Aida Karina Dieffenbach

CHRNA5 Risk Variant Predicts Delayed Smoking Cessation and Earlier Lung Cancer Diagnosis—A Meta-Analysis

BACKGROUND Recent meta-analyses show strong evidence of associations among genetic variants in CHRNA5 on chromosome 15q25, smoking quantity, and lung cancer. This meta-analysis tests whether the CHRNA5 variant rs16969968 predicts age of smoking cessation and age of lung cancer diagnosis. METHODS Meta-analyses examined associations between rs16969968, age of quitting smoking, and age of lung cancer diagnosis in 24 studies of European ancestry (n = 29 072). In each dataset, we used Cox regression models to evaluate the association between rs16969968 and the two primary phenotypes (age of smoking cessation among ever smokers and age of lung cancer diagnosis among lung cancer case patients) and the secondary phenotype of smoking duration. Heterogeneity across studies was assessed with the Cochran Q test. All statistical tests were two-sided. RESULTS The rs16969968 allele (A) was associated with a lower likelihood of smoking cessation (hazard ratio [HR] = 0.95, 95% confidence interval [CI] = 0.91 to 0.98, P = .0042), and the AA genotype was associated with a four-year delay in median age of quitting compared with the GG genotype. Among smokers with lung cancer diagnoses, the rs16969968 genotype (AA) was associated with a four-year earlier median age of diagnosis compared with the low-risk genotype (GG) (HR = 1.08, 95% CI = 1.04 to 1.12, P = 1.1*10(-5)). CONCLUSION These data support the clinical significance of the CHRNA5 variant rs16969968. It predicts delayed smoking cessation and an earlier age of lung cancer diagnosis in this meta-analysis. Given the existing evidence that this CHRNA5 variant predicts favorable response to cessation pharmacotherapy, these findings underscore the potential clinical and public health importance of rs16969968 in CHRNA5 in relation to smoking cessation success and lung cancer risk.

Oxidative Stress Markers and All-Cause Mortality at Older Age: A Population-Based Cohort Study

BACKGROUND The free radical/oxidative stress theory of aging has recently received much attention but the association of oxidative stress markers with all-cause mortality was not yet assessed in humans. METHODS We measured derivatives of reactive oxygen metabolites (d-ROM) as a proxy for the reactive oxygen species concentration and total thiol levels (TTL) as a proxy for the redox control status in 2,932 participants of a population-based cohort study from Germany. RESULTS The median age of the population was 70 years and 120 (4.1%) study participants died during a mean follow-up of 3.3 years. Compared with the bottom tertiles, the top tertiles of d-ROM and TTL concentrations were both associated with all-cause mortality in models adjusted for age, sex, education, smoking, physical activity, and alcohol consumption (hazard ratios and 95% confidence intervals: 1.63 [1.01; 2.63] and 0.68 [0.53; 0.87], respectively). Adding diseases, the inflammatory marker C-reactive protein or a cumulative somatic morbidity index did not alter the results for TTL. However, the association of d-ROM and mortality was attenuated and no longer statistically significant after adding C-reactive protein and the somatic morbidity index to the model. CONCLUSIONS This study adds epidemiological evidence to the free radical/oxidative stress theory of aging. Both d-ROM and TTL were associated with mortality at older age. For TTL, this association was independent of baseline health status. Inflammation and higher general morbidity could be intermediate states on the pathway from high d-ROM levels to mortality. This hypothesis should to be explored by future studies with repeated measurements.

Association between Oxidative Stress and Frailty in an Elderly German Population: Results from the ESTHER Cohort Study

Background: Oxidative stress (OS) and inflammatory biomarkers have been postulated to be important factors in the development of age-related diseases. While causes of frailty are complex and multidimensional based on the interaction of genetic, biological, physical, and environmental factors, the biological basis of frailty has been difficult to establish. Objective: In this study, we aimed to assess the possible association between different OS and inflammatory biomarkers and frailty. Methods: This cross-sectional analysis was performed among 2,518 subjects participating in a large population-based cohort study on aging conducted in Germany. Frailty was assessed as proposed by Fried et al. [J Gerontol A Biol Sci Med Sci 2001;56:M146-M156]. OS biomarkers, biological antioxidant potential (BAP), derivate of reactive oxygen metabolites (d-ROM) and total thiol levels (TTL), and an established biomarker of inflammation C-reactive protein (CRP) were measured by spectrophotometry and immunoturbidimetry. Logistic regression models were performed to assess the relationship between the OS biomarkers and frailty status. Odds ratios (OR) and 95% confidence intervals (CI) were calculated to quantify the associations. Results: Mean levels of d-ROM, TTL, and CRP differed between frail and non-frail participants (p values <0.0001). Comparing highest and lowest quartiles of the biomarkers, statistically significant positive associations with frailty were observed for d-ROM (OR: 2.02, 95% CI: 1.25-3.25) and CRP (OR: 3.15, 95% CI: 2.00-4.96), respectively, after controlling for age and sex. An inverse statistically significant association with frailty was observed for TTL (OR: 0.42, 95% CI: 0.25-0.69). Conclusion: The strong associations with OS biomarkers and CRP support a major role of OS and inflammation in the development of frailty, which should be followed up in further longitudinal studies on frailty.

Frailty and telomere length: Cross-sectional analysis in 3537 older adults from the ESTHER cohort

Both telomere length and frailty were observed to be associated with aging. Whether and to what extent telomere length is related to frailty is essentially unknown. In this cross-sectional analysis of baseline data of 3537 community-dwelling adults aged 50 to 75 years of a large German cohort study, we assessed the hypothesis that shorter telomere length might be a biological marker for frailty. Using whole blood DNA we examined mean telomere repeat copy to single gene copy number (T/S ratio) using quantitative PCR. Construction of a frailty index (FI) was based on a deficit accumulation approach, which quantifies frailty as ratio of the deficits present divided by the total number of deficits considered. Mean FI was determined according to age by tertiles of T/S ratio. Furthermore, we used correlation analyses stratified for gender and age groups to examine the association of the T/S ratio with frailty. Mean FI value was similar across tertiles of the T/S ratio (0.24±0.14, 0.24±0.14 and 0.23±0.14, respectively (p=0.09)), and FI and the T/S ratio were uncorrelated in gender- and age-specific analyses. In conclusion, T/S ratio and frailty were unrelated in this large sample of older adults. T/S ratio may therefore not be a meaningful biological marker for frailty.

Identification of new genetic susceptibility Loci for breast cancer through consideration of gene-environment interactions

Genes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene‐environment (G × E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,475 cases and 34,786 controls of European ancestry from up to 23 studies in the Breast Cancer Association Consortium were included. Overall, 71,527 single nucleotide polymorphisms (SNPs), enriched for association with breast cancer, were tested for interaction with 10 environmental risk factors using three recently proposed hybrid methods and a joint test of association and interaction. Analyses were adjusted for age, study, population stratification, and confounding factors as applicable. Three SNPs in two independent loci showed statistically significant association: SNPs rs10483028 and rs2242714 in perfect linkage disequilibrium on chromosome 21 and rs12197388 in ARID1B on chromosome 6. While rs12197388 was identified using the joint test with parity and with age at menarche (P‐values = 3 × 10−07), the variants on chromosome 21 q22.12, which showed interaction with adult body mass index (BMI) in 8,891 postmenopausal women, were identified by all methods applied. SNP rs10483028 was associated with breast cancer in women with a BMI below 25 kg/m2 (OR = 1.26, 95% CI 1.15–1.38) but not in women with a BMI of 30 kg/m2 or higher (OR = 0.89, 95% CI 0.72–1.11, P for interaction = 3.2 × 10−05). Our findings confirm comparable power of the recent methods for detecting G × E interaction and the utility of using G × E interaction analyses to identify new susceptibility loci.

Smoking habits and leukocyte telomere length dynamics among older adults: Results from the ESTHER cohort.

BACKGROUND & AIMS Leukocyte telomere length (LTL) shortens with age and short LTL has been associated with increased mortality and increased risk for some age-related outcomes. This study aims to analyse the associations of smoking habits with LTL and rate of LTL change per year in older adults. METHODS LTL was measured by quantitative PCR at baseline in 3600 older adults, who were enrolled in a population-based cohort study in Germany. For longitudinal analyses, measurements were repeated in blood samples obtained at 8-year follow-up from 1000 participants. Terminal Restriction Fragment analysis was additionally performed in a sub-sample to obtain absolute LTL in base pairs. Multivariate linear regression models were used to estimate associations of smoking habits with baseline LTL and changes in LTL over time. RESULTS LTL was inversely associated with age (r=-0.090, p<0.0001). Women had longer LTL than men (p<0.0001). Smoking was inversely associated with LTL. On average, current smokers had 73 base pairs (BP) shorter LTL compared to never smokers. Smoking intensity and pack-years of smoking were also inversely associated with LTL, and a positive association was observed with years since smoking cessation. Slower LTL attrition rates were observed in ever smokers over 8years of follow-up. CONCLUSIONS Our cross-sectional analysis supports suggestions that smoking might contribute to shortening of LTL but this relationship could not be shown longitudinally. The overall rather small effect sizes observed for smoking-related variables suggest that LTL reflects smoking-related health hazards only to a very limited extent.

TERT gene harbors multiple variants associated with pancreatic cancer susceptibility

A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT–CLPTM1L gene region on chromosome 5p15.33. Because this region is characterized by low linkage disequilibrium, we sought to identify whether additional single nucleotide polymorphisms (SNPs) could be related to pancreatic cancer risk, independently of rs401681. We performed an in‐depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia. We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, odds ratio = 0.85; 95% confidence interval = 0.80–0.90, p = 8.3 × 10−8). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low linkage disequilibrium between them (r2 = 0.07, D′ = 0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (p = 3.0 × 10−5), rs4583925 (p = 4.0 × 10−5) and rs2735948 (p = 5.0 × 10−5). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants.

Investigation of gene‐environment interactions between 47 newly identified breast cancer susceptibility loci and environmental risk factors

A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC. Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes‐type shrinkage estimator. Six SNPs showed interactions with associated p‐values (pint) <1.1 × 10−3. None of the observed interactions was significant after accounting for multiple testing. The Bayesian False Discovery Probability was used to rank the findings, which indicated three interactions as being noteworthy at 1% prior probability of interaction. SNP rs6828523 was associated with increased ER‐negative BC risk in women ≥170 cm (OR = 1.22, p = 0.017), but inversely associated with ER‐negative BC risk in women <160 cm (OR = 0.83, p = 0.039, pint = 1.9 × 10−4). The inverse association between rs4808801 and overall BC risk was stronger for women who had had four or more pregnancies (OR = 0.85, p = 2.0 × 10−4), and absent in women who had had just one (OR = 0.96, p = 0.19, pint = 6.1 × 10−4). SNP rs11242675 was inversely associated with overall BC risk in never/former smokers (OR = 0.93, p = 2.8 × 10−5), but no association was observed in current smokers (OR = 1.07, p = 0.14, pint = 3.4 × 10−4). In conclusion, recently identified BC susceptibility loci are not strongly modified by established risk factors and the observed potential interactions require confirmation in independent studies.

Body mass index and leukocyte telomere length dynamics among older adults: Results from the ESTHER cohort.

OBJECTIVE Telomere length (TL) has been proposed as a biomarker of ageing, which might be used to identify individuals at higher risk of age-related diseases. Obesity is a well-known risk factor for several diseases. This study aims to analyse the associations of BMI with TL and the rate of TL change in older adults. METHODS Leukocyte TL (LTL) was measured by quantitative PCR in blood samples of 3600 older adults aged 50-75 years obtained at the baseline examination of a population-based cohort study in Germany. For longitudinal analyses, measurements were repeated in blood samples obtained at 8-year follow-up from 1000 participants. Multivariate linear regression models were used to estimate associations of BMI with LTL and changes in LTL over time. RESULTS LTL was inversely associated with age (r = -0.090, p < 0.0001). BMI and LTL associations varied according to age (p for interaction = 0.021). BMI was significantly inversely associated with LTL in those younger than 60 years (-6 basepairs per 1 kg/m(2) difference in BMI). In particular, weight gain during adulthood was inversely associated with LTL in a dose-response manner in this age group, with those having gained ≥ 30 kg having significantly shorter telomeres (-209 basepairs) than those who maintained their weight. No clear patterns were observed between any of BMI-related variables and the rate of LTL change. CONCLUSIONS Our cross-sectional analysis supports suggestions that weight gain during adulthood and obesity may contribute to shorter telomere length below 60 years of age, but this relationship could not be shown longitudinally.

Risk of multiple myeloma is associated with polymorphisms within telomerase genes and telomere length

Compelling biological and epidemiological evidences point to a key role of genetic variants of the TERT and TERC genes in cancer development. We analyzed the genetic variability of these two gene regions using samples of 2,267 multiple myeloma (MM) cases and 2,796 healthy controls. We found that a TERT variant, rs2242652, is associated with reduced MM susceptibility (OR = 0.81; 95% CI: 0.72–0.92; p = 0.001). In addition we measured the leukocyte telomere length (LTL) in a subgroup of 140 cases who were chemotherapy‐free at the time of blood donation and 468 controls, and found that MM patients had longer telomeres compared to controls (OR = 1.19; 95% CI: 0.63–2.24; ptrend = 0.01 comparing the quartile with the longest LTL versus the shortest LTL). Our data suggest the hypothesis of decreased disease risk by genetic variants that reduce the efficiency of the telomerase complex. This reduced efficiency leads to shorter telomere ends, which in turn may also be a marker of decreased MM risk.