Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology

Abstract

Telomeres are engaged in a host of cellular functions, and their length is regulated by multiple genes. Telomere shortening, in the course of somatic cell replication, ultimately leads to replicative senescence. In humans, rare mutations in genes that regulate telomere length have been identified in monogenic diseases such as dyskeratosis congenita and idiopathic pulmonary fibrosis, which are associated with shortened leukocyte telomere length (LTL) and increased risk for aplastic anemia. Shortened LTL is observed in a host of aging-related complex genetic diseases and is associated with diminished survival in the elderly. We report results of a genome-wide association study of LTL in a consortium of four observational studies (n = 3,417 participants with LTL and genome-wide genotyping). SNPs in the regions of the oligonucleotide/ oligosaccharide-binding folds containing one gene (OBFC1; rs4387287; P = 3.9 × 10 −9) and chemokine (C-X-C motif) receptor 4 gene (CXCR4; rs4452212; P = 2.9 × 10 −8) were associated with LTL at a genome-wide significance level (P < 5 × 10 −8). We attempted replication of the top SNPs at these loci through de novo genotyping of 1,893 additional individuals and in silico lookup in another observational study (n = 2,876), and we confirmed the association findings for OBFC1 but not CXCR4. In addition, we confirmed the telomerase RNA component (TERC) as a gene associated with LTL (P = 1.1 × 10 −5). The identification of OBFC1 through genome-wide association as a locus for interindividual variation in LTL in the general population advances the understanding of telomere biology in humans and may provide insights into agingrelated disorders linked to altered LTL dynamics.eukocyte telomere length (LTL) undergoes progressive attrition with age and is relatively short in aging-related diseases, most notably atherosclerosis (1, 2). LTL displays high interindividual variation at birth (3, 4) and thereafter (5-7), and it is longer in women than in men (8-11) and longer in African Americans than in whites of European descent (10). Although controversy existed regarding the relation of LTL to survival in the elderly, recent studies in same-sex elderly twins have found that the twin with shorter LTL was more likely to die before the twin with longer LTL (12, 13).

Meta-analysis of telomere length in 19 713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect

“…11 Genetic association studies have revealed associations between single-nucleotide polymorphisms (SNPs) in the TERC and TERT genes and TL. [11][12][13][14][15][16][17] Other studies reported associations between SNPs in TERC and POT1 with human longevity, 11,17,18 suggesting that genes regulating TL may influence human longevity.…”

Common variants near TERC are associated with leukocyte telomere length in the Chinese Han population

“…This SNP is in strong linkage disequilibrium (LD) with rs12696304 (r 2 ¼0.91). 9 However, it is unclear whether this locus recently identified in Europeans and Americans exerts a similar effect on LTL in the Chinese population. In the present study, we sought to validate these reported associations between SNPs near TERC (rs12696304 and rs16847897) and LTL in 4016 unrelated individuals based on the Chinese Han population.…”

Human Stn1 protects telomere integrity by promoting efficient lagging-strand synthesis at telomeres and mediating C-strand fill-in

“…Deficiency of Ctc1 or Stn1 lengthens G-overhangs [2][3][4]. Genetic variants of Stn1 are associated with increased telomere length in leukocytes [7] and expressing a deletion mutant of Stn1 in cancer cells causes telomere lengthening [5], suggesting that Stn1 may be involved in telomere length regulation. Recently, mutations in Ctc1 have been isolated from patients with telomere disorder dyskeratosis congenita (DC) and patients with Coats Plus (CP) syndrome, a complex genetic disease clinically related to DC [8][9][10].…”