Loci for human leukocyte telomere length in the Singaporean Chinese population and trans-ethnic genetic studies

Dorajoo, Rajkumar; Chang, Xuling; Gurung, Resham L; Li, Zheng; Wang, Ling; Wang, Renwei; Beckman, Kenneth B.; Adams-Haduch, Jennifer; Yiamunaa, M; Liu, Sylvia; Meah, Wee Yang; Sim, Kar Seng; Lim, Su Chi; Friedlander, Yechiel; Liu, Jing; Dam, Rob M van; Yuan, Jian‐Min; Koh, Woon‐Puay; Khor, Chiea Chuen; Heng, Chew‐Kiat

doi:10.1038/s41467-019-10443-2

Cited by 71 publications

(108 citation statements)

References 66 publications

Supporting

Mentioning

100

Contrasting

Order By: Relevance

“…These six SNPs exhibit strong linkage disequilibrium (LD) (R 2 > 0.71) with rs2251795 in JPT. This result is concordant with the previous studies that indicated the association of rs2293607 (T allele) and rs10936599 (C allele) (absolute linkage equilibrium with T allele of rs2251795 in JPT) with longer leukocyte telomere length 30,43 . On the other hand, the previous study reported that the risk allele of rs2736100 on TERT (5p15.33) was associated with shorter telomere length, while TERC loci (rs10936600 on 3q26.2) was not associated with telomere length in leiomyoma tissues 15 .…”

Section: Discussionsupporting

confidence: 93%

Identification of a novel uterine leiomyoma GWAS locus in a Japanese population

Sakai

Tanikawa

Hirasawa

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Uterine leiomyoma is one of the most common gynaecologic benign tumours, but its genetic basis remains largely unknown. Six previous GWAS identified 33 genetic factors in total. Here, we performed a two-staged GWAS using 13,746 cases and 70,316 controls from the Japanese population, followed by a replication analysis using 3,483 cases and 4,795 controls. The analysis identified 9 significant loci, including a novel locus on 12q23.2 (rs17033114, P = 6.12 × 10 −25 with an OR of 1.177 (1.141-1.213), LINC00485). Subgroup analysis indicated that 5 loci (3q26.2, 5p15.33, 10q24.33, 11p15.5, 13q14.11) exhibited a statistically significant effect among multiple leiomyomas, and 2 loci (3q26.2, 10q24.33) exhibited a significant effect among submucous leiomyomas. Pleiotropic analysis indicated that all 9 loci were associated with at least one proliferative disease, suggesting the role of these loci in the common neoplastic pathway. Furthermore, the risk T allele of rs2251795 (3q26.2) was associated with longer telomere length in both normal and tumour tissues. Our findings elucidated the significance of genetic factors in the pathogenesis of leiomyoma. Uterine leiomyoma is one of the most common gynaecologic benign tumours. Its estimated lifetime risk is 30-50% in Japan 1 and 70-80% in European populations 2,3. Although leiomyoma is a benign neoplasm, patients exhibit many types of symptoms, such as vaginal bleeding, pelvic pain, or infertility 4. Over 600,000 hysterectomies were performed per year in the USA due to leiomyomas, and 9.4 billion dollars for annual medical expenses were needed in the USA 5. Therefore, leiomyomas are gaining much attention in health economics. Leiomyoma growth is stimulated by sex steroids, such as oestrogen and progesterone, and several aetiological factors, such as age, early age at menarche, obesity, and parity, are linked to an increased leiomyoma risk 2,6-11. In

show abstract

Section: Discussionsupporting

confidence: 93%

Identification of a novel uterine leiomyoma GWAS locus in a Japanese population

Sakai

Tanikawa

Hirasawa

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…The LTL for each sample was measured in duplicates and the average T/S ratio was used for subsequent analysis. Detailed description for LTL measurement in SCHS, including standard curve generation, PCR condition and coefficients of variation was published previously [ 18 ].…”

Section: Methodsmentioning

confidence: 99%

“…Genetic studies have identified several loci associated with leukocyte telomere length (LTL) [ 17 , 18 ]. However, the contribution of these variants, even in combination, to the overall heritability of LTL is modest.…”

Section: Introductionmentioning

confidence: 99%

Effect of plasma polyunsaturated fatty acid levels on leukocyte telomere lengths in the Singaporean Chinese population

Chang

Dorajoo

Sun

et al. 2020

Nutr J

Self Cite

View full text Add to dashboard Cite

Background Shorter telomere length (TL) has been associated with poor health behaviors, increased risks of chronic diseases and early mortality. Excessive shortening of telomere is a marker of accelerated aging and can be influenced by oxidative stress and nutritional deficiency. Plasma n6:n3 polyunsaturated fatty acid (PUFA) ratio may impact cell aging. Increased dietary intake of marine n-3 PUFA is associated with reduced telomere attrition. However, the effect of plasma PUFA on leukocyte telomere length (LTL) and its interaction with genetic variants are not well established. Methods A nested coronary artery disease (CAD) case-control study comprising 711 cases and 638 controls was conducted within the Singapore Chinese Health Study (SCHS). Samples genotyped with the Illumina ZhongHua-8 array. Plasma n-3 and n-6 PUFA were quantified using mass spectrometry (MS). LTL was measured with quantitative PCR method. Linear regression was used to test the association between PUFA and LTL. The interaction between plasma PUFAs and genetic variants was assessed by introducing an additional term (PUFA×genetic variant) in the regression model. Analysis was carried out in cases and controls separately and subsequently meta-analyzed using the inverse-variance weighted method. We further assessed the association of PUFA and LTL with CAD risk by Cox Proportional-Hazards model and whether the effect of PUFA on CAD was mediated through LTL by using structural equation modeling. Results Higher n6:n3 ratio was significantly associated with shorter LTL (p = 0.018) and increased CAD risk (p = 0.005). These associations were mainly driven by elevated plasma total n-3 PUFAs, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (p < 0.05). There was a statistically significant interaction for an intergenic single nucleotide polymorphism (SNP) rs529143 with plasma total n-3 PUFA and DHA on LTL beyond the genome-wide threshold (p < 5 × 10− 8). Mediation analysis showed that PUFA and LTL affected CAD risk independently. Conclusions Higher plasma n6:n3 PUFA ratio, and lower EPA and DHA n-3 PUFAs were associated with shorter LTL and increased CAD risk in this Chinese population. Furthermore, genetic variants may modify the effect of PUFAs on LTL. PUFA and LTL had independent effect on CAD risk in our study population.

show abstract

“…Some types of cancer are positively associated with telomere length. A number of groups such as the Telomeres Mendelian Randomization Collaboration [ 126 ] have analyzed genomic variants associated with telomere length at various loci, including POT1 [ 127 ], and have reported causal relationships between longer telomeres and the risk of cancers, including the following: melanoma, glioma, non-small-cell lung, serous ovarian, bladder, testicular germ cell, renal and endometrial [ 126 ]. It is interesting to speculate that this may because long telomeres allow a larger number of cell divisions while pro-oncogenic mutations are accumulating in nascent tumor cells, and that mutations in POT1 may also have the effect of increasing telomere length in telomerase-positive tissue stem cells through a decreased ability of the mutant POT1 protein to inhibit telomerase activity.…”

Section: Potential Mechanisms Of the Contribution Of Pot1 Dysfunctmentioning

confidence: 99%

Role of POT1 in Human Cancer

Poulos

Reddel

2020

Cancers

View full text Add to dashboard Cite

Telomere abnormalities facilitate cancer development by contributing to genomic instability and cellular immortalization. The Protection of Telomeres 1 (POT1) protein is an essential subunit of the shelterin telomere binding complex. It directly binds to single-stranded telomeric DNA, protecting chromosomal ends from an inappropriate DNA damage response, and plays a role in telomere length regulation. Alterations of POT1 have been detected in a range of cancers. Here, we review the biological functions of POT1, the prevalence of POT1 germline and somatic mutations across cancer predisposition syndromes and tumor types, and the dysregulation of POT1 expression in cancers. We propose a framework for understanding how POT1 abnormalities may contribute to oncogenesis in different cell types. Finally, we summarize the clinical implications of POT1 alterations in the germline and in cancer, and possible approaches for the development of targeted cancer therapies.

show abstract

Loci for human leukocyte telomere length in the Singaporean Chinese population and trans-ethnic genetic studies

Cited by 71 publications

References 66 publications

Identification of a novel uterine leiomyoma GWAS locus in a Japanese population

Identification of a novel uterine leiomyoma GWAS locus in a Japanese population

Effect of plasma polyunsaturated fatty acid levels on leukocyte telomere lengths in the Singaporean Chinese population

Role of POT1 in Human Cancer

Contact Info

Product

Resources

About