Chronic periodontitis (CP) is a common oral disease that confers substantial systemic inflammatory and microbial burden and is a major cause of tooth loss. Here, we present the results of a genome-wide association study of CP that was carried out in a cohort of 4504 European Americans (EA) participating in the Atherosclerosis Risk in Communities (ARIC) Study (mean age—62 years, moderate CP—43% and severe CP—17%). We detected no genome-wide significant association signals for CP; however, we found suggestive evidence of association (P < 5 × 10−6) for six loci, including NIN, NPY, WNT5A for severe CP and NCR2, EMR1, 10p15 for moderate CP. Three of these loci had concordant effect size and direction in an independent sample of 656 adult EA participants of the Health, Aging, and Body Composition (Health ABC) Study. Meta-analysis pooled estimates were severe CP (n = 958 versus health: n = 1909)—NPY, rs2521634 [G]: odds ratio [OR = 1.49 (95% confidence interval (CI = 1.28–1.73, P = 3.5 × 10−7))]; moderate CP (n = 2293)—NCR2, rs7762544 [G]: OR = 1.40 (95% CI = 1.24–1.59, P = 7.5 × 10−8), EMR1, rs3826782 [A]: OR = 2.01 (95% CI = 1.52–2.65, P = 8.2 × 10−7). Canonical pathway analysis indicated significant enrichment of nervous system signaling, cellular immune response and cytokine signaling pathways. A significant interaction of NUAK1 (rs11112872, interaction P = 2.9 × 10−9) with smoking in ARIC was not replicated in Health ABC, although estimates of heritable variance in severe CP explained by all single nucleotide polymorphisms increased from 18 to 52% with the inclusion of a genome-wide interaction term with smoking. These genome-wide association results provide information on multiple candidate regions and pathways for interrogation in future genetic studies of CP.

Telomere length (TL) is emerging as a biomarker for aging and survival. To evaluate factors influencing this trait, we measured TL in a large homogeneous population, estimated the heritability (h 2 ), and tested for parental effects on TL variation. Our sample included 356 men and 551 women, aged 18 -92 years, from large Amish families. Mean TL in leukocytes was measured by quantitative PCR (mean: 6,198 ؎ 1,696 bp). The h 2 of TL was 0.44 ؎ 0.06 (P < 0.001), after adjusting for age, sex, and TL assay batch. As expected, TL was negatively correlated with age (r ‫؍‬ ؊0.40; P < 0.001). There was no significant difference in TL between men and women, consistent with our previous findings that Amish men lived as long as Amish women. There was a stronger and positive correlation and association between TL in the offspring and paternal TL (r ‫؍‬ 0.46, P < 0.001; ␤ ‫؍‬ 0.22, P ‫؍‬ 0.006) than offspring and maternal TL (r ‫؍‬ 0.18, P ‫؍‬ 0.04; ␤ ‫؍‬ ؊0.02, P ‫؍‬ 0.4). Furthermore, we observed a positive correlation and association between daughter's TL and paternal lifespan (r ‫؍‬ 0.20, P < 0.001; ␤ ‫؍‬ 0.21, P ‫؍‬ 0.04), but not between daughter's TL and maternal lifespan (r ‫؍‬ ؊0.01, ␤ ‫؍‬ 0.04; both P ‫؍‬ not significant). Our data, which are based on one of the largest family studies of human TL, support a link between TL and aging and lifespan and suggest a strong genetic influence, possibly via an imprinting mechanism, on TL regulation.heritability ͉ parental effects ͉ sex specific ͉ imprinting ͉ Amish T elomeres are DNA capping structures that protect the ends of eukaryotic chromosomes. In vitro studies in mammalian cells suggest that telomere shortening triggers cellular senescence or apoptosis, depending on cell type (1-4). Studies in humans have shown that telomeres shorten with aging in various mitotic tissues and cell types (5-7). The rate of telomere attrition is slower in long-lived mammals compared with short-lived ones (8). Senescent cells accumulate with increasing age in vivo (9) and are thought to play an important role in organismal aging (10), which is characterized by physiologic and metabolic decline (4) and increasing susceptibility to several diseases associated with death (11). Thus, it is likely that telomere shortening may be mechanistically linked to organismal lifespan.Factors influencing telomere homeostasis are not fully known; however, it is likely that both environmental and biological factors play roles. Among the biological factors, a growing body of evidence suggests that genes play a very important role. Several genes that influence telomere length (TL) have been identified in model organisms (12, 13). In humans, shelterin, the protein complex that shapes and safeguards telomeres is made up of six subunits: TRF1, TRF2, TIN2, Rap1, TPP1, and POT1 (14). Other genes, such as TERT, UP1, Tankyrase, EST1, EST2, and EST3 are known to influence telomere homeostasis, and other genes such as YKU70, SIR4, and RIF2, encode proteins that bind specifically to the telomeres (13). In humans, the re...

Summary The insulin/IGF1 signaling pathways affect lifespan in several model organisms, including worms, flies and mice. To investigate whether common genetic variation in this pathway influences lifespan in humans, we genotyped 291 common variants in 30 genes encoding proteins in the insulin/IGF1 signaling pathway in a cohort of elderly Caucasian women selected from the Study of Osteoporotic Fractures (SOF), including 293 long-lived cases (lifespan ≥ 92 years (y), mean ± standard deviation (SD) = 95.3 ± 2.2y) and 603 average-lifespan controls (lifespan ≤ 79y, mean=75.7 ± 2.6y). Variants were selected for genotyping using a haplotype tagging approach. We found a modest excess of variants nominally associated with longevity. We then replicated nominally significant variants in two additional Caucasian cohorts containing both males and females: the Cardiovascular Health Study (CHS) and Ashkenazi Jewish Centenarians (AJC). An intronic single nucleotide polymorphism (SNP) in AKT1, rs3803304, was significantly associated with lifespan in a meta-analysis across the three cohorts (odds ratio (OR)=0.78 (95% confidence interval (CI)=0.68-0.89), adjusted p=0.043); two intronic SNPs in FOXO3A demonstrated a significant lifespan association among women only (rs1935949, OR=1.35, 95% CI=1.15-1.57, adjusted p=0.0093). Conclusion: common variants in several insulin/IGF1 pathway genes are associated with human lifespan.

BackgroundLeukocyte telomere length (LTL) is an emerging marker of biological age. Chronic inflammatory activity is commonly proposed as a promoter of biological aging in general, and of leukocyte telomere shortening in particular. In addition, senescent cells with critically short telomeres produce pro-inflammatory factors. However, in spite of the proposed causal links between inflammatory activity and LTL, there is little clinical evidence in support of their covariation and interaction.Methodology/Principal FindingsTo address this issue, we examined if individuals with high levels of the systemic inflammatory markers interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP) had increased odds for short LTL. Our sample included 1,962 high-functioning adults who participated in the Health, Aging and Body Composition Study (age range: 70–79 years). Logistic regression analyses indicated that individuals with high levels of either IL-6 or TNF-α had significantly higher odds for short LTL. Furthermore, individuals with high levels of both IL-6 and TNF-α had significantly higher odds for short LTL compared with those who had neither high (OR = 0.52, CI = 0.37–0.72), only IL-6 high (OR = 0.57, CI = 0.39–0.83) or only TNF-α high (OR = 0.67, CI = 0.46–0.99), adjusting for a wide variety of established risk factors and potential confounds. In contrast, CRP was not associated with LTL.Conclusions/SignificanceResults suggest that cumulative inflammatory load, as indexed by the combination of high levels of IL-6 and TNF-α, is associated with increased odds for short LTL. In contrast, high levels of CRP were not accompanied by short LTL in this cohort of older adults. These data provide the first large-scale demonstration of links between inflammatory markers and LTL in an older population.

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10−8) or suggestively genome wide (p < 2.3 × 10−6). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.