Genetic Determinants of Telomere Length in African American Youth

Zeiger, Andrew M.; White, Marquitta J.; Eng, Celeste; Oh, Sam S.; Witonsky, Jonathan; Goddard, Pagé C.; Contreras, María G.; Elhawary, Jennifer R.; Hu, Donglei; Mak, Angel C. Y.; Lee, Eunice; Keys, Kevin L.; Samedy‐Bates, Lesly‐Anne; Risse-Adams, Oona; Magaña, Joaquín; Huntsman, Scott; Salazar, Sandra; Davis, Adam; Meade, Kelley; Brigino-Buenaventura, Emerita; LeNoir, Michael A.; Farber, Harold J.; Bibbins‐Domingo, Kirsten; Borrell, Luisa N.; Burchard, Esteban G.

doi:10.1038/s41598-018-31238-3

Cited by 21 publications

(12 citation statements)

References 70 publications

(103 reference statements)

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“…This immunological advantage may be at the expense of increased cancer risk through a reduced tumor suppressor function and increased replicative life span for somatic cells. To date, no single gene variant has been strongly associated with telomere-length differences [32]. Our studies in LCLs suggests that the S47 variant results in shorter, unstable telomeres with increased sensitivity to DNA damage and reduced replicative senescence.…”

Section: Discussionmentioning

confidence: 83%

Elevated telomere dysfunction in cells containing the African-centric Pro47Ser cancer-risk variant of TP53

et al. 2019

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Subtelomeric transcription and chromatin can have a significant impact on telomere repeat maintenance and chromosome stability. We have previously found that tumor suppressor protein p53 (TP53) can bind to retrotransposon-like elements in a majority of human subtelomeres to regulate TERRA transcription and telomeric histone acetylation in response to DNA damage. TP53 also prevents the accumulation of γH2AX DNA-damage signaling at telomeres. We now show that the inherited TP53 polymorphism Pro47Ser (hereafter S47), which is enriched in populations of African descent, is associated with elevated marks of telomere dysfunction. We found that human and mouse cells carrying the S47 variant show increased γH2AX DNA-damage signals at telomeres, as well as reduced TERRA transcription and subtelomeric histone acetylation in response to DNA damage stress. Cell-lines containing inducible genes for P47 or S47 versions of p53, as well mouse embryo fibroblasts (MEFs) reconstituted with human p53, showed elevated telomere-induced DNA damage foci and metaphase telomere signal loss in cells with S47. Human lymphoblastoid cell lines (LCLs) derived from individuals homozygous for S47, show increased accumulation of subtelomeric γH2AX and unstable telomere repeats in response to DNA damage relative to age matched LCLs homozygous for P47. Furthermore, LCLs with S47 had reduced replicative lifespan. These studies indicate that the naturally occurring S47 variant of p53 can affect telomeric chromatin, telomere repeat stability, and replicative capacity. We discuss the potential evolutionary significance of the S47 variant to African populations with respect to telomere regulation and the implications for inherited health disparities.

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Section: Discussionmentioning

confidence: 83%

Elevated telomere dysfunction in cells containing the African-centric Pro47Ser cancer-risk variant of TP53

et al. 2019

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“…The rich genetic structure of Africans (Zeiger et al 2018) has received much attention. As indicated before, largescale migration events that occurred throughout history and a large mixture of ancestries caused a massive and subdivided population structure in Africa (Tishkoff et al 2009).…”

Section: Discussionmentioning

confidence: 99%

A different view on fine-scale population structure in Western African populations

et al. 2019

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Due to its long genetic evolutionary history, Africans exhibit more genetic variation than any other population in the world. Their genetic diversity further lends itself to subdivisions of Africans into groups of individuals with a genetic similarity of varying degrees of granularity. It remains challenging to detect fine-scale structure in a computationally efficient and meaningful way. In this paper, we present a proof-of-concept of a novel fine-scale population structure detection tool with Western African samples. These samples consist of 1396 individuals from 25 ethnic groups (two groups are African American descendants). The strategy is based on a recently developed tool called IPCAPS. IPCAPS, or Iterative Pruning to CApture Population Structure, is a genetic divisive clustering strategy that enhances iterative pruning PCA, is robust to outliers and does not require a priori computation of haplotypes. Our strategy identified in total 12 groups and 6 groups were revealed as fine-scale structure detected in the samples from Cameroon, Gambia, Mali, Southwest USA, and Barbados. Our finding helped to explain evolutionary processes in the analyzed West African samples and raise awareness for fine-scale structure resolution when conducting genome-wide association and interaction studies.

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“…However, these have primarily been performed in populations of European ancestry and explained only a modest proportion of LTL variation (approximately 2% of phenotypic variation) 17 . Given that genetic determinants of telomere length may differ by ethnicity 2,23,24 , it is likely that performing genetic studies in diverse populations could uncover additional genetic loci associated with LTL, as already seen in the South-Asian and African ancestry populations 22,25 and illuminate on cellular processes involved in human telomere length homeostasis.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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Genetic factors underlying leukocyte telomere length (LTL) may provide insights into telomere homeostasis, with direct links to disease susceptibility. Genetic evaluation of 23,096 Singaporean Chinese samples identifies 10 genome-wide loci ( P < 5 × 10 −8 ). Several of these contain candidate genes ( TINF2 , PARP1 , TERF1 , ATM and POT1 ) with potential roles in telomere biology and DNA repair mechanisms. Meta-analyses with additional 37,505 European individuals reveals six more genome-wide loci, including associations at MPHOSPH6 , NKX2-3 and TYMS . We demonstrate that longer LTL associates with protection against respiratory disease mortality [HR = 0.854(0.804–0.906), P = 1.88 × 10 −7 ] in the Singaporean Chinese samples. We further show that the LTL reducing SNP rs7253490 associates with respiratory infections ( P = 7.44 × 10 −4 ) although this effect may not be strongly mediated through LTL. Our data expands on the genetic basis of LTL and may indicate on a potential role of LTL in immune competence.

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Genetic Determinants of Telomere Length in African American Youth

Cited by 21 publications

References 70 publications

Elevated telomere dysfunction in cells containing the African-centric Pro47Ser cancer-risk variant of TP53

Elevated telomere dysfunction in cells containing the African-centric Pro47Ser cancer-risk variant of TP53

A different view on fine-scale population structure in Western African populations

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

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