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1.  Absence of association of a single-nucleotide polymorphism in the TERT-CLPTM1L locus with age-related phenotypes in a large multicohort study: the HALCyon programme 
Aging Cell  2011;10(3):520-532.
Several age-related traits are associated with shorter telomeres, the structures that cap the end of linear chromosomes. A common polymorphism near the telomere maintenance gene TERT has been associated with several cancers, but relationships with other aging traits such as physical capability have not been reported. As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, men and women aged between 44 and 90 years from nine UK cohorts were genotyped for the single-nucleotide polymorphism (SNP) rs401681. We then investigated relationships between the SNP and 30 age-related phenotypes, including cognitive and physical capability, blood lipid levels and lung function, pooling within-study genotypic effects in meta-analyses. No significant associations were found between the SNP and any of the cognitive performance tests (e.g. pooled beta per T allele for word recall z-score = 0.02, 95% CI: −0.01 to 0.04, P-value = 0.12, n = 18 737), physical performance tests (e.g. pooled beta for grip strength = −0.02, 95% CI: −0.045 to 0.006, P-value = 0.14, n = 11 711), blood pressure, lung function or blood test measures. Similarly, no differences in observations were found when considering follow-up measures of cognitive or physical performance after adjusting for its measure at an earlier assessment. The lack of associations between SNP rs401681 and a wide range of age-related phenotypes investigated in this large multicohort study suggests that while this SNP may be associated with cancer, it is not an important contributor to other markers of aging.
PMCID: PMC3094481  PMID: 21332924
aging; cognition; middle-aged; physical; telomere
2.  Associations between a Polymorphism in the Pleiotropic GCKR and Age-Related Phenotypes: The HALCyon Programme 
PLoS ONE  2013;8(7):e70045.
The glucokinase regulatory protein encoded by GCKR plays an important role in glucose metabolism and a single nucleotide polymorphism (SNP) rs1260326 (P446L) in the gene has been associated with several age-related biomarkers, including triglycerides, glucose, insulin and apolipoproteins. However, associations between SNPs in the gene and other ageing phenotypes such as cognitive and physical capability have not been reported.
As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, men and women from five UK cohorts aged between 44 and 90+ years were genotyped for rs1260326. Meta-analysis was used to pool within-study genotypic associations between the SNP and several age-related phenotypes, including body mass index (BMI), blood lipid levels, lung function, and cognitive and physical capability.
We confirm the associations between the minor allele of the SNP and higher triglycerides and lower glucose levels. We also observed a triglyceride-independent association between the minor allele and lower BMI (pooled beta on z-score = −0.04, p-value = 0.0001, n = 16,251). Furthermore, there was some evidence for gene-environment interactions, including physical activity attenuating the effects on triglycerides. However, no associations were observed with measures of cognitive and physical capability.
Findings from middle-aged to older adults confirm associations between rs1260326 GCKR and triglycerides and glucose, suggest possible gene-environment interactions, but do not provide evidence that its relevance extends to cognitive and physical capability.
PMCID: PMC3720952  PMID: 23894584
3.  TERT-CLPTM1L Rs401681 C>T Polymorphism Was Associated with a Decreased Risk of Esophageal Cancer in a Chinese Population 
PLoS ONE  2014;9(7):e100667.
Esophageal cancer was the fifth most commonly diagnosed cancer and the fourth leading cause of cancer-related death in China in 2009. Esophageal squamous cell carcinoma (ESCC) accounts for more than 90 percent of esophageal cancers. Genetic factors probably play an important role in the ESCC carcinogenesis.
We conducted a hospital based case-control study to evaluate functional hTERT rs2736098 G>A and TERT-CLPTM1L rs401681 C>T single nucleotide polymorphisms (SNPs) on the risk of ESCC. Six hundred and twenty-nine ESCC cases and 686 controls were recruited. Their genotypes were determined using the ligation detection reaction (LDR) method.
When the TERT-CLPTM1L rs401681 CC homozygote genotype was used as the reference group, the CT genotype was associated with a significantly decreased risk of ESCC (adjusted OR  = 0.74, 95% CI  = 0.58–0.94, p = 0.012); the CT/TT variants were associated with a 26% decreased risk of ESCC (adjusted OR  = 0.74, 95% CI  = 0.59–0.93, P = 0.009). The significantly decreased risk of ESCC associated with the TERT-CLPTM1L rs401681 C>T polymorphism was associated with male sex, young age (<63 years in our study) and alcohol consumption. No association between the hTERT rs2736098 G>A polymorphism and ESCC risk was observed.
TERT-CLPTM1L rs401681 CT and CT/TT genotypes were associated with decreased risk of ESCC, particularly among men, young patients and those reported to be drinkers. However, our results are preliminary conclusions. Larger studies with more rigorous study designs are required to confirm the current findings.
PMCID: PMC4089909  PMID: 25007268
4.  Genetic variants in telomere-maintaining genes and skin cancer risk 
Human genetics  2010;129(3):247-253.
Telomere-related genes play an important role in maintaining the integrity of the telomeric structure that protects chromosome ends, and telomere dysfunction may lead to tumorigenesis. We evaluated the associations between 39 SNPs, including 38 tag-SNPs in telomere-related genes (TERT, TRF1, TRF2, TNKS2, and POT1) and one SNP (rs401681) in the TERT-CLPTM1L locus which has been identified as a susceptibility locus to skin cancer in the previous GWAS, and the risk of skin cancer in a case-control study of Caucasians nested within the Nurses’ Health Study (NHS) among 218 melanoma cases, 285 squamous cell carcinoma (SCC) cases, 300 basal cell carcinoma (BCC) cases, and 870 controls. Of the 39 SNPs evaluated, ten showed a nominal significant association with the risk of at least one type of skin cancer. After correction for multiple testing within each gene, two SNPs in the TERT gene (rs2853676 and rs2242652) and one SNP in the TRF1 gene (rs2981096) showed significant associations with the risk of melanoma. Also, the SNP rs401681 in the TERT-CLPTM1L locus was replicated for the association with melanoma risk. The additive odds ratio (OR) (95% confidence interval (95% CI)) of these four SNPs (rs2853676[T], rs2242652[A], rs2981096[G], and rs401681[C]) for the risk of melanoma was 1.43 (1.14–1.81), 1.50 (1.14–1.98), 1.87 (1.19–2.91), and 0.73 (0.59–0.91), respectively. Moreover, we found that the rs401681[C] was associated with shorter relative telomere length (p for trend, 0.05). We did not observe significant associations for SCC or BCC risk. Our study provides evidence for the contribution of genetic variants in the telomere-maintaining genes to melanoma susceptibility.
PMCID: PMC3443196  PMID: 21116649
SNP; Telomere-maintaining gene; Skin cancer
5.  No association between TERT-CLPTM1L SNP rs401681 and mean telomere length or cancer risk 
A recent study reported genetic variants in the TERT-CLPTM1L locus to be associated with mean telomere length, and with risk of multiple cancers.
We evaluated the association between SNP rs401681 [c>t] and mean telomere length, using quantitative Real Time PCR, in blood-extracted DNA collected from 11,314 cancer-free participants from the Sisters in Breast Screening (SIBS) study, the MAPLES melanoma family study, and the SEARCH Breast, Colorectal, Melanoma studies. We also examined the relationship between rs401618 genotype and susceptibility to breast cancer (6800 cases, 6608 controls), colorectal cancer (2259 cases, 2181 controls) and melanoma (787 cases, 999 controls).
The ‘per t allele’ change in mean telomere length (ΔCt), adjusted for age, study plate, gender and family, was 0.001 (95%CI -0.01 – 0.02), p-trend=0.61. The ‘per t allele’ Odds Ratio (OR) for each cancer was: breast cancer OR=1.01 (95% Confidence Intervals 0.96-1.06), p-trend=0.64; colorectal cancer OR=1.02 (95%CI 0.94-1.11), p-trend=0.66; and melanoma OR=0.99 (95%CI 0.84-1.15), p-trend=0.87.
We found no evidence that this SNP is associated with mean telomere length, or with risk of breast cancer, colorectal cancer or melanoma.
Our results indicate that observed associations between rs401681 and several cancer types may be weaker than previously described. The lack of an association in our study between this SNP and mean telomere suggests that any association with cancer risk at this locus is not mediated through TERT.
PMCID: PMC2901592  PMID: 20570912
6.  Associations between APOE and low-density lipoprotein cholesterol genotypes and cognitive and physical capability: the HALCyon programme 
Age  2014;36(4):9673.
The APOE ε2/3/4 genotype has been associated with low-density lipoprotein cholesterol (LDL-C) and Alzheimer disease. However, evidence for associations with measures of cognitive performance in adults without dementia has been mixed, as it is for physical performance. Associations may also be evident in other genotypes implicated in LDL-C levels. As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, genotypic information was obtained for APOE ε2/3/4, rs515135 (APOB), rs2228671 (LDLR) and rs629301 (SORT1) from eight cohorts of adults aged between 44 and 90 + years. We investigated associations with four measures of cognitive (word recall, phonemic fluency, semantic fluency and search speed) and physical capability (grip strength, get up and go/walk speed, timed chair rises and ability to balance) using meta-analyses. Overall, little evidence for associations between any of the genotypes and measures of cognitive capability was observed (e.g. pooled beta for APOE ε4 effect on semantic fluency z score = −0.02; 95 % CI = −0.05 to 0.02; p value = 0.3; n = 18,796). However, there was borderline evidence within studies that negative effects of APOE ε4 on nonverbal ability measures become more apparent with age. Few genotypic associations were observed with physical capability measures. The findings from our large investigation of middle-aged to older adults in the general population suggest that effects of APOE on cognitive capability are at most modest and are domain- and age-specific, while APOE has little influence on physical capability. In addition, other LDL-C-related genotypes have little impact on these traits.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-014-9673-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4150901  PMID: 25073452
Ageing; Apolipoprotein E; Cognition; Single nucleotide polymorphism
7.  Genetic Variant rs401681 at 5p15.33 Modifies Susceptibility to Lung Cancer but Not Esophageal Squamous Cell Carcinoma 
PLoS ONE  2013;8(12):e84277.
The human 5p15.33 locus contains two well-known genes, the telomerase reverse transcriptase (TERT) and cleft lip and palate transmembrane 1-like (CLPTM1L) genes, which have been implicated in carcinogenesis. A common sequence variant, rs401681, located in an intronic region of CLPTM1L, has been reported to be associated with lung cancer risk based on genome-wide association study. However, subsequent replication studies in diverse populations have yielded inconsistent results. In addition, genetic variants at 5p15.33, including rs401681, have been shown to be involved in the susceptibility to multiple malignancies. Nevertheless, the role of these TERT-CLPTM1L variants in the etiology of esophageal squamous cell carcinoma (ESCC) remains unknown.
We genotyped the rs401681 polymorphism using TaqMan methodology and analyzed its association with the risk of lung cancer and ESCC in a case–control study of 1,479 cancer patients (726 with lung cancer and 753 with ESCC) and 860 healthy individuals.
Logistic regression analyses revealed that rs401681 T genotypes were associated with a significantly decreased risk of lung cancer (CT vs. CC: adjusted OR = 0.782, 95% CI = 0.625–0.978, P = 0.031; CT/TT vs. CC: adjusted OR = 0.786; 95% CI = 0.635–0.972, P = 0.026). Stratification analysis by histology type indicated that rs401681 T genotypes were associated with a significantly reduced risk of both adenocarcinoma and squamous cell carcinoma. Furthermore, no significant association was observed between rs401681 and the risk of ESCC (CT vs. CC: adjusted OR = 0.910, 95% CI = 0.734–1.129, P = 0.392; TT vs. CC: adjusted OR = 0.897, 95%CI = 0.624–1.290, P = 0.558; CT/TT vs. CC: adjusted OR = 0.908, 95% CI = 0.740–1.114, P = 0.355).
Our findings provide further evidence supporting rs401681 as a genetic variant associated with the risk of lung cancer. In addition, we investigated the correlation between the rs401681 variant and the risk of ESCC in a Han Chinese population, and our results suggest that this genetic variant may not be involved in ESCC risk.
PMCID: PMC3875515  PMID: 24386361
8.  Genetic Polymorphisms of TERT and CLPTM1L and Risk of Lung Cancer – a Case- Control Study in a Chinese Population 
Genetic variants of Telomerase reverse transcriptase (TERT) and cleft lip and palate trans-membrane 1 like (CLPTM1L) genes in chromosome 5p15.33 region were previously identified to influence the susceptibility to lung cancer. We examined the association of single nucleotide polymorphisms (SNPs) in TERT and CLPTM1L genes with lung cancer and explored their potential modifying effects on the relationship between environmental risk factors and lung cancer in a Chinese population.
We genotyped rs2736100 (TERT) and rs401681 (CLPTM1L) SNPs in a case-control study with 399 lung cancer cases and 466 controls form Taiyuan, China. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression models. Potential confounders were controlled for in the adjusted models.
We found that the GG genotype of TERT was positively associated with lung cancer (OR = 1.47, 95% CI: 1.00 – 2.16). The association was stronger in participants older than 60 years, exposed to low indoor air pollution and adenocarcinoma and squamous cell carcinoma (SCC) in recessive model analysis. The GA genotype of CLPTM1L was inversely associated with lung cancer (OR = 0.72, 95% CI: 0.54 – 0.97). The association was stronger in participants 60 years old or younger, males, heavy smokers, exposed to low indoor air pollution and SCC in dominant model analysis. Individuals carrying both TERT and CLPTM1L risk genotypes had higher risk of lung cancer (OR = 1.80, 95% CI: 1.15 – 2.82). Significant interaction was observed between CLPTM1L and indoor air pollution in association with lung cancer.
Our results reiterate that genetic variants of TERT and CLPTM1L contribute to lung cancer susceptibility in Chinese population. These associations need to be verified in larger and different populations.
PMCID: PMC3627395  PMID: 23433592
Lung cancer; TERT; CLPTM1L; SNPs; Susceptibility; Chinese population
9.  Genetic variations in TERT–CLPTM1L genes and risk of squamous cell carcinoma of the head and neck 
Carcinogenesis  2010;31(11):1977-1981.
Single-nucleotide polymorphisms (SNPs) of TERT-rs2736098 (C > T) and CLPTM1L-rs401681(C > T) at the 5p15.33 locus are significantly associated with cancer risk as reported in genome-wide association studies (GWAS), but there are no reported studies for squamous cell carcinoma of the head and neck (SCCHN). In a case–control study of 1079 SCCHN cases and 1115 cancer-free controls of non-Hispanic whites who were frequency matched by age and sex, we genotyped for these two SNPs and assessed their associations with SCCHN risk. Compared with the CC genotypes of each polymorphism, the associations of a slightly reduced risk of SCCHN with the variant genotypes of CT + TT of both polymorphisms were approaching statistical significance [Odds ratio (OR) = 0.90, 95% confidence interval (CI) = 0.76–1.08 for TERT-rs2736098 and OR = 0.86, 95% CI = 0.71–1.04 for CLPTM1L-rs401681, respectively]. When the two SNPs were combined, the variant genotypes of the two SNPs were significantly associated a moderately reduced risk of SCCHN (OR = 0.82, 95% CI = 0.67–0.99), and the number of variant genotypes was associated with a significantly reduced risk in a dose–response manner (P = 0.028). Furthermore, the reduced risk was more pronounced in ever smokers, ever drinkers and patients with oropharyngeal cancer. Our results suggested that these two SNPs at the 5p15.33 locus may be associated with a reduced risk of SCCHN, particularly for their combined effect. Although we added additional evidence for the association of the two SNPs with cancer risk as reported in GWAS, additional studies are needed to replicate our findings.
PMCID: PMC2966556  PMID: 20802237
10.  A Multi-Cohort Study of Polymorphisms in the GH/IGF Axis and Physical Capability: The HALCyon Programme 
PLoS ONE  2012;7(1):e29883.
Low muscle mass and function have been associated with poorer indicators of physical capability in older people, which are in-turn associated with increased mortality rates. The growth hormone/insulin-like growth factor (GH/IGF) axis is involved in muscle function and genetic variants in genes in the axis may influence measures of physical capability.
As part of the Healthy Ageing across the Life Course (HALCyon) programme, men and women from seven UK cohorts aged between 52 and 90 years old were genotyped for six polymorphisms: rs35767 (IGF1), rs7127900 (IGF2), rs2854744 (IGFBP3), rs2943641 (IRS1), rs2665802 (GH1) and the exon-3 deletion of GHR. The polymorphisms have previously been robustly associated with age-related traits or are potentially functional. Meta-analysis was used to pool within-study genotypic effects of the associations between the polymorphisms and four measures of physical capability: grip strength, timed walk or get up and go, chair rises and standing balance.
Few important associations were observed among the several tests. We found evidence that rs2665802 in GH1 was associated with inability to balance for 5 s (pooled odds ratio per minor allele = 0.90, 95% CI: 0.82–0.98, p-value = 0.01, n = 10,748), after adjusting for age and sex. We found no evidence for other associations between the polymorphisms and physical capability traits.
Our findings do not provide evidence for a substantial influence of these common polymorphisms in the GH/IGF axis on objectively measured physical capability levels in older adults.
PMCID: PMC3254646  PMID: 22253814
11.  Genetic Variants Influencing Biomarkers of Nutrition Are Not Associated with Cognitive Capability in Middle-Aged and Older Adults123 
The Journal of Nutrition  2013;143(5):606-612.
Several investigations have observed positive associations between good nutritional status, as indicated by micronutrients, and cognitive measures; however, these associations may not be causal. Genetic polymorphisms that affect nutritional biomarkers may be useful for providing evidence for associations between micronutrients and cognitive measures. As part of the Healthy Ageing across the Life Course (HALCyon) program, men and women aged between 44 and 90 y from 6 UK cohorts were genotyped for polymorphisms associated with circulating concentrations of iron [rs4820268 transmembrane protease, serine 6 (TMPRSS6) and rs1800562 hemochromatosis (HFE)], vitamin B-12 [(rs492602 fucosyltransferase 2 (FUT2)], vitamin D ([rs2282679 group-specific component (GC)] and β-carotene ([rs6564851 beta-carotene 15,15'-monooxygenase 1 (BCMO1)]. Meta-analysis was used to pool within-study effects of the associations between these polymorphisms and the following measures of cognitive capability: word recall, phonemic fluency, semantic fluency, and search speed. Among the several statistical tests conducted, we found little evidence for associations. We found the minor allele of rs1800562 was associated with poorer word recall scores [pooled β on Z-score for carriers vs. noncarriers: −0.05 (95% CI: −0.09, −0.004); P = 0.03, n = 14,105] and poorer word recall scores for the vitamin D–raising allele of rs2282679 [pooled β per T allele: −0.03 (95% CI: −0.05, −0.003); P = 0.03, n = 16,527]. However, there was no evidence for other associations. Our findings provide little evidence to support associations between these genotypes and cognitive capability in older adults. Further investigations are required to elucidate whether the previous positive associations from observational studies between circulating measures of these micronutrients and cognitive performance are due to confounding and reverse causality.
PMCID: PMC3738233  PMID: 23468552
12.  Genetic Variations rs11892031 and rs401681 Are Associated with Bladder Cancer Risk in a Chinese Population 
Genome-wide association studies (GWAS) have identified a number of genetic variants associated with risk of bladder cancer in populations of European descent. Here, we assessed association of two of these variants, rs11892031 (2q37.1 region) and rs401681 (5p15.33 region) in a Chinese case-control study, which included 367 bladder cancer cases and 420 controls. We found that the AC genotype of rs11892031 was associated with remarkably decreased risk of bladder cancer (adjusted odds ratio (OR), 0.27; 95% confidence interval (CI), 0.09–0.81; p = 0.019), compared with the AA genotype of rs11892031; and that CT/CC genotypes of rs401681 were associated with significantly increased risk of bladder cancer (adjusted OR, 1.79; 95% CI, 1.10–2.91; p = 0.02), compared with the TT genotype of rs401681. We further conducted stratification analysis to examine the correlation between single nucleotide polymorphism (SNP) rs11892031/rs401681 and tumor grade/stage. Results showed that heterogeneity in ORs of tumor categories was not significant for either rs11892031 or rs401681 (p > 0.05), indicating that the two SNPs seemingly do not associate with tumor grade and stage of bladder cancer in our study population. The present study suggests that the SNPs rs11892031 and rs401681 are associated with bladder cancer risk in a Chinese population. Future analyses will be conducted with more participants recruited in a case-control study.
PMCID: PMC4264113  PMID: 25347272
bladder cancer; genetic variations; polymorphism; genome-wide association studies
13.  Role of Nicotine Dependence on the Relationship between Variants in the Nicotinic Receptor Genes and Risk of Lung Adenocarcinoma 
PLoS ONE  2014;9(9):e107268.
Several variations in the nicotinic receptor genes have been identified to be associated with both lung cancer risk and smoking in the genome-wide association (GWA) studies. However, the relationships among these three factors (genetic variants, nicotine dependence, and lung cancer) remain unclear. In an attempt to elucidate these relationships, we applied mediation analysis to quantify the impact of nicotine dependence on the association between the nicotinic receptor genetic variants and lung adenocarcinoma risk. We evaluated 23 single nucleotide polymorphisms (SNPs) in the five nicotinic receptor related genes (CHRNB3, CHRNA6, and CHRNA5/A3/B4) previously reported to be associated with lung cancer risk and smoking behavior and 14 SNPs in the four ‘control’ genes (TERT, CLPTM1L, CYP1A1, and TP53), which were not reported in the smoking GWA studies. A total of 661 lung adenocarcinoma cases and 1,347 controls with a smoking history, obtained from the Environment and Genetics in Lung Cancer Etiology case-control study, were included in the study. Results show that nicotine dependence is a mediator of the association between lung adenocarcinoma and gene variations in the regions of CHRNA5/A3/B4 and accounts for approximately 15% of this relationship. The top two CHRNA3 SNPs associated with the risk for lung adenocarcinoma were rs1051730 and rs12914385 (p-value = 1.9×10−10 and 1.1×10−10, respectively). Also, these two SNPs had significant indirect effects on lung adenocarcinoma risk through nicotine dependence (p = 0.003 and 0.007). Gene variations rs2736100 and rs2853676 in TERT and rs401681 and rs31489 in CLPTM1L had significant direct associations on lung adenocarcinoma without indirect effects through nicotine dependence. Our findings suggest that nicotine dependence plays an important role between genetic variants in the CHRNA5/A3/B4 region, especially CHRNA3, and lung adenocarcinoma. This may provide valuable information for understanding the pathogenesis of lung adenocarcinoma and for conducting personalized smoking cessation interventions.
PMCID: PMC4169410  PMID: 25233467
14.  TERT-CLPTM1L Polymorphism rs401681 Contributes to Cancers Risk: Evidence from a Meta-Analysis Based on 29 Publications 
PLoS ONE  2012;7(11):e50650.
Some common genetic variants of TERT-CLPTM1L gene, which encode key protein subunits of telomerase, have been suggested to play a crucial role in tumorigenesis. The TERT-CLPTM1L polymorphism rs401681 was of special interest for cancers risk but with inconclusive results.
Methodology/Principal Findings
We performed a comprehensive meta-analysis of 29 publications with a total of 91263 cases and 735952 controls. We assessed the strength of the association between rs401681 and overall cancers risk and performed subgroup analyses by cancer type, ethnicity, source of control, sample size and expected power. Rs401681 C allele was found to be associated with marginally increased cancers risk, with per allele OR of 1.04 (95%CI = 1.00–1.08, Pheterogeneity<0.001) and an expected power of 1.000. Following further stratified analyses, the increased cancers risk were discovered in subgroups of lung, bladder, prostate, basal cell carcinomas and Asians, while a declined risk of pancreatic cancer and melanoma were detected.
These findings suggested that rs401681 C allele was a low-penetrance risk allele for the development of cancers of lung, bladder, prostate and basal cell carcinoma, but a potential protective allele for melanoma and pancreatic cancer.
PMCID: PMC3511286  PMID: 23226346
15.  Genetic markers of bone and joint health and physical capability in older adults: the HALCyon programme 
Bone  2013;52(1):278-285.
Good bone and joint health is essential for the physical tasks of daily living and poorer indicators of physical capability in older adults have been associated with increased mortality rates. Genetic variants of indicators of bone and joint health may be associated with measures of physical capability.
As part of the Healthy Ageing across the Life Course (HALCyon) programme, men and women aged between 52 and 90 + years from six UK cohorts were genotyped for a polymorphism associated with serum calcium (rs1801725, CASR), two polymorphisms associated with bone mineral density (BMD) (rs2941740, ESR1 and rs9594759, RANKL) and one associated with osteoarthritis risk rs3815148 (COG5). Meta-analysis was used to pool within-study effects of the associations between each of the polymorphisms and measures of physical capability: grip strength, timed walk or get up and go, chair rises and standing balance.
Few important associations were observed among the several tests. We found that carriers of the serum calcium-raising allele had poorer grip strength compared with non-carriers (pooled p = 0.05, n = 11,239) after adjusting for age and sex. Inconsistent results were observed for the two variants associated with BMD and we found no evidence for an association between rs3815148 (COG5) and any of the physical capability measures.
Our findings suggest elevated serum calcium levels may lead to lower grip strength, though this requires further replication. Our results do not provide evidence for a substantial influence of these variants in ESR1, RANKL and COG5 on physical capability in older adults.
► We examined associations between bone-related genotypes and physical capability. ► We conducted a meta-analysis on 12,836 middle-age adults. ► We found CASR may be associated with grip strength. ► No substantial support for specific bone mineral density variants and physical capability.
PMCID: PMC3526776  PMID: 23072920
BMD, bone mineral density; OA, osteoarthritis; BMI, body mass index; SNP, single nucleotide polymorphism; CaPS, Caerphilly Prospective Study; ELSA, English Longitudinal Study of Ageing; HAS, Hertfordshire Ageing Study; HCS, Hertfordshire Cohort Study; LBC1921, The Lothian Birth Cohort 1921; NSHD, National Survey of Health and Development; HWE, Hardy–Weinberg equilibrium; WHR, waist–hip ratio; GWAS, genome-wide association studies; Aging; Grip strength; Calcium; Bone mineral density; Osteoarthritis
16.  Novel genetic variants in the chromosome 5p15.33 region associate with lung cancer risk 
Carcinogenesis  2011;32(10):1493-1499.
Chromosome 5p15.33 has been identified by genome-wide association studies as one of the regions that associate with lung cancer risk. A few single-nucleotide polymorphisms (SNPs) in the telomerase reverse transcriptase (TERT) and cleft lip and palate transmembrane 1-like (CLPTM1L) genes located in this region have shown consistent associations. We performed dense genotyping of SNPs in this region to refine the previously reported association signals for lung cancer risk. Two hundred and fifteen SNPs were genotyped on an Illumina iSelect panel, in a hospital-based case–control study of 1681 lung cancer cases and 1235 unaffected controls. Association was tested using unconditional logistic regression, while adjusting for age, sex and pack-years smoked. Furthermore, since many of the SNPs were in linkage disequilibrium (LD), haplotype blocks were constructed, from which tagging SNPs at an r2 threshold of ≥0.95 were included in a stepwise forward selection logistic regression model. Of the 215 SNPs, 69 were significant at P < 0.05 in univariate analysis; of these, 35 SNPs meeting the r2 threshold were included in the multiple logistic regression model. Two SNPs, rs370348 (odds ratio = 0.76, P = 1.6 × 10−6) and rs4975538 (odds ratio = 1.18, P = 0.005), significantly associated with risk in the overall sample. Among ever smokers, rs4975615 (odds ratio = 0.75, P = 1.2 × 10−4) and rs4975538 (odds ratio = 1.26, P = 0.002) were significant, whereas among never-smokers, rs451360 (odds ratio = 0.62, P = 7.6 × 10−5) was significant. We refined the consistent association signal in this region, allowing for the considerable LD between SNPs and identified four novel SNPs that were independently and significantly associated with lung cancer risk. Results of these analyses strongly suggest effects on risk from several loci in the TERT/CLPTM1L region.
PMCID: PMC3179422  PMID: 21771723
17.  The association of telomere length and genetic variation in telomere biology genes 
Human mutation  2010;31(9):1050-1058.
Telomeres cap chromosome ends and are critical for genomic stability. Many telomere-associated proteins are important for telomere length maintenance. Recent genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) in genes encoding telomere-associated proteins (RTEL1 and TERT-CLPTM1) as markers of cancer risk. We conducted an association study of telomere length and 743 SNPs in 43 telomere biology genes. Telomere length in peripheral blood DNA was determined by Q-PCR in 3,646 participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and Nurses' Health Study. We investigated associations by SNP, gene, and pathway (functional group). We found no associations between telomere length and SNPs in TERT-CLPTM1L or RTEL1. Telomere length was not significantly associated with specific functional groups. Thirteen SNPs from four genes (MEN1, MRE11A, RECQL5, and TNKS) were significantly associated with telomere length. The strongest findings were in MEN1 (Gene-based P=0.006), menin, which associates with the telomerase promoter and may negatively regulate telomerase. This large association study did not find strong associations with telomere length. The combination of limited diversity and evolutionary conservation suggest that these genes may be under selective pressure. More work is needed to explore the role of genetic variants in telomere length regulation.
PMCID: PMC2932868  PMID: 20597107
Telomere length; single-nucleotide polymorphism; SNP; telomere biology; epidemiology
18.  The Impact of Polymorphic Variations in the 5p15, 6p12, 6p21 and 15q25 Loci on the Risk and Prognosis of Portuguese Patients with Non-Small Cell Lung Cancer 
PLoS ONE  2013;8(9):e72373.
Polymorphic variants in the 5p15, 6p12, 6p21, and 15q25 loci were demonstrated to potentially contribute to lung cancer carcinogenesis. Therefore, this study was performed to assess the role of those variants in non-small cell lung cancer (NSCLC) risk and prognosis in a Portuguese population.
Materials and Methods
Blood from patients with NSCLC was prospectively collected. To perform an association study, DNA from these patients and healthy controls were genotyped for a panel of 19 SNPs using a Sequenom® MassARRAY platform. Kaplan-Meier curves were used to assess the overall survival (OS) and progression-free survival (PFS).
One hundred and forty-four patients with NSCLC were successfully consecutively genotyped for the 19 SNPs. One SNP was associated with NSCLC risk: rs9295740 G/A. Two SNPs were associated with non-squamous histology: rs3024994 (VEGF intron 2) T/C and rs401681 C/T. Three SNPs were associated with response rate: rs3025035 (VEGF intron 7) C/T, rs833061 (VEGF –460) C/T and rs9295740 G/A. One SNP demonstrated an influence on PFS: rs401681 C/T at 5p15, p = 0.021. Four SNPs demonstrated an influence on OS: rs2010963 (VEGF +405 G/C), p = 0.042; rs3025010 (VEGF intron 5 C/T), p = 0.047; rs401681 C/T at 5p15, p = 0.046; and rs31489 C/A at 5p15, p = 0.029.
Our study suggests that SNPs in the 6p12, 6p21, and 5p15 loci may serve as risk, predictive and prognostic NSCLC biomarkers. In the future, SNPs identified in the genomes of patients may improve NSCLC screening strategies and therapeutic management as well.
PMCID: PMC3765163  PMID: 24039754
19.  Replication and Predictive Value of SNPs Associated with Melanoma and Pigmentation Traits in a Southern European Case-Control Study 
PLoS ONE  2013;8(2):e55712.
Genetic association studies have revealed numerous polymorphisms conferring susceptibility to melanoma. We aimed to replicate previously discovered melanoma-associated single-nucleotide polymorphisms (SNPs) in a Greek case-control population, and examine their predictive value.
Based on a field synopsis of genetic variants of melanoma (MelGene), we genotyped 284 patients and 284 controls at 34 melanoma-associated SNPs of which 19 derived from GWAS. We tested each one of the 33 SNPs passing quality control for association with melanoma both with and without accounting for the presence of well-established phenotypic risk factors. We compared the risk allele frequencies between the Greek population and the HapMap CEU sample. Finally, we evaluated the predictive ability of the replicated SNPs.
Risk allele frequencies were significantly lower compared to the HapMap CEU for eight SNPs (rs16891982 – SLC45A2, rs12203592 – IRF4, rs258322 – CDK10, rs1805007 – MC1R, rs1805008 - MC1R, rs910873 - PIGU, rs17305573- PIGU, and rs1885120 - MTAP) and higher for one SNP (rs6001027 – PLA2G6) indicating a different profile of genetic susceptibility in the studied population. Previously identified effect estimates modestly correlated with those found in our population (r = 0.72, P<0.0001). The strongest associations were observed for rs401681-T in CLPTM1L (odds ratio [OR] 1.60, 95% CI 1.22–2.10; P = 0.001), rs16891982-C in SCL45A2 (OR 0.51, 95% CI 0.34–0.76; P = 0.001), and rs1805007-T in MC1R (OR 4.38, 95% CI 2.03–9.43; P = 2×10−5). Nominally statistically significant associations were seen also for another 5 variants (rs258322-T in CDK10, rs1805005-T in MC1R, rs1885120-C in MYH7B, rs2218220-T in MTAP and rs4911442-G in the ASIP region). The addition of all SNPs with nominal significance to a clinical non-genetic model did not substantially improve melanoma risk prediction (AUC for clinical model 83.3% versus 83.9%, p = 0.66).
Overall, our study has validated genetic variants that are likely to contribute to melanoma susceptibility in the Greek population.
PMCID: PMC3564929  PMID: 23393597
20.  TERT’s role in colorectal carcinogenesis 
Molecular carcinogenesis  2012;52(7):507-513.
Telomerase reverse transcriptase (TERT) is one of the main functional subunits of the telomerase enzyme, which functions to increase telomere length. Studies have suggested that TERT may be important to the etiology of colorectal cancer. In this study we evaluate seven TERT SNPs in 1555 incident colon cancer cases and 1956 matched controls and in 754 incident rectal cancer cases and 959 matched controls. We observed that two TERT SNPs were associated with colon cancer. TERT rs2736118 was associated with increased risk of colon cancer (OR =1.31, 95% CI 1.02,1.69) and TERT-CLPTM1L rs2853668 was inversely associated with colon cancer (OR = 0.71, 95% CI 0.55,0.92). TERT-CLPTM1L rs2853668 also was inversely associated with rectal cancer (OR 0.62 95% CI 0.43,0.90). BMI interacted significantly with three TERT SNPs to alter risk of colon cancer. Those with the variant allele and who were obese had the greatest risk of colon cancer. TERT-CLPTM1L rs2853668 interacted significantly with aspirin/NSAID use, where those with the AA genotype had a much lower risk of colon cancer when using aspirin/NSAIDs than those with the other genotypes. Several TERT SNPs were uniquely associated with CIMP+ and MSI tumors. These data confirm earlier reports of the association between TERT-CLPTM1L and colon and rectal cancer. Our detection of a significant interaction with BMI for multiple TERT SNPs and unique associations with CIMP+ tumors enhance our understanding of TERT’s role in colon carcinogenesis.
PMCID: PMC3426620  PMID: 22351525
Colon Cancer; Rectal Cancer; TERT; CIMP+; BMI
21.  Association between Genetic Variants in DNA and Histone Methylation and Telomere Length 
PLoS ONE  2012;7(7):e40504.
Telomere length, a biomarker of aging and age-related diseases, exhibits wide variation between individuals. Common genetic variation may explain some of the individual differences in telomere length. To date, however, only a few genetic variants have been identified in the previous genome-wide association studies. As emerging data suggest epigenetic regulation of telomere length, we investigated 72 single nucleotide polymorphisms (SNPs) in 46 genes that involve DNA and histone methylation as well as telomerase and telomere-binding proteins and DNA damage response. Genotyping and quantification of telomere length were performed in blood samples from 989 non-Hispanic white participants of the Sister Study, a prospective cohort of women aged 35–74 years. The association of each SNP with logarithmically-transformed relative telomere length was estimated using multivariate linear regression. Six SNPs were associated with relative telomere length in blood cells with p-values<0.05 (uncorrected for multiple comparisons). The minor alleles of BHMT rs3733890 G>A (p = 0.041), MTRR rs2966952 C>T (p = 0.002) and EHMT2 rs558702 G>A (p = 0.008) were associated with shorter telomeres, while minor alleles of ATM rs1801516 G>A (p = 0.031), MTR rs1805087 A>G (p = 0.038) and PRMT8 rs12299470 G>A (p = 0.019) were associated with longer telomeres. Five of these SNPs are located in genes coding for proteins involved in DNA and histone methylation. Our results are consistent with recent findings that chromatin structure is epigenetically regulated and may influence the genomic integrity of telomeric region and telomere length maintenance. Larger studies with greater coverage of the genes implicated in DNA methylation and histone modifications are warranted to replicate these findings.
PMCID: PMC3394714  PMID: 22792358
22.  Detection of Pleiotropy through a Phenome-Wide Association Study (PheWAS) of Epidemiologic Data as Part of the Environmental Architecture for Genes Linked to Environment (EAGLE) Study 
PLoS Genetics  2014;10(12):e1004678.
We performed a Phenome-wide association study (PheWAS) utilizing diverse genotypic and phenotypic data existing across multiple populations in the National Health and Nutrition Examination Surveys (NHANES), conducted by the Centers for Disease Control and Prevention (CDC), and accessed by the Epidemiological Architecture for Genes Linked to Environment (EAGLE) study. We calculated comprehensive tests of association in Genetic NHANES using 80 SNPs and 1,008 phenotypes (grouped into 184 phenotype classes), stratified by race-ethnicity. Genetic NHANES includes three surveys (NHANES III, 1999–2000, and 2001–2002) and three race-ethnicities: non-Hispanic whites (n = 6,634), non-Hispanic blacks (n = 3,458), and Mexican Americans (n = 3,950). We identified 69 PheWAS associations replicating across surveys for the same SNP, phenotype-class, direction of effect, and race-ethnicity at p<0.01, allele frequency >0.01, and sample size >200. Of these 69 PheWAS associations, 39 replicated previously reported SNP-phenotype associations, 9 were related to previously reported associations, and 21 were novel associations. Fourteen results had the same direction of effect across more than one race-ethnicity: one result was novel, 11 replicated previously reported associations, and two were related to previously reported results. Thirteen SNPs showed evidence of pleiotropy. We further explored results with gene-based biological networks, contrasting the direction of effect for pleiotropic associations across phenotypes. One PheWAS result was ABCG2 missense SNP rs2231142, associated with uric acid levels in both non-Hispanic whites and Mexican Americans, protoporphyrin levels in non-Hispanic whites and Mexican Americans, and blood pressure levels in Mexican Americans. Another example was SNP rs1800588 near LIPC, significantly associated with the novel phenotypes of folate levels (Mexican Americans), vitamin E levels (non-Hispanic whites) and triglyceride levels (non-Hispanic whites), and replication for cholesterol levels. The results of this PheWAS show the utility of this approach for exposing more of the complex genetic architecture underlying multiple traits, through generating novel hypotheses for future research.
Author Summary
The Epidemiological Architecture for Genes Linked to Environment (EAGLE) study performed a Phenome-Wide Association Study (PheWAS) to investigate comprehensive associations between a wide range of phenotypes and single-nucleotide polymorphisms using the diverse genotypic and phenotypic data that exists across multiple populations in the National Health and Nutrition Examination Surveys (NHANES), conducted by the Centers for Disease Control and Prevention (CDC). In this study, we replicated known genotype-phenotype associations, identified genotypes associated with phenotypes related to previously reported associations, and most importantly, identified a series of novel genotype-phenotype associations. We also identified potential pleiotropy; that is, SNPs associated with more than one phenotype. We explored the features of these PheWAS results, characterizing any potential functionality of the SNPs of this study, determining association results that were found in more than one racial/ethnic group for the same SNP and phenotype, identifying novel direction of effect relationships for SNPs demonstrating potential pleiotropy, and investigating the association results in the context of gene-based biological networks. Through considering the SNP associations on multiple phenotypic outcomes, as well as through exploring pleiotropy, we may be able to leverage the results of PheWAS to uncover more of the complex underlying genomic architecture of complex traits.
PMCID: PMC4256091  PMID: 25474351
23.  A Genome-wide Association Study Identifies a Locus on Chromosome 14q21 as a Predictor of Leukocyte Telomere Length and as a Marker of Susceptibility for Bladder Cancer 
Telomeres play a critical role in maintaining genome integrity. Telomere shortening is associated with the risk of many aging-related diseases. Classic twin studies have shown that genetic components may contribute up to 80% of the heritability of telomere length. In the study we report here, we used a multi-stage genome-wide association study (GWAS) to identify genetic determinants of telomere length. The mean telomere length in peripheral blood leukocytes was measured by quantitative real-time polymerase chain reaction. We first analyzed 300,000 single-nucleotide polymorphisms (SNPs) in 459 healthy controls, finding 15,120 SNPs associated with telomere length at P < 0.05. We then validated these SNPs in two independent populations comprising 890 and 270 healthy controls, respectively. Four SNPs, including rs398652 on 14q21, were associated with telomere length across all three populations (pooled P-values of < 10−5). The variant alleles of these SNPs were associated with longer telomere length. We then analyzed the association of these SNPs with the risk of bladder cancer in a large case-control study. The variant allele of rs398652 was associated with a significantly reduced risk of bladder cancer (odds ratio = 0.81; 95% confidence interval, 0.67–0.97; P = 0.025), consistent with the correlation of this variant allele with longer telomeres. We then conducted a mediation analysis to examine whether the association between rs398652 and reduced bladder cancer risk is mediated by telomere length, finding that telomere length was a significant mediator of the relationship between rs398652 and bladder cancer (P = 0.013), explaining 14% of the effect. In conclusion, we found that the SNP rs398652 on 14q21 was associated with longer telomere length and a reduced risk of bladder cancer and that a portion of the effect of this SNP on bladder cancer risk was mediated by telomere length.
PMCID: PMC3076128  PMID: 21460395
SNP; telomere length; GWAS; bladder cancer risk
24.  Genetic Variation in Telomere Maintenance Genes, Telomere Length and Breast Cancer Risk 
PLoS ONE  2012;7(9):e44308.
Telomeres at the ends of eukaryotic chromosomes play a critical role in maintaining the integrity and stability of the genome and participate in the initiation of DNA damage/repair responses.
We performed a case-control study to evaluate the role of three SNPs (TERT-07, TERT-54 and POT1-03) in telomere maintenance genes previously found to be significantly associated with breast cancer risk. We used sister-sets obtained from the New York site of the Breast Cancer Family Registry (BCFR). Among the 313 sister-sets, there were 333 breast cancer cases and 409 unaffected sisters who were evaluated in the current study. We separately applied conditional logistic regression and generalized estimating equations (GEE) models to evaluate associations between the three SNPs and breast cancer risk within sister-sets. We examined the associations between genotype, covariates and telomere length among unaffected sisters using a GEE model.
We found no significant associations between the three SNPs in telomere maintenance genes and breast cancer risk by both conditional logistic regression and GEE models, nor were these SNPs significantly related to telomere length. Among unaffected sisters, shortened telomeres were statistically significantly correlated with never hormone replacement therapy (HRT) use. Increased duration of HRT use was significantly associated with reduced telomere length. The means of telomere length were 0.77 (SD = 0.35) for never HRT use, 0.67 (SD = 0.29) for HRT use <5yrs and 0.59 (SD = 0.24) for HRT use ≥5yrs after adjusting for age of blood donation and race and ethnicity.
We found that exogenous hormonal exposure was inversely associated with telomere length. No significant associations between genetic variants and telomere length or breast cancer risk were observed. These findings provide initial evidence to understand hormonal exposure in the regulation of telomere length and breast cancer risk but need replication in prospective studies.
PMCID: PMC3435409  PMID: 22970196
25.  A genome-wide SNP-association study confirms a sequence variant (g.66493737C>T) in the equine myostatin (MSTN) gene as the most powerful predictor of optimum racing distance for Thoroughbred racehorses 
BMC Genomics  2010;11:552.
Thoroughbred horses have been selected for traits contributing to speed and stamina for centuries. It is widely recognized that inherited variation in physical and physiological characteristics is responsible for variation in individual aptitude for race distance, and that muscle phenotypes in particular are important.
A genome-wide SNP-association study for optimum racing distance was performed using the EquineSNP50 Bead Chip genotyping array in a cohort of n = 118 elite Thoroughbred racehorses divergent for race distance aptitude. In a cohort-based association test we evaluated genotypic variation at 40,977 SNPs between horses suited to short distance (≤ 8 f) and middle-long distance (> 8 f) races. The most significant SNP was located on chromosome 18: BIEC2-417495 ~690 kb from the gene encoding myostatin (MSTN) [Punadj. = 6.96 × 10-6]. Considering best race distance as a quantitative phenotype, a peak of association on chromosome 18 (chr18:65809482-67545806) comprising eight SNPs encompassing a 1.7 Mb region was observed. Again, similar to the cohort-based analysis, the most significant SNP was BIEC2-417495 (Punadj. = 1.61 × 10-9; PBonf. = 6.58 × 10-5). In a candidate gene study we have previously reported a SNP (g.66493737C>T) in MSTN associated with best race distance in Thoroughbreds; however, its functional and genome-wide relevance were uncertain. Additional re-sequencing in the flanking regions of the MSTN gene revealed four novel 3' UTR SNPs and a 227 bp SINE insertion polymorphism in the 5' UTR promoter sequence. Linkage disequilibrium was highest between g.66493737C>T and BIEC2-417495 (r2 = 0.86).
Comparative association tests consistently demonstrated the g.66493737C>T SNP as the superior variant in the prediction of distance aptitude in racehorses (g.66493737C>T, P = 1.02 × 10-10; BIEC2-417495, Punadj. = 1.61 × 10-9). Functional investigations will be required to determine whether this polymorphism affects putative transcription-factor binding and gives rise to variation in gene and protein expression. Nonetheless, this study demonstrates that the g.66493737C>T SNP provides the most powerful genetic marker for prediction of race distance aptitude in Thoroughbreds.
PMCID: PMC3091701  PMID: 20932346

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