Hypothyroidism has been linked with an increased risk of other morbidities, such as cardiovascular diseases and diabetes mellitus. However, the temporal relationship between these diseases and the diagnosis of hypothyroidism is not well illuminated. Such information may provide insight into causal relationships between hypothyroidism and other morbidities.
To investigate the type and extent of somatic morbidity before and after a diagnosis of hypothyroidism.
Observational cohort study. From official Danish health registers, 2822 hypothyroid singletons were identified and matched 1:4 with non-hypothyroid controls and observed over a mean period of 6 years. Frequency of different morbidities was obtained by person-to-person linking in the registers. Logistic and Cox regression models were used to assess the risk of morbidity before and after the diagnosis of hypothyroidism, respectively.
Prior to the diagnosis of hypothyroidism there was a significantly increased risk of being diagnosed with cardiovascular diseases (odds ratio (OR) 1.37; 95% confidence interval (CI): 1.19–1.58), lung diseases (OR 1.25; 95% CI: 1.13–1.39), diabetes mellitus (OR 1.92; 95% CI: 1.61–2.29), as well as malignant diseases (OR 1.24; 95% CI: 1.06–1.45). Following the diagnosis of hypothyroidism there was a significantly increased risk of being diagnosed with cardiovascular diseases (hazard ratio (HR) 1.36; 95% CI: 1.15–1.60); lung diseases (HR 1.51; 95% CI: 1.30–1.75); and diabetes mellitus (HR 1.40; 95% CI: 1.11–1.77).
Prior to the diagnosis of hypothyroidism there is an excess risk of being diagnosed with cardiovascular diseases, lung diseases, diabetes mellitus, and malignant diseases. Following the diagnosis of hypothyroidism we demonstrate an increased frequency of cardiovascular diseases, lung diseases, and diabetes mellitus.
To identify genetic variants contributing to preterm birth using a linkage candidate gene approach.
We studied 99 single nucleotide polymorphisms for 33 genes in 257 families with preterm births segregating. Nonparametric and parametric analyses were used. Premature infants and mothers of premature infants were defined as affected cases in independent analyses.
Analyses with the infant as the case identified two genes with evidence of linkage: CRHR1 (p=0.0012) and CYP2E1 (p=0.0011). Analyses with the mother as the case identified four genes with evidence of linkage: ENPP1 (p=0.003), IGFBP3 (p=0.006), DHCR7 (p=0.009), and TRAF2 (p=0.01). DNA sequence analysis of the coding exons and splice sites for CRHR1 and TRAF2 identified no new likely etiologic variants.
These findings suggest the involvement of six genes acting through the infant and/or the mother in the etiology of preterm birth.
The accumulation of epigenetic changes was proposed to contribute to the age-related increase in the risk for most common diseases. In this study on 230 monozygotic twin pairs (MZ pairs), aged 18 to 89 years old, we investigated the occurrence of epigenetic changes over the adult lifespan. Using mass spectrometry, we investigated variation in global (LINE1) DNA methylation and in DNA methylation at INS, KCNQ1OT1, IGF2, GNASAS, ABCA1, LEP, and CRH, candidate loci for common diseases. Except for KCNQ1OT1, inter-individual variation in locus specific DNA methylation was larger in old individuals than in young individuals, ranging from 1.2 fold larger at ABCA1 (p = 0.010) to 1.6 fold larger at INS (p = 3.7 * 10−07). Similarly, there was more within-MZ-pair discordance in old as compared with young MZ pairs, except for GNASAS, ranging from an 8 % increase in discordance each decade at CRH (p = 8.9 * 10−06) to a 16 % increase each decade at LEP (p = 2.0 * 10−08). Still, old MZ pairs with strikingly similar DNA methylation were also observed at these loci. After 10 year follow-up in elderly twins, the variation in DNA methylation showed a similar pattern of change as observed cross-sectionally. The age-related increase in methylation variation was generally due to unique environmental factors, except for CRH, for which familial factors may play a more important role. In conclusion, sustained epigenetic differences arise from early adulthood to old age and contribute to an increasing discordance of MZ twins during ageing.
Epigenetics; Aging; MZ twin design; Full adult lifespan; DNA methylation; Stochastic variation
Sporadic, genetically complex essential tremor (ET) is one of the most common movement disorders and may lead to severe impairment of the quality of life. Despite high heritability, the genetic determinants of ET are largely unknown. We performed the second genome-wide association study (GWAS) for ET to elucidate genetic risk factors of ET.
Using the Affymetrix Genome-Wide SNP Array 6.0 (1000K) we conducted a two-stage GWAS in a total of 990 subjects and 1,537 control subjects from Europe to identify genetic variants associated with ET.
We discovered association of an intronic variant of the main glial glutamate transporter (SLC1A2) gene with ET in the first-stage sample (rs3794087, p = 6.95 × 10−5, odds ratio [OR] = 1.46). We verified the association of rs3794087 with ET in a second-stage sample (p = 1.25 × 10−3, OR = 1.38). In the subgroup analysis of patients classified as definite ET, rs3794087 obtained genome-wide significance (p = 3.44 × 10−10, OR = 1.59) in the combined first- and second-stage sample. Genetic fine mapping using nonsynonymous single nucleotide polymorphisms (SNPs) and SNPs in high linkage disequilibrium with rs3794087 did not reveal any SNP with a stronger association with ET than rs3794087.
We identified SLC1A2 encoding the major glial high-affinity glutamate reuptake transporter in the brain as a potential ET susceptibility gene. Acute and chronic glutamatergic overexcitation is implied in the pathogenesis of ET. SLC1A2 is therefore a good functional candidate gene for ET.
The Interplay of Genes and Environment across Multiple Studies (IGEMS) group is a consortium of eight longitudinal twin studies established to explore the nature of social context effects and gene-environment interplay in late-life functioning. The resulting analysis of the combined data from over 17,500 participants aged 25–102 at baseline (including nearly 2,600 monogygotic and 4,300 dizygotic twin pairs and over 1,700 family members) aims to understand why early life adversity, and social factors such as isolation and loneliness, are associated with diverse outcomes including mortality, physical functioning (health, functional ability), and psychological functioning (well-being, cognition), particularly in later life.
twins; gene-environment interaction; aging; longitudinal
Older adults’ subjective feelings of fatigue have been considered an important indicator of functional decline in old age. However, fatigue in the fastest growing segment of the older population, the oldest old, has not been reported in previous studies. The aim of this study was to evaluate the prevalence and associated health factors of indoor mobility related fatigability among nonagenarians.
A cross-sectional observational study of all Danes born 1905 assessed in 1998.
Community, sheltered housing and nursing homes.
92-93-year old persons (n=1181) who were independent of help in basic indoor mobility.
Fatigability in basic indoor mobility was defined as a subjective feeling of fatigue when transferring or walking indoors. Other standardized assessments include self-report measures of medical history, as well as performance-based assessments of walking speed and maximum hand grip strength.
In total, every fourth (26%) of the participants reported fatigability when transferring or walking indoors and fatigability was more common among participants living in sheltered housing as compared to those living independently (32% vs. 23%, p<.001). Cardiovascular diseases, musculoskeletal pain, medications, walking speed and depressive symptoms were independently associated with fatigability.
Fatigability in very basic everyday mobility is relatively common in non-disabled nonagenarians. The results also indicate important associations between fatigability and potentially modifiable health factors.
Fatigue; Aging; Nonagenarians; Health; Mobility limitation
We analyzed the association between mean height and old age cognition in two Nordic twin cohorts with different childhood living conditions. The cognitive performance of 4720 twin individuals from Denmark (mean age 81.6 years, SD = 4.59) and Finland (mean age 74.4 years, SD = 5.26) was measured using validated cognitive screens. Taller height was associated with better cognitive performance in Finland (β-estimates 0.18 SD/10cm, p value < .001, for men and 0.13 SD, p = .008, for women), but this association was not significant in Denmark (β-estimates 0.0093 SD, p value = .16, for men and 0.0075 SD, p value = .016, for women) when adjusted for age and education/social class. Among Finnish participants higher variability of cognitive performance within shorter height quintiles was observed. Analysis using gene-environment interaction models showed that environmental factors exerted a greater impact on cognitive performance in shorter participants, whereas in taller participants' it was explained mainly by genetic factors. Our results suggest that shorter participants with childhood adversity are more vulnerable to environmental risk factors for cognitive impairment.
twins; genetics; height; cognition; dementia; risk factor
Hyperthyroidism has been linked with different morbidities, like atrial fibrillation, stroke and diabetes mellitus. However, our knowledge regarding the extent and temporal relation between hyperthyroidism and other diseases is fragmented. Here, we aimed at evaluating various morbidities before and after the diagnosis of hyperthyroidism.
Observational cohort study. From nationwide Danish health registers 2631 hyperthyroid singletons and 375 twin pairs discordant for hyperthyroidism were identified and followed for an average of 6 years (range 0–13). Data on the occurrence of cardiovascular diseases, lung diseases, diabetes mellitus, rheumatic diseases and malignant diseases was obtained by person-to-person record linkage with the National Danish Patient Register and/or the Danish National Prescription Registry (lung diseases and diabetes mellitus). Logistic and Cox regression models were used to assess the risk of morbidity before and after the diagnosis of hyperthyroidism, respectively. All Cox regression analyses were adjusted for the degree of co-morbidity preceding the diagnosis of hyperthyroidism, using the Charlson score.
Hyperthyroid individuals had a significantly higher risk of being diagnosed with cardiovascular diseases (odds ratio (OR) 1.65; 95% confidence interval (CI): 1.45–1.87), lung diseases (OR 1.53; 95% CI: 1.29–1.60), and diabetes mellitus (OR 1.43, 95% CI: 1.20–1.72), but not with malignant diseases (OR 1.16, 95% CI: 0.99–1.36) prior to the diagnosis of hyperthyroidism. After the diagnosis of hyperthyroidism, subjects had a significantly higher risk of being diagnosed with cardiovascular diseases (hazard ratio (HR) 1.34; 95% CI: 1.15–1.56), lung diseases (HR 1.28; 95% CI: 1.10–1.49), and diabetes mellitus (HR 1.46; 95% CI: 1.16–1.84), but not with rheumatic diseases (HR 1.39, 95% CI: 0.92–2.09) or malignant diseases (HR 1.18, 95% CI 0.97–1.42).
We demonstrate a significantly increased burden of morbidity, both before and after the diagnosis of hyperthyroidism.
Genome-wide association studies are now used routinely to identify genes implicated in complex traits. The panels used for such analyses can detect single nucleotide polymorphisms and copy number variants, both of which may help to identify small deleted regions of the genome that may contribute to a particular disease
We performed a candidate gene analysis involving 1221 SNPs in 333 candidate genes for orofacial clefting using 2823 samples from 725 two- and three-generation families with a proband with clefts of the lip and/or palate. We used SNP genotyping, DNA sequencing, high-resolution DNA microarray analysis and long-range PCR to confirm and characterize the deletion events
This dataset had a high duplicate reproducibility rate (99.98%), high Mendelian consistency rate (99.93%), and low missing data rate (0.55%), which provided a powerful opportunity for deletion detection. Apparent Mendelian inconsistencies between parents and child suggested deletion events in 15 individuals in 11 genomic regions. We confirmed deletions involving CYP1B1, FGF10, SP8, SUMO1, TBX1, TFAP2A, and UGT7A1, including both de novo and familial cases. Deletions of SUMO1, TBX1, and TFAP2A are likely to be etiologic
These deletions suggest the potential roles of genes or regulatory elements contained within deleted regions in the etiology of clefting. Our analysis took advantage of genotypes from a candidate-gene-based SNP survey and proved to be an efficient analytical approach to interrogate genes potentially involved in clefting. This can serve as a model to find genes playing a role in complex traits in general.
cleft lip; cleft palate; microdeletion; SNPs; CNV; candidate genes
Frailty is a physiological state characterized by the deregulation of multiple physiologic systems of an aging organism determining the loss of homeostatic capacity, which exposes the elderly to disability, diseases, and finally death. An operative definition of frailty, useful for the classification of the individual quality of aging, is needed. On the other hand, the documented heterogeneity in the quality of aging among different geographic areas suggests the necessity for a frailty classification approach providing population-specific results. Moreover, the contribution of the individual genetic background on the frailty status is still questioned. We investigated the applicability of a cluster analysis approach based on specific geriatric parameters, previously set up and validated in a southern Italian population, to two large longitudinal Danish samples. In both cohorts, we identified groups of subjects homogeneous for their frailty status and characterized by different survival patterns. A subsequent survival analysis availing of Accelerated Failure Time models allowed us to formulate an operative index able to correlate classification variables with survival probability. From these models, we quantified the differential effect of various parameters on survival, and we estimated the heritability of the frailty phenotype by exploiting the twin pairs in our sample. These data suggest the presence of a genetic influence on the frailty variability and indicate that cluster analysis can define specific frailty phenotypes in each population.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9257-x) contains supplementary material, which is available to authorized users.
Frailty; Aging; Heritability; Twins; Life Sciences; Molecular Medicine; Geriatrics/Gerontology; Cell Biology
Schooling generally is positively associated with better health-related outcomes—for example, less hospitalization and later mortality—but these associations do not measure whether schooling causes better health-related outcomes. Schooling may in part be a proxy for unobserved endowments—including family background and genetics—that both are correlated with schooling and have direct causal effects on these outcomes. This study addresses the schooling-health-gradient issue with twins methodology, using rich data from the Danish Twin Registry linked to population-based registries to minimize random and systematic measurement error biases. We find strong, significantly negative associations between schooling and hospitalization and mortality, but generally no causal effects of schooling.
Health-schooling gradients; Schooling; Mortality; Hospitalization; Twins
Animal models and a few human studies have suggested a complex interaction between cancer risk and longevity indicating a trade-off where low cancer risk is associated with accelerating aging phenotypes and, vice versa, that longevity potential comes with the cost of increased cancer risk. This hypothesis predicts that longevity in one twin is associated with increased cancer risk in the cotwin.
A total of 4,354 twin pairs born 1900–1918 in Denmark were followed for mortality in the Danish Civil Registration System through 2008 and for cancer incidence in the period 1943–2008 through the Danish Cancer Registry.
The 8,139 twins who provided risk time for cancer occurrence entered the study between ages 24 and 43 (mean 33 years), and each participant was followed up to death, emigration, or at least 90 years of age. The total follow-up time was 353,410 person-years and, 2,524 cancers were diagnosed. A negative association between age at death of a twin and cancer incidence in the cotwin was found in the overall analyses as well as in the subanalysis stratified on sex, zygosity, and random selection of one twin from each twin pair.
This study did not find evidence of a cancer–longevity trade-off in humans. On the contrary, it suggested that longevity in one twin is associated with lower cancer incidence in the cotwin, indicating familial factors associated with both low cancer occurrence and longevity.
Cancer; Longevity; Trade-off; Twins; Mortality
Here we explore association with human longevity of common genetic variation in three major candidate pathways: GH/IGF-1/insulin signaling, DNA damage signaling and repair and pro/antioxidants by investigating 1273 tagging SNPs in 148 genes composing these pathways. In a case-control study of 1089 oldest-old (age 92–93) and 736 middle-aged Danes we found 1 pro/antioxidant SNP (rs1002149 (GSR)), 5 GH/IGF-1/INS SNPs (rs1207362 (KL), rs2267723 (GHRHR), rs3842755 (INS), rs572169 (GHSR), rs9456497 (IGF2R)) and 5 DNA repair SNPs (rs11571461 (RAD52), rs13251813 (WRN), rs1805329 (RAD23B), rs2953983 (POLB), rs3211994 (NTLH1)) to be associated with longevity after correction for multiple testing.
In a longitudinal study with 11 years of follow-up on survival in the oldest-old Danes we found 2 pro/antioxidant SNPs (rs10047589 (TNXRD1), rs207444 (XDH)), 1 GH/IGF-1/INS SNP (rs26802 (GHRL)) and 3 DNA repair SNPs (rs13320360 (MLH1), rs2509049 (H2AFX) and rs705649 (XRCC5)) to be associated with mortality in late life after correction for multiple testing.
When examining the 11 SNPs from the case-control study in the longitudinal data, rs3842755 (INS), rs13251813 (WRN) and rs3211994 (NTHL1) demonstrated the same directions of effect (p<0.05), while rs9456497 (IGF2R) and rs1157146 (RAD52) showed non-significant tendencies, indicative of effects also in late life survival. In addition, rs207444 (XDH) presented the same direction of effect when inspecting the 6 SNPs from the longitudinal study in the case-control data, hence, suggesting an effect also in survival from middle age to old age.
No formal replications were observed when investigating the 11 SNPs from the case-control study in 1613 oldest-old (age 95–110) and 1104 middle-aged Germans, although rs11571461 (RAD52) did show a supportive non-significant tendency (OR = 1.162, 95% CI = 0.927–1.457). The same was true for rs10047589 (TNXRD1) (HR = 0.758, 95%CI = 0.543–1.058) when examining the 6 SNPs from the longitudinal study in a Dutch longitudinal cohort of oldest-old (age 85+, N = 563).
In conclusion, the present candidate gene based association study, the largest to date applying a pathway approach, points to potential new longevity loci, but does also underline the difficulties of replicating association findings in independent study populations and thus the difficulties in identifying universal longevity polymorphisms.
human longevity; association study; case-control data; longitudinal data
Alanine aminotransferase (ALT) and γ-glutamyltransferase (GGT) are widely used markers of liver disease. Several population-based cohort studies have found associations of these liver enzymes with all-cause mortality. None of these studies controlled for genetic variation as well as fetal and early life exposure, whether environmental or genetic.
We studied the associations of ALT and GGT with all-cause mortality using data for 686 twins (73–94 years old) included in the Longitudinal Study of Aging Danish Twins.
An increase in 1 logged U/L of GGT was associated with a 15% increase in the hazard ratio (HR) for mortality [95% confidence interval (CI) 0.99, 1.32] but there was no strong evidence of an association of ALT with all-cause mortality (HR = 1.07, 95% CI 0.82, 1.40) when controlling for potential confounders. In this analysis, the study population was treated as individuals, with similarities between twins accounted for by using robust standard errors. However, an intrapair analysis in which the proportion of twin pairs in which the twin with the higher level of ALT or GGT died first was compared with 50% (expected under the null hypothesis), found no strong evidence that higher ALT or GGT was associated with earlier death within twin pairs; the results were consistent in both monozygotic and dizygotic twins.
γ-glutamyltransferase but not ALT predicts mortality among older Danish twins when using traditional methods for controlling for potential confounders and existing diabetes and cardiovascular disease. Environmental developmental origins may explain the association, but larger twin studies are required to replicate our findings.
alanine aminotransferase; γ glutamyltransferase; mortality; twin studies
Leukocyte telomere length, representing the mean length of all telomeres in leukocytes, is ostensibly a bioindicator of human aging. The authors hypothesized that shorter telomeres might forecast imminent mortality in elderly people better than leukocyte telomere length. They performed mortality analysis in 548 same-sex Danish twins (274 pairs) aged 73–94 years, of whom 204 pairs experienced the death of one or both co-twins during 9–10 years of follow-up (1997–2007). From the terminal restriction fragment length (TRFL) distribution, the authors obtained the mean TRFL (mTRFL) and the mean values of the shorter 50% (mTRFL50) and shortest 25% (mTRFL25) of TRFLs in the distribution and computed the mode of TRFL (MTRFL). They analyzed the proportions of twin pairs in which the co-twin with the shorter telomeres died first. The proportions derived from the intrapair comparisons indicated that the shorter telomeres predicted the death of the first co-twin better than the mTRFL did (mTRFL: 0.56, 95% confidence interval (CI): 0.49, 0.63; mTRFL50: 0.59, 95% CI: 0.52, 0.66; mTRFL25: 0.59, 95% CI: 0.52, 0.66; MTRFL: 0.60, 95% CI: 0.53, 0.67). The telomere-mortality association was stronger in years 3–4 than in the rest of the follow-up period, and it grew stronger with increasing intrapair difference in all telomere parameters. Leukocyte telomere dynamics might help explain the boundaries of the human life span.
aged; leukocytes; mortality; survival analysis; telomere; twins
Odor identification ability and cognition were measured in a population-based cohort of 1,222 very old twins and singletons, including 91 centenarians. Heritability for identifying odors was low, in contrast to that for cognition. Common genes were found to contribute to both olfaction and cognition. In a multiple regression model, sex, age, cognitive function, and smoking, but not APOEε4 status, were significant predictors of the olfactory test scores (all ps < 0.001). This study, along with data from other studies, suggests that indices of heritability for odor identification decline with age, likely reflecting adverse environmental influences on the smell system.
olfaction; genetics; epidemiology; cognition; age
To disentangle the influences on health of selection processes related to genetic and rearing environmental factors from factors related to marriage benefits. We compared health status among same-sex male and female twin pairs who lived together during childhood and were discordant or concordant on adult marital status.
A cross-sectional survey of a random sample of middle-aged Danish twins was conducted in 1998 to 1999. This study included 1175 same-sex twin pairs (52.5% monozygotic (MZ) and 47.5% dizygotic (DZ)). Data were obtained on adult marital status and on height, body mass index (BMI), depression symptoms, self-rated health, cognitive function, physical activity, smoking, and alcohol intake.
Among all 2350 individual twins, men who were divorced/widowed or never married had higher depression scores, lower cognitive test scores, lower physical activity scores, and were also less often moderate drinkers and nonsmokers compared with married men. Divorced/widowed women had higher depression scores and those divorced/widowed or never married were more often smokers than married women. Within twin pairs discordant on marital status, the divorced/widowed twin had higher average depression scores and was more likely to be a smoker. Never married twins had lower physical activity scores and never married male twins had higher BMI and higher depression scores than their married co-twin.
This study suggests that the relationships of adult divorce with depression and smoking in Danish twins are due to the stressful effects of marital dissolution, but that marital differences in other health and behavioral outcomes are most consistent with selection effects related to genetic or rearing environmental factors.
marital status; health status; twin study
This review examines sex differences in health and survival, with a focus on the Nordic countries. There is a remarkable discrepancy between the health and survival of the sexes: men are physically stronger and have fewer disabilities, but have substantially higher mortality at all ages compared with women: the so-called male-female health-survival paradox. A number of proposed explanations for this paradox are rooted in biological, social, and psychological interpretations. It is likely to be due to multiple causes that include fundamental biological differences between the sexes such as genetic factors, immune system responses, hormones, and disease patterns. Behavioral differences such as risk-taking and reluctance to seek and comply with medical treatment may also play a role. Another consideration is that part of the difference may be due to methodological challenges, such as selective non-participation and under-reporting of health problems, and delayed seeking of treatment by men. The Nordic countries provide a unique opportunity for such studies, as theyhave good-quality data in their national health registers, which cover the whole population, and a long tradition of high participation rates in surveys.
Health; mortality; Nordic countries; review; sex differences
Over the last 60 years, the resources and the research in the Danish Twin Registry (DTR) have periodically been summarized. Here, we give a short overview of the DTR and a more comprehensive description of new developments in the twenty-first century. First, we outline our experience over the last decade of combining questionnaire and survey data with national demographic, social, and health registers in Statistics Denmark. Second, we describe our most recent data collection effort, which was conducted during the period 2008–2011 and included both in-person assessments of 14,000+ twins born 1931–1969 and sampling of biological material, hereby expanding and consolidating the DTR biobank. Third, two examples of intensively studied twin cohorts are given. The new developments in the DTR in the last decade have facilitated the ongoing research and laid the groundwork for new research directions.
twin register; biobank; register-based research; metabolic syndrome; birth weight discordance; Denmark
Genetics in the post-genomic period is shifting from structural to functional genetics or genomics. Meanwhile, the use of twins is largely expanding from traditional heritability estimation for disease phenotypes to the study of both diseases and various molecular phenotypes, such as the regulatory phenotypes in functional genomics concerning gene expression and regulation, by engaging both classical twin design and marker-based gene mapping techniques in genetic epidemiology. New research designs have been proposed for making novel uses of twins in studying the molecular basis in the epigenetics of human diseases. Besides, twins not only serve as ideal samples for disease gene mapping using conventional genetic markers but also represent an excellent model for associating DNA copy number variations, a structural genetic marker, with human diseases. It is believed that, with the rapid development in biotechniques and new advances in bioinformatics, the unique samples of twins will make new contributions to our understanding of the nature and nurture in complex disease development and in human health. This paper aims at summarizing the new uses of twins in current genetic studies and suggesting novel proposes together with useful design and analytical strategies.
Twins; Genetics; Genomics
An efficient uncoupling process is generally considered to have a protective effect on the aging muscle by slowing down its age-related decay. Genetic polymorphisms in the Uncoupling Protein 3 (UCP3) gene, whose product is mainly expressed in skeletal muscle, were suggested to be associated with hand grip (HG) performances in elderly populations. Considering the population specificity of the quality of aging, we aimed to add further support to this evidence by analyzing the association between four SNPs in the UCP3 gene and relative haplotypes in two large cohorts of middle aged (N = 708) and oldest old Danes (N = 908). We found that the variability at rs1685354 and rs11235972 was associated with HG levels both at single and haplotypic level in both cohorts. Furthermore, taking advantage of large cohort and period survival data of the oldest cohort, we tested the association of each SNP with survival at 10 years from the baseline visit. Interestingly, we found that allele A at rs11235972, associated in this cohort with lowest HG scores, influences also the survival patterns, with people carrying this allele showing higher mortality rates. On the whole, our work supports the role of UCP3 gene in functional status and survival at old age.
Uncoupling proteins; Hand grip; Longevity
The widespread microarray technology capable of analyzing global gene expression at the level of transcription is expanding its application in not only medicine but also studies on basic biology. This paper presents our analysis on microarray gene expression data in the CEPH Utah families focusing on the demographic characteristics such as age and sex on differential gene expression patterns. Our results show that the differential gene expression pattern between age groups is dominated by down-regulated transcriptional activities in the old subjects. Functional analysis on age regulated genes identifies cell-cell signaling as an important functional category implicated in human aging. Sex-dependent gene expression is characterized by genes that may escape X-inactivation and, most interestingly, such a pattern is not affected by the aging process. Analysis on sibship correlation on gene expression revealed a large number of significant genes suggesting the importance of a genetic mechanism in regulating transcriptional activities. In addition, we observe an interesting pattern of sibship correlation on gene expression that increases exponentially with the mean of gene expression reflecting the enhanced genetic control over the functionally active genes.
Gene expression; Aging; X-inactivation; Intra-class correlation coefficient
We performed a genome wide association analysis of maternally-mediated genetic effects and parent-of-origin effects on risk of orofacial clefting using over 2,000 case-parent triads collected through an international cleft consortium. We used log-linear regression models to test individual SNPs. For SNPs with a p-value <10−5 for maternal genotypic effects, we also applied a haplotype-based method, TRIMM, to extract potential information from clusters of correlated SNPs. None of the SNPs were significant at the genome wide level. Our results suggest neither maternal genome nor parent of origin effects play major roles in the etiology of orofacial clefting in our sample. This finding is consistent with previous genetic studies and recent population-based cohort studies in Norway and Denmark, which showed no apparent difference between mother-to-offspring and father-to-offspring recurrence of clefting. We, however, cannot completely rule out maternal genome or parent of origin effects as risk factors because very small effects might not be detectable with our sample size, they may influence risk through interactions with environmental exposures or may act through a more complex network of interacting genes. Thus the most promising SNPs identified by this study may still be worth further investigation.
GWAS; CL/P; CP; maternal genes; parent-of-origin; family-based study; association study
Telomerase is of key importance for telomere maintenance and variants of the genes encoding its major subunits, TERT and TERC, are candidates for inter-individual variation in telomere length. Recently, the two SNPs rs3772190 and rs12696304 in the TERC locus were reported to be associated with leukocyte telomere length (LTL) in two genome-wide association studies, while one haplotype of TERT (rs2853669, rs2736098, rs33954691, and rs2853691) has been reported to be associated with both LTL and longevity in a candidate gene study.
In this study we investigated the two TERC and four TERT SNPs in middle-aged, old, and oldest-old Danes (58–100 years) and their association with LTL (n=864) and longevity (n=1069). Furthermore, data on 11 TERT tagging SNPs in 1089 oldest-old and 736 middle-aged Danes were investigated with respect to longevity. For all SNPs, the association with longevity was investigated using both a cross-sectional and a longitudinal approach.
Applying an additive model we found association of LTL with the minor TERC alleles of rs3772190 (A) and rs12696304 (G), such that a shorter LTL was seen in rs3772190 A carriers (regression coefficient = −0.08, p = 0.011) and in male rs12696304 G carriers (regression coefficient = −0.13, p = 0.014). No TERT variations showed association. Moreover, the A allele of rs3772190 (TERC) was found to be associated with longevity (HR (AG+AA) = 1.31, p = 0.006). No associations with longevity were observed for the TERT SNPs or haplotypes. Our study, thus, indicates that TERC is associated with both LTL and longevity in humans.
human longevity; leukocyte telomere length (LTL); telomerase reverse transcriptase (TERT); telomerase RNA component (TERC); association study; cross sectional data and longitudinal data
Background: The European Innovation Partnership on Active and Healthy Ageing seeks an increase of two healthy life years (HLY) at birth in the EU27 for the next 10 years. We assess the feasibility of doing so between 2010 and 2020 and the differential impact among countries by applying different scenarios to current trends in HLY. Methods: Data comprised HLY and life expectancy (LE) at birth 2004–09 from Eurostat. We estimated HLY in 2010 in each country by multiplying the Eurostat projections of LE in 2010 by the ratio HLY/LE obtained either from country and sex-specific linear regression models of HLY/LE on year (seven countries retaining same HLY question) or extrapolating the average of HLY/LE in 2008 and 2009 to 2010 (20 countries and EU27). The first scenario continued these trends with three other scenarios exploring different HLY gap reductions between 2010 and 2020. Results: The estimated gap in HLY in 2010 was 17.5 years (men) and 18.9 years (women). Assuming current trends continue, EU27 HLY increased by 1.4 years (men) and 0.9 years (women), below the European Innovation Partnership on Active and Healthy Ageing target, with the HLY gap between countries increasing to 18.3 years (men) and 19.5 years (women). To eliminate the HLY gap in 20 years, the EU27 must gain 4.4 HLY (men) and 4.8 HLY (women) in the next decade, which, for some countries, is substantially more than what the current trends suggest. Conclusion: Global targets for HLY move attention from inter-country differences and, alongside the current economic crisis, may contribute to increase health inequalities.