (rectangle) calculations are also shown.

metric28 value (I2   0%) confirmed the absence of between- study heterogeneity. In absence of heterogeneity between the two datasets, we obtained identical estimates of the ORs and the 95% CIs for homozygous minor versus homozygous ma- jor alleles from both fixed26 and random effects27 models —   (OR 2.66; 95% CI, 1.74–4.07; p 0.0001) (Fig. 3).

is possible that variants that affect genes of this pathway are gender-specific enriched/depleted as the populations age. Hence, variants that influence longevity in males may not affect female longevity and vice versa.