aminoacyl-tRNA Synthetase Genes Research Articles

Lethal NARS2-Related Disorder Associated With Rapidly Progressive Intractable Epilepsy and Global Brain Atrophy

BackgroundInfantile epileptic encephalopathy is a heterogeneous condition that has been associated with variants in more than 200 genes. The variability in findings and prognosis creates challenges to making the correct diagnosis and initiating the appropriate therapy. Biallelic variants in NARS2, a mitochondrial aminoacyl-tRNA synthetase gene, were recently associated with neurodegenerative disorders that include epilepsy. MethodsWe describe two infant brothers who presented with focal status epilepticus that progressed to lethal epileptic encephalopathy. We compared the cost of diagnostic laboratory evaluation for each child. Detailed NARS2 protein analysis was performed using a sequence-to-structure-to-function workflow, merging multiple homologous structures, to suggest biologic impact of the NARS2 variants. ResultsBrain magnetic resonance imaging showed rapid progression to generalized atrophy. Extensive metabolic, infectious, chromosomal and genetic testing of the first infant failed to reach a specific diagnosis. The younger brother presented similarly. Rapid whole exome sequencing was performed revealing novel biallelic variants in NARS2. The variants c.167A>G (p.Gln56Arg) and c.631T>A (p.Phe211Ile) were confirmed in a reserved sample from the older brother. Management was then redirected toward palliative care and the child died at age nine months. ConclusionsNARS2-related disorder should be considered in infants presenting with refractory seizures and rapid brain atrophy. Metabolic screening tests may be normal or yield nonspecific findings. Rapid whole exome sequencing in children with fulminant onset intractable epilepsy may minimize extensive diagnostic evaluation and aid in prognosis and medical management.

The role of tRNA synthetases in neurological and neuromuscular disorders.

Aminoacyl‐tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for charging tRNAs with their cognate amino acids, therefore essential for the first step in protein synthesis. Although the majority of protein synthesis happens in the cytosol, an additional translation apparatus is required to translate the 13 mitochondrial DNA‐encoded proteins important for oxidative phosphorylation. Most ARS genes in these cellular compartments are distinct, but two genes are common, encoding aminoacyl‐tRNA synthetases of glycine (GARS) and lysine (KARS) in both mitochondria and the cytosol. Mutations in the majority of the 37 nuclear‐encoded human ARS genes have been linked to a variety of recessive and dominant tissue‐specific disorders. Current data indicate that impaired enzyme function could explain the pathogenicity, however not all pathogenic ARSs mutations result in deficient catalytic function; thus, the consequences of mutations may arise from other molecular mechanisms. The peripheral nerves are frequently affected, as illustrated by the high number of mutations in cytosolic and bifunctional tRNA synthetases causing Charcot–Marie–Tooth disease (CMT). Here we provide insights on the pathomechanisms of CMT‐causing tRNA synthetases with specific focus on the two bifunctional tRNA synthetases (GARS, KARS).

A single Danio rerio hars gene encodes both cytoplasmic and mitochondrial histidyl-tRNA synthetases.

Histidyl tRNA Synthetase (HARS) is a member of the aminoacyl tRNA synthetase (ARS) family of enzymes. This family of 20 enzymes is responsible for attaching specific amino acids to their cognate tRNA molecules, a critical step in protein synthesis. However, recent work highlighting a growing number of associations between ARS genes and diverse human diseases raises the possibility of new and unexpected functions in this ancient enzyme family. For example, mutations in HARS have been linked to two different neurological disorders, Usher Syndrome Type IIIB and Charcot Marie Tooth peripheral neuropathy. These connections raise the possibility of previously undiscovered roles for HARS in metazoan development, with alterations in these functions leading to complex diseases. In an attempt to establish Danio rerio as a model for studying HARS functions in human disease, we characterized the Danio rerio hars gene and compared it to that of human HARS. Using a combination of bioinformatics, molecular biology, and cellular approaches, we found that while the human genome encodes separate genes for cytoplasmic and mitochondrial HARS protein, the Danio rerio genome encodes a single hars gene which undergoes alternative splicing to produce the respective cytoplasmic and mitochondrial versions of Hars. Nevertheless, while the HARS genes of humans and Danio differ significantly at the genomic level, we found that they are still highly conserved at the amino acid level, underscoring the potential utility of Danio rerio as a model organism for investigating HARS function and its link to human diseases in vivo.

Capture and Release of tRNA by the T-Loop Receptor in the Function of the T-Box Riboswitch.

In Gram-positive bacteria, the tRNA-dependent T-box riboswitch system regulates expression of amino acid biosynthetic and aminoacyl-tRNA synthetase genes through a transcription attenuation mechanism. Binding of uncharged tRNA "closes" the switch, allowing transcription read-through. Structural studies of the 100-nucleotide stem I domain reveal tRNA utilizes base pairing and stacking interactions to bind the stem, but little is known structurally about the 180-nucleotide riboswitch core (stem I, stem III, and antiterminator stem) in complex with tRNA or the mechanism of coupling of the intermolecular binding domains crucial to T-box function. Here we utilize solution structural and biophysical methods to characterize the interplay of the different riboswitch-tRNA contact points using Bacillus subtilis and Oceanobacillus iheyensis glycyl T-box and T-box:tRNA constructs. The data reveal that tRNA:riboswitch core binding at equilibrium involves only Specifier-anticodon and antiterminator-acceptor stem pairing. The elbow:platform stacking interaction observed in studies of the T-box stem I domain is released after pairing between the acceptor stem and the bulge in the antiterminator helix. The results are consistent with the model of T-box riboswitch:tRNA function in which tRNA is captured by stem I of the nascent mRNA followed by stabilization of the antiterminator helix and the paused transcription complex.

Emerging mechanisms of aminoacyl-tRNA synthetase mutations in recessive and dominant human disease.

Aminoacyl-tRNA synthetases (ARSs) are responsible for charging amino acids to cognate tRNA molecules, which is the essential first step of protein translation. Interestingly, mutations in genes encoding ARS enzymes have been implicated in a broad spectrum of human inherited diseases. Bi-allelic mutations in ARSs typically cause severe, early-onset, recessive diseases that affect a wide range of tissues. The vast majority of these mutations show loss-of-function effects and impair protein translation. However, it is not clear how a subset cause tissue-specific phenotypes. In contrast, dominant ARS-mediated diseases specifically affect the peripheral nervous system-most commonly causing axonal peripheral neuropathy-and usually manifest later in life. These neuropathies are linked to heterozygosity for missense mutations in five ARS genes, which points to a shared mechanism of disease. However, it is not clear if a loss-of-function mechanism or a toxic gain-of-function mechanism is responsible for ARS-mediated neuropathy, or if a combination of these mechanisms operate on a mutation-specific basis. Here, we review our current understanding of recessive and dominant ARS-mediated disease. We also propose future directions for defining the molecular mechanisms of ARS mutations toward designing therapies for affected patient populations.

Increased Transcription of the Seryl‐tRNA Synthetase (SARS) Gene in Response to Amino Acid Limitation is Mediated by an Intronic C/EBP‐ATF Response Element (CARE) that Functions as an Distal Enhancer

Amino acid (AA) limitation activates transcription from 16 of the 20 genes encoding cytoplasmic‐localized aminoacyl‐tRNA synthetase (ARS) genes via action of activating transcription factor 4 (ATF4) binding at C/EBP‐ATF‐Response‐Element (CARE) enhancers. Most of the activated genes have a functional CARE near the transcription start site (TSS), but for some the CARE is located downstream within the first intron. For all ARS genes, regardless of the CARE location, there is constitutive association of RNA polymerase II (Pol II) and the general transcription machinery (GTM) near the TSS. For those genes with a downstream CARE, during AA limitation there is enhanced recruitment of ATF4, Pol II, and the GTM to the CARE, not the TSS region. The AAR‐induced expression of ARS genes results from modulation of transcription elongation. Using the seryl‐tRNA synthetase (SARS) gene as a model, the goal of the present research was to further characterize the mechanism by which an intronic CARE enhancer, about 1 kb downstream of the TSS, functions to increase transcription in response to AA limitation. Using CRISPR‐CAS9 technology and HepG2 hepatoma cells, the SARS CARE was deleted and then the wild type and SARS‐CARE−/− cells were subjected to AA limitation. Analysis at both the promoter and the CARE regions of the SARS gene revealed significant changes in association of the GTM, transcription elongation factors, and enhancer binding proteins, in a CARE‐specific manner. Likewise, the absence of the CARE caused changes in localized histone modification within the SARS genomic locus. Collectively, the results indicate that intronic CARE enhancers, such as those contained within the ARS gene family, modulate transcription from the corresponding promoter through changes in histone modification and recruitment of specific factors that control elongation.Support or Funding Informationthis work was supported by a grant to MSK from The National Cancer Institute, CA203565.

Predicting the pathogenicity of aminoacyl-tRNA synthetase mutations.

Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed, essential enzymes responsible for charging tRNA with cognate amino acids-the first step in protein synthesis. ARSs are required for protein translation in the cytoplasm and mitochondria of all cells. Surprisingly, mutations in 28 of the 37 nuclear-encoded human ARS genes have been linked to a variety of recessive and dominant tissue-specific disorders. Current data indicate that impaired enzyme function is a robust predictor of the pathogenicity of ARS mutations. However, experimental model systems that distinguish between pathogenic and non-pathogenic ARS variants are required for implicating newly identified ARS mutations in disease. Here, we outline strategies to assist in predicting the pathogenicity of ARS variants and urge cautious evaluation of genetic and functional data prior to linking an ARS mutation to a human disease phenotype.

Decrypting ENCODEd epigenetic marks of human tRN-A-RS genes in normal, stem and cancer cell lines

Screening large-scale ENCODE data of 625 cytoplasmic transfer RNA (tRNAs) and 37 aminoacyl tRNA synthetase (AARSs) human genes, we deconstruct the array of relations between 10 histone marks affecting 15 chromatin states; their tissue specificity and variations and interchange amongst normal, cancerous and stem cells. The histone marks of RNA Pol II transcribed AARS genes share, but also contrast with that on RNA Pol III transcribed tRNA genes. tRNAs with identical/similar sequences may be in significantly varying states even within the same cell line; the chromatin scaffold, where the tRNA gene resides, is the key determinant. Hepatocellular carcinoma cell line has dominant H3K27me3, and singular clustering of other marks. Leukaemic cell line has hyperactive genes. The quiescence of the stem cells is encoded in the markers. Leaving aside the important exceptions in stem cells and elsewhere, tRNAs with cove scores above 50 have active markers and precise sets of transcription factors, and are usually well conserved compared to the low-scoring ones. Pseudo tRNAs are in heterochromatin/repressed state with anomalous exceptions in cancer cells. We motivate that Epigenetic-Phishing hacks the translation apparatus through the chromatin states governed by the histone marks of tRNA and AARS genes, and speculate on their therapeutic implications in cancer and on stem cells.

EPRS is a critical regulator of cell proliferation and estrogen signaling in ER+ breast cancer.

Aminoacyl tRNA synthetases (ARSs) are a class of enzymes with well-conserved housekeeping functions in cellular translation. Recent evidence suggests that ARS genes may participate in a wide array of cellular processes, and may contribute to the pathology of autoimmune disease, cancer, and other diseases. Several studies have suggested a role for the glutamyl prolyl tRNA synthetase (EPRS) in breast cancers, although none has identified any underlying mechanism about how EPRS contributes to carcinogenesis. In this study, we identified EPRS as upregulated in estrogen receptor positive (ER+) human breast tumors in the TCGA and METABRIC cohorts, with copy number gains in nearly 50% of samples in both datasets. EPRS expression is associated with reduced overall survival in patients with ER+ tumors in TCGA and METABRIC datasets. EPRS expression was also associated with reduced distant relapse-free survival in patients treated with adjuvant tamoxifen monotherapy for five years, and EPRS-correlated genes were highly enriched for genes predictive of a poor response to tamoxifen. We demonstrated the necessity of EPRS for proliferation of tamoxifen-resistant ER+ breast cancer, but not ER- breast cancer cells. Transcriptomic profiling showed that EPRS regulated cell cycle and estrogen response genes. Finally, we constructed a causal gene network based on over 2500 ER+ breast tumor samples to build up an EPRS-estrogen signaling pathway. EPRS and its regulated estrogenic gene network may offer a promising alternative approach to target ER+ breast cancers that are refractory to current anti-estrogens.

The C/ebp-Atf response element (CARE) location reveals two distinct Atf4-dependent, elongation-mediated mechanisms for transcriptional induction of aminoacyl-tRNA synthetase genes in response to amino acid limitation.

The response to amino acid (AA) limitation of the entire aminoacyl-tRNA synthetase (ARS) gene family revealed that 16/20 of the genes encoding cytoplasmic-localized enzymes are transcriptionally induced by activating transcription factor 4 (Atf4) via C/ebp-Atf-Response-Element (CARE) enhancers. In contrast, only 4/19 of the genes encoding mitochondrial-localized ARSs were weakly induced. Most of the activated genes have a functional CARE near the transcription start site (TSS), but for others the CARE is downstream. Regardless of the location of CARE enhancer, for all ARS genes there was constitutive association of RNA polymerase II (Pol II) and the general transcription machinery near the TSS. However, for those genes with a downstream CARE, Atf4, C/ebp-homology protein (Chop), Pol II and TATA-binding protein exhibited enhanced recruitment to the CARE during AA limitation. Increased Atf4 binding regulated the association of elongation factors at both the promoter and the enhancer regions, and inhibition of cyclin-dependent kinase 9 (CDK9), that regulates these elongation factors, blocked induction of the AA-responsive ARS genes. Protein pull-down assays indicated that Atf4 directly interacts with CDK9 and its associated protein cyclin T1. The results demonstrate that AA availability modulates the ARS gene family through modulation of transcription elongation.

Novel (Ovario) Leukodystrophy Related to a Mutation on Mitochondrial Alanine Amino Acyl tRNA Synthetase Gene Misdiagnosed as Multiple Sclerosis (P6.145)

Novel (Ovario) Leukodystrophy Related to a Mutation on Mitochondrial Alanine Amino Acyl tRNA Synthetase Gene Misdiagnosed as Multiple Sclerosis (P6.145)

Dimerization is required for GARS-mediated neurotoxicity in dominant CMT disease.

Charcot-Marie-Tooth (CMT) disease is a genetically heterogeneous group of peripheral neuropathies. Mutations in several aminoacyl-tRNA synthetase (ARS) genes have been implicated in inherited CMT disease. There are 12 reported CMT-causing mutations dispersed throughout the primary sequence of the human glycyl-tRNA synthetase (GARS). While there is strong genetic evidence linking GARS mutations to CMT disease, the molecular pathology underlying the neuromuscular and sensory phenotypes is still not fully understood. In particular, it is unclear whether the mutations result in a toxic gain of function, a partial loss of activity related to translation, or a combination of these mechanisms. We identified a zebrafish allele of gars (gars(s266)). Homozygous mutant embryos carry a C->A transversion, that changes a threonine to a lysine, in a residue next to a CMT-associated human mutation. We show that the neuromuscular phenotype observed in animals homozygous for T209K Gars (T130K in GARS) is due to a loss of dimerization of the mutated protein. Furthermore, we show that the loss of function, dimer-deficient and human disease-associated G319R Gars (G240R in GARS) mutant protein is unable to rescue the above phenotype. Finally, we demonstrate that another human disease-associated mutant G605R Gars (G526 in GARS) dimerizes with the remaining wild-type protein in animals heterozygous for the T209K Gars and reduces the function enough to elicit a neuromuscular phenotype. Our data indicate that dimerization is required for the dominant neurotoxicity of disease-associated GARS mutations and provide a rapid, tractable model for studying newly identified GARS variants for a role in human disease.

Essentiality Assessment of Cysteinyl and Lysyl-tRNA Synthetases of Mycobacterium smegmatis.

Discovery of mupirocin, an antibiotic that targets isoleucyl-tRNA synthetase, established aminoacyl-tRNA synthetase as an attractive target for the discovery of novel antibacterial agents. Despite a high degree of similarity between the bacterial and human aminoacyl-tRNA synthetases, the selectivity observed with mupirocin triggered the possibility of targeting other aminoacyl-tRNA synthetases as potential drug targets. These enzymes catalyse the condensation of a specific amino acid to its cognate tRNA in an energy-dependent reaction. Therefore, each organism is expected to encode at least twenty aminoacyl-tRNA synthetases, one for each amino acid. However, a bioinformatics search for genes encoding aminoacyl-tRNA synthetases from Mycobacterium smegmatis returned multiple genes for glutamyl (GluRS), cysteinyl (CysRS), prolyl (ProRS) and lysyl (LysRS) tRNA synthetases. The pathogenic mycobacteria, namely, Mycobacterium tuberculosis and Mycobacterium leprae, were also found to possess two genes each for CysRS and LysRS. A similar search indicated the presence of additional genes for LysRS in gram negative bacteria as well. Herein, we describe sequence and structural analysis of the additional aminoacyl-tRNA synthetase genes found in M. smegmatis. Characterization of conditional expression strains of Cysteinyl and Lysyl-tRNA synthetases generated in M. smegmatis revealed that the canonical aminoacyl-tRNA synthetase are essential, while the additional ones are not essential for the growth of M. smegmatis.

Niemeyer Virus: A New Mimivirus Group A Isolate Harboring a Set of Duplicated Aminoacyl-tRNA Synthetase Genes.

It is well recognized that gene duplication/acquisition is a key factor for molecular evolution, being directly related to the emergence of new genetic variants. The importance of such phenomena can also be expanded to the viral world, with impacts on viral fitness and environmental adaptations. In this work we describe the isolation and characterization of Niemeyer virus, a new mimivirus isolate obtained from water samples of an urban lake in Brazil. Genomic data showed that Niemeyer harbors duplicated copies of three of its four aminoacyl-tRNA synthetase genes (cysteinyl, methionyl, and tyrosyl RS). Gene expression analysis showed that such duplications allowed significantly increased expression of methionyl and tyrosyl aaRS mRNA by Niemeyer in comparison to APMV. Remarkably, phylogenetic data revealed that Niemeyer duplicated gene pairs are different, each one clustering with a different group of mimivirus strains. Taken together, our results raise new questions about the origins and selective pressures involving events of aaRS gain and loss among mimiviruses.

Expanded roles of leucine-responsive regulatory protein in transcription regulation of the Escherichia coli genome: Genomic SELEX screening of the regulation targets.

Leucine-responsive regulatory protein (Lrp) is a transcriptional regulator for the genes involved in transport, biosynthesis and catabolism of amino acids in Escherichia coli. In order to identify the whole set of genes under the direct control of Lrp, we performed Genomic SELEX screening and identified a total of 314 Lrp-binding sites on the E. coli genome. As a result, the regulation target of Lrp was predicted to expand from the hitherto identified genes for amino acid metabolism to a set of novel target genes for utilization of amino acids for protein synthesis, including tRNAs, aminoacyl-tRNA synthases and rRNAs. Northern blot analysis indicated alteration of mRNA levels for at least some novel targets, including the aminoacyl-tRNA synthetase genes. Phenotype MicroArray of the lrp mutant indicated significant alteration in utilization of amino acids and peptides, whilst metabolome analysis showed variations in the concentration of amino acids in the lrp mutant. From these two datasets we realized a reverse correlation between amino acid levels and cell growth rate: fast-growing cells contain low-level amino acids, whilst a high level of amino acids exists in slow-growing cells. Taken together, we propose that Lrp is a global regulator of transcription of a large number of the genes involved in not only amino acid transport and metabolism, but also amino acid utilization.

Novel, compound heterozygous, single-nucleotide variants in MARS2 associated with developmental delay, poor growth, and sensorineural hearing loss.

Novel, single-nucleotide mutations were identified in the mitochondrial methionyl amino-acyl tRNA synthetase gene (MARS2) via whole exome sequencing in two affected siblings with developmental delay, poor growth, and sensorineural hearing loss.We show that compound heterozygous mutations c.550C>T:p.Gln 184* and c.424C>T:p.Arg142Trp in MARS2 lead to decreased MARS2 protein levels in patient lymphoblasts. Analysis of respiratory complex enzyme activities in patient fibroblasts revealed decreased complex I and IV activities. Immunoblotting of patient fibroblast and lymphoblast samples revealed reduced protein levels of NDUFB8 and COXII, representing complex I and IV, respectively. Additionally, overexpression of wild-type MARS2 in patient fibroblasts increased NDUFB8 and COXII protein levels. These findings suggest that recessive single-nucleotide mutations in MARS2 are causative for a new mitochondrial translation deficiency disorder with a primary phenotype including developmental delay and hypotonia. Identification of additional patients with single-nucleotide mutations in MARS2 is necessary to determine if pectus carinatum is also a consistent feature of this syndrome.

Whole-Genome Sequence of Borrelia garinii Strain 935T Isolated from Ixodes persulcatus in South Korea.

We report here the genome sequence of Borrelia garinii strain 935T isolated from Ixodes persulcatus in South Korea. The 1,176,739 bp (G+C content, 27.73%) genome consists of 1,194 coding regions, 4 rRNA genes, and 33 aminoacyl-tRNA synthetase genes. This is the first whole-genome report of a Korean Borrelia species isolate.

Development of DNA mismatch repair gene, MutS, as a diagnostic marker for detection and phylogenetic analysis of algal Megaviruses

Megaviruses are generically defined as giant viruses with genomes up to 1.26Mb that infect eukaryotic unicellular protists; they are clearly delineated in DNA polymerase B phylogenetic trees; in addition, common features often include an associated virophage observed during infection; the presence of an amino acyl tRNA synthetase gene; and a nucleic acid mismatch repair protein, MutS gene. The archetypal representative of this evolving putative family is Mimivirus, an opportunistic pathogen of Acanthamoeba spp. originally thought to be a bacterium until its genome sequence was published in 2004. Subsequent analysis of marine metagenomic data revealed Megaviruses are likely ubiquitous on the surface ocean. Analysis of genome sequences of giant viruses isolated from naturally occurring marine protists such as microalgae and a microflagellate grazer, started the expansion of the Megaviridae. Here, we explored the possibility of developing Megavirus specific markers for mutS that could be used in virus molecular ecology studies. MutS is split into 15 different clades representing a wide range of cellular life, and two that contain Megaviruses, clade MutS7 and clade MutS8. We developed specific PCR primers that recognized Megavirus clade MutS8, a clade that we propose discriminates most of the algal Megaviruses. Analysis of seawater off the coast of Maine, US, revealed novel groups of algal Megaviruses that were present in all samples tested. The Megavirus clade MutS8 marker should be considered as a tool to reveal new diversity and distribution of this enigmatic group of viruses.

Genome sequencing and annotation of Amycolatopsis azurea DSM 43854(T).

We report the 9.2 Mb genome of the azureomycin A and B antibiotic producing strain Amycolatopsis azurea isolated from a Japanese soil sample. The draft genome of strain DSM 43854T consists of 9,223,451 bp with a G + C content of 69.0% and the genome contains 3 rRNA genes (5S–23S–16S) and 58 aminoacyl-tRNA synthetase genes. The homology searches revealed that the PKS gene clusters are supposed to be responsible for the biosynthesis of naptomycin, macbecin, rifamycin, mitomycin, maduropeptin enediyne, neocarzinostatin enediyne, C-1027 enediyne, calicheamicin enediyne, landomycin, simocyclinone, medermycin, granaticin, polyketomycin, teicoplanin, balhimycin, vancomycin, staurosporine, rubradirin and complestatin.

Potentially functional polymorphisms in aminoacyl-tRNA synthetases genes are associated with breast cancer risk in a Chinese population

Aminoacyl-tRNA synthetases (ARSs) are responsible for cellular protein synthesis and cell viability involving in various process of tumorigenesis. We hypothesized that genetic variants in core ARSs genes may play an important role in the development of breast cancer. Thus, we conducted a case-control study including 1064 breast cancer cases and 1073 cancer-free controls to evaluate the associations of 28 potentially functional polymorphisms in 12 core ARSs genes (AARS, CARS, EPRS, HARS, KARS, LARS, MARS, QARS, RARS, VARS, WARS, and YARS) with breast cancer risk. We found significant associations with the risk of breast cancer for rs34087264 in AARS [odds ratio (OR) = 1.15, 95% confidence interval (CI) = 1.01-1.31], rs801186 in HARS (OR = 1.29, 95% CI = 1.08-1.54), rs193466 in RARS (OR = 1.17, 95% CI = 1.02-1.35), and rs2273802 in WARS (OR = 1.14, 95% CI = 1.01-1.30). We further observed significant interactions between rs2273802 and age at the first live birth (P = 0.041), and between rs801186 and age on breast cancer risk (P = 0.018). Combined analysis of these four SNPs showed a significant allele-dosage association between the number of risk alleles and breast cancer risk (Ptrend = 2.00 × 10(-4) ). Compared with individuals with "0-2" risk alleles, those carrying "3," "4," or "5 or more" risk alleles had a 1.32 (95% CI = 1.07-1.64), 1.48 (95% CI = 1.45-1.91), or 1.60 folds (95% CI = 1.06-2.41) risk of breast cancer, respectively. These findings indicate that genetic variants in core ARSs genes may modify the individual susceptibility to breast cancer in Chinese population.