The genotype and allele distribution conformed to Hardy-Weinberg equilibrium for all markers in both the control and octogenarian samples. We evaluated differences in genotype and allele distribution between octogenarians and controls, considering all subjects, gender between groups, and gender within each group (Table 1). No statistical differences were observed for single-marker genotype association modeled as dominant (common allele homozygotes and heterozygotes versus rare allele homozygotes), recessive (rare allele homozygotes versus common allele homozygotes and heterozygotes), and codominant (cross-genotype comparison). Allele distribution did not differ in any comparison performed (Table 1). The linkage disequilibrium pattern in the control sample was in accordance with available data for Caucasian populations (Fang et al. 2005), and block structure (D0 [0.8) was observed for markers rs11568820-rs4516035 (block-1, Figure 1b) and markers rs1544410-rs17878969 (block-2, Figure 1b). Exon-2 polymorphism (rs10735810) did not show any significantGenotype failure: 0 (0), 0 (0), 0 (0), 1 (1.0), 0 (0), 1 (1.4), rs17878969 (PolyA). LL: 43 (39.8), 10 (28.6), 33 (45.2), 36 (35.3), 11 (34.4), 25 (35.7). LS: 48 (44.5), 17 (48.6), 31 (42.5), 44 (43.1), 12 (37.5), 32 (45.7). SS: 17 (15.7), 8 (22.8), 9 (12.3), 22 (21.6), 9 (28.1), 13 (18.6). L: 134 (62), 37 (52.9), 37 (52.9), 116 (56.9), 34 (53.1), 82 (58.6). S: 82 (38), 33 (47.1), 33(47.1),88(43.1) ,30(46.9) ,58(41.4) . Genotype failure:2(1.8) ,0(0) ,2(2.7) ,2(1.9) ,0(0) ,2(2,8). Global genotype failure:10(1,8) ,0(0) ,10(2,6) ,26(5,0) ,9(5,6) ,17(4,7). Number of subjects with missing genotypes prevalence(all subjects)>60%,50%,40%,30%,20%,10%. PHASE PAC-likelihood P=0,01 GLAS ALHaplotypes at 3' region. GS prevalence (males). PHASE PAC-likelihood P=0.017. 0%,60%,50%,40%,30%,20%,10%,0%. GL AS AL 6sHaplotypes at 3' region. Prevalence (males). PHASE PAC-likelihood P=0.017. 0%,60%,50%,40%,30%,20%,10%,0%. GL AS AL 6sHaplotypes at 3' region implemented in PHASE 2.1.1 (Li and Stephens, 2003). Haplotype-specific tests were performed by a 2x2 contingency table analysis. An experiment-wide significance threshold of P = 0.036 was required to keep the Type I error rate at 5%. Fig. 2: 30UTR haplotype prevalence in controls (CTR) and octogenarians (OCT). Histogram plots of the 30UTR haplotype prevalence in all subjects (a) and in males (b). Bars indicate the 95% confidence interval of the proportion. Global distribution of haplotypes was compared by the PAC-likelihood test and was mainly due to males (0.07% in controls versus 9.5% in octogenarians, OR out of range; P = 0.014; Fig. 3b). The distribution of carriers of at least one copy of GGCGS haplotype (0.5% in controls and 8.3% in octogenarians, P = 0.023) is presented in Table 2. Males carrying at least one copy of GGCGS haplotype represent just 0.1% in controls but 18.9% in octogenarians (P = 0.012). Haplotype-specific tests revealed that rs1544410-G:rs17878969-S (GS) haplotype was overrepresented in octogenarians (7.3 versus 0.8%; odds ratio (OR): 15.3, 95% confidence interval (CI): 2.3-37; P < 0.001) (Fig. 2a). This difference was greater in males (14.2% in octogenarians versus 0.3% in controls, OR out of range, P = 0.006) (Fig. 2b). We also estimated the haplotype carrier status of each individual. The distribution of carriers of at least one copy of 30UTR GS haplotype is presented in Table 2. Carriers of at least one copy of GS haplotype were common in octogenarians (13.3%) but rare in controls (1.6%) (P = 0.008). Among males, nearly a quarter of the octogenarians carried at least one copy of GS haplotype, whereas GS carriers represent less than 1% of controls (24.4 versus The response caused vitamin D deficiency and toxicity, respectively. However, conferring middle VDR mRNA stability can be considered protective, as vitamin D response can remain in the homeostatic region, which is responsible for its genomic action. Several VDR gene polymorphic variants have been described to affect VDR gene expression (rs11568820 and rs4516035), protein structure (rs10735810), and mRNA stability (rs1544410 and rs17878969) (Fang et al. 2005; Uitterlinden et al. 2004a). Variability at the VDR locus has been associated with cancer, osteoporosis, cardiovascular diseases, and diabetes (Uitterlinden et al. 2004b) as well as mycobacterium (Bellamy and Hill 1998) and viral infections (Fibla and Caruz 2010). Although the effect of VDR variability on aging has been well-studied, its role in aging and longevity has only been evaluated in relation to diseases; no data exist about its role in aging and longevity. In this case-control study, we compared allele, genotype, and haplotype distribution of five VDR gene variants between healthy-living octogenarians and younger controls to assess VDR as a candidate gene affecting aging and longevity. Our study is the first to provide evidence of an association between VDR gene polymorphisms and longevity, as reflected by the differential distribution of VDR haplotypes that we observed. The positive significant association between longevity and the 30UTR GS and five-marker GGCGS haplotypes was observed in octogenarian males but not in women. Epidemiological data on long-lived subjects document a clear-cut prevalence of females compared to males, suggesting that sex-specific mortality rates follow different trajectories. Demographic and behavioral risk factors have been considered in the literature, but do not account for the overall sex-related difference in mortality rates (Wingard 1984). In addition, the role of biological factors has been explored with contentious results (Austad 2006). Our finding of a sex-specific association was in accordance with previous reports that certain polymorphisms of the interleukin (IL)-6, IL-10 and interferon-gamma genes are male-specific markers for longevity (Bonafe et al. 2001; Di Bona et al. 2009; Giacconi et al. 2004; Lio et al. 2002a, b),