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Original Research

Associations of BRAP polymorphisms with the risk of alcohol dependence and scores on the Alcohol Use Disorders Identification Test

, , , , , & show all
Pages 83-94 | Published online: 24 Dec 2018

Abstract

Background

Alcohol dependence (AD) is a common disorder that is influenced by genetic as well as environmental factors. A previous genome-wide association study (GWAS) of the Korean population performed by our research group identified a number of genes, including BRCA1-associated protein (BRAP) and protein arginine methyltransferase 8 (PRMT8), as novel genetic markers of AD.

Methods

The present investigation was a fine-mapping follow-up study of 459 AD and 455 non-AD subjects of Korean descent to determine the associations between BRAP and PRMT8 polymorphisms and AD. The Alcohol Use Disorders Identification Test (AUDIT) was administered to screen for the degree of AD risk in the subjects and 58 genetic variants, 5 for BRAP and 53 for PRMT8, were genotyped for subsequent association analyses.

Results

In the present case–control analysis, BRAP rs3782886 showed the most significant association signal with a risk of AD (P=1.29×10−16, Pcorr =7.74×10−16, OR =0.19). There were also significant differences in the overall and subcategory scores for the BRAP genetic variants, including rs3782886 (P=9.94×10−31, Pcorr =5.96×10−30 at rs3782886 for the overall AUDIT score). However, the genetic effects of PRMT8 polymorphisms observed in our previous GWAS were not replicated in the present study (minimum P=0.0005, Pcorr >0.05, OR =0.30 at rs4766139 in the recessive model). Furthermore, the single-nucleotide polymorphisms of PRMT8 were not associated with the overall and subcategory AUDIT scores.

Conclusion

The present findings suggest that the genetic variants of BRAP may contribute to a predisposition for an alcohol use disorder.

Introduction

Alcohol dependence (AD) is a severe psychiatric disorder with a multifactorial etiology that includes complex gene-to-gene and gene-to-environment interactions.Citation1Citation3 Adoption and twin studies conducted to clarify the effects of genes in this etiology have revealed that genetic factors comprise 50%–60% of the heritability of AD susceptibility.Citation4,Citation5 Additionally, adoptees are more similar to their biologic parents than their adoptive parents in terms of AD susceptibilityCitation6,Citation7 and the higher concordance for AD susceptibility between twins is derived from shared genetic components.Citation8 In fact, several candidate studies assessing the risk loci for AD were designed to target gene variants related to alcohol metabolism or neurobiology.Citation9Citation13

Recently, a number of genome-wide association studies (GWASs) have investigated genetic markers of AD, including the genomic region of chromosome 4q22-q32, which includes alcohol dehydrogenase (ADH) cluster genes.Citation14Citation17 Furthermore, a recent GWAS of a Korean AD cohort revealed that three chromosomal regions are associated with AD, including the ADH gene cluster and ALDH2, which participate in alcohol metabolism (minimum P=6.46×10−8, OR =2.73 at ADH7 rs10516441 of the ADH gene cluster and P=8.42×10−8, OR =0.22 at ALDH2 rs671). The genetic effects of the ADH gene cluster were also replicated in a Korean population (minimum P=2.63×10−21 at ADH1B rs1229984). In addition to genes related to alcohol metabolism, genes known to participate in neurodevelopment, such as BRCA1-associated protein (BRAP) and protein arginine methyltransferase 8 (PRMT8), have multiple association signals with the risk of AD (P=4.65×10−6, OR =0.31 at BRAP rs3782886 and P=1.77×10−5, OR =1.96 at PRMT8 rs876594).Citation18 Based on the polygenic hypothesis of AD pathophysiology, it is possible that multiple genetic loci associated with neurobiologic pathways could be associated with the risk of AD. Thus, the present investigation conducted followup replication studies of our previous GWAS of a Korean cohort with AD to identify associations between the risk of AD and novel candidate genes other than those related to alcohol metabolism.

Methods

Subject recruitment and the Alcohol Use Disorders Identification Test (AUDIT)

The present study recruited 914 individuals of Korean descent from Hangang Sacred Heart, Keyo, Dasarang, KARF, and Humanity and Youth Rehabilitation Hospitals. Of these individuals, 459 were alcoholic subjects and 455 were nonalcoholic subjects; the nonalcoholic subjects were recruited from the industrial medical center of Hangang Sacred Heart Hospital. All subjects enrolled in this study underwent inpatient therapy for >30 days due to their drinking problems and the patients who comprised a subgroup in our previous study did not have major medical or comorbid psychiatric illnesses other than an alcohol-related disorder.Citation11,Citation19 AD was diagnosed clinically with a semi-structured interview based on the guidelines of the Diagnostic and Statistical Manual of Mental Disorders IVCitation20 by skilled psychiatrists as well as on information provided by their caregivers; diagnostic validity was high because all subjects were hospitalized in alcohol-related hospitals. Most of the healthy controls were nondrinkers, although some were occasional light drinkers as revealed by a drinking habit questionnaire. Subjects who had first-degree relatives with major psychiatric disorders, including schizophrenia, mood disorders, and/or substance abuse disorders other than nicotine dependence, were excluded from the present analyses. The study protocol was approved by the institutional review board of each hospital. All participants provided written informed consent, and that this study was conducted in accordance with the Declaration of Helsinki.

The AUDIT was administered to screen for the degree of AD risk in the subjects.Citation21 The AUDIT consists of ten items and is often used in Asian populations, including the Korean population. This tool includes three domain structures: items 1–3 measure alcohol consumption, items 4–6 assess AD, and items 7–10 evaluate alcohol-related harm.Citation22,Citation23 All items are equally weighted, the scores range from 0 to 4, and the total AUDIT score is determined by summing all subcategory scores; a higher AUDIT score is indicative of a higher risk in each category.

Genotyping of the BRAP and PRMT8 polymorphisms

To assess genomic DNA precisely, a DNA quantification analysis was performed using Quanti-iT PicoGreen fluorescence dye (Molecular Probes, Eugene, OR, USA). The quantification reactions were performed according to the manufacturer’s instructions (Manual No: MP0758) and the concentration of each type of genomic DNA was measured with a Fluorescence Reader (VICTOR2 fluorometer; Perkin Elmer, CA, USA). Candidate single-nucleotide polymorphisms (SNPs) of BRAP and PRMT8 were selected from among Japanese and Han Chinese genotype data using the 1,000 Genomes database (http://browser.1000genomes.org/index.html) based on the following conditions: 1) minor allele frequency (MAF) >5%; 2) linkage disequilibrium (LD) status based on an LD coefficient (r2) >0.98; 3) positions within the gene; and 4) amino acid changes. A total of 58 SNPs (5 from BRAP and 53 from PRMT8) were genotyped in the 459 alcoholic subjects and 455 nonalcoholic subjects using the Illumina Golden Gate genotyping system at a multiplex level.Citation24 The genotyping quality score for retaining data was set to 0.25 and SNPs that did not satisfy the following criteria were excluded: 1) a minimum call rate of 95% and 2) no duplicate errors.

Statistical analysis

The LD was obtained using Haploview v4.2 software (http://www.broadinstitute.org/mpg/haploview) based on assessments of Lewontin’s D′ (|D′|) and the r2 between all pairs of biallelic loci.Citation25 Haplotypes were determined using PHASE v2.0 softwareCitation26 and comparisons of the genotype distributions between alcoholic and nonalcoholic subjects were carried out with a logistic regression model adjusted for age (continuous value) and sex (male =0, female =1) using SAS, version 9.4 (SAS Institute Inc., Cary, NC, USA). Associations between SNPs and AUDIT scores were also calculated using a linear regression model adjusted for age and sex. Statistical power of single associations was calculated using the Power for Genetic Association Analyses software,Citation27 with false positive rate of 5%, disease prevalence of 4%,Citation28 given MAFs and sample sizes, and assuming a relative risk of 1.5. Corrected P-values for multiple testing were calculated using the Bonferroni correction method.

Results

The present study included a total of 914 subjects who were categorized as either AD (n=459, mean age =47.37 years, range =21–80 years, 410 males and 49 females) or non-AD (n=455, mean age =44.21 years, range =20–79 years, 351 males and 104 females; ); there were no significant differences between the AD and non-AD subjects in terms of age or sex. The degree of AD risk was estimated using AUDIT scores.

Table 1 Clinical profiles of study subjects

Table 2 Follow-up analysis of BRAP polymorphisms with the risk of alcohol dependence in Korean subjects

Genotyping and haplotype analyses of BRAP and PRMT8 SNPs

A total of 58 SNPs (5 from BRAP and 53 from PRMT8) were genotyped in all subjects. The position, LD, and haplotype information of the investigated SNPs are shown in . The BRAP and PRMT8 polymorphisms investigated in the present study were parsed into 1 LD block and 11 LD blocks, respectively. Not all haplotypes were selected for subsequent analyses because some haplotypes were tagged by SNPs on each gene.

Association analyses of BRAP and PRMT8 SNPs with AD

Logistic regression analyses were conducted to investigate the associations between BRAP and PRMT8 genetic variants and the risk of AD. In the case–control analysis, three genetic variants of BRAP (rs847895, rs3782886, and rs3803171) were associated with the risk of AD (minimum P=1.29×10−16, OR =0.19 at rs3782886) under the codominant model (). Of the PRMT8 SNPs, one genetic variant (rs12581829) was marginally associated with the risk of AD under the codominant model (P=0.02, OR =0.72) and two SNPs (rs4766138 and rs4766139) showed nominal associations with the risk of AD under the recessive model (P=0.002, OR =0.33 and P=0.0005, OR =0.30, respectively; ). However, the statistical significance of the PRMT8 SNPs disappeared after corrections for multiple analyses were performed.

Associations of BRAP and PRMT8 SNPs with the degree of AD risk

To screen for the degree of risk of AD, additional association analyses between the AUDIT score and genetic variants of BRAP or PRMT8 that showed associations with the risk of AD were conducted. For BRAP, three SNPs (rs3803171, rs3782886, and rs847895) and one haplotype (ht1) were significantly associated with the overall AUDIT score (minimum P=9.94×10−31 and minimum Pcorr =5.96×10−30 at rs3782886) and three SNPs had significant association signals with alcohol use disorders (minimum P=3.30×10−46 and Pcorr =1.98×10−45 at rs3782886 for alcohol consumption, minimum P=1.95×10−17 and Pcorr =1.17×10−16 at rs3782886 for AD, and minimum P=3.89×10−22 and Pcorr =2.34×10−21 at rs3782886 for alcohol-related harm) based on the AUDIT scoring (). The strengths of the associations between the BRAP SNPs and alcohol use disorders were greater in non-AD subjects. Additionally, BRAP rs3782886 was strongly associated with the overall AUDIT score (P=1.40×10−24 and Pcorr =8.39×10−24) and the subcategories of the AUDIT (P=6.46×10−32 and Pcorr =3.87×10−31 for alcohol consumption, P=2.59×10−7 and Pcorr =1.56×10−6 for AD, and P=3.88×10−10, and Pcorr =2.32×10−9 for alcohol-related harm; ).

Table 3 Association analysis of BRAP polymorphisms with the AUDIT and subcategorical scores in all study subjects (n=914)

Table 4 Association analysis of BRAP polymorphisms with the AUDIT and subcategorical scores in non-alcohol dependence subjects (n=455)

The association analysis of the PRMT8 SNPs revealed that individuals with three SNPs (rs4766138, rs4766139, and rs12581829) showed a marginal association signal with the overall AUDIT score (P=0.01, 0.01, and 0.008, respectively; ). However, the statistical significance of these associations disappeared after corrections for multiple analyses were performed.

Discussion

AD is a distressing chronic disease that results in significant human, social, and economic burdens.Citation29 Drinking alcohol influences brain function by affecting brain tissues, brain cells, and the central nervous system (CNS). Accordingly, excessive alcohol consumption may result in severe deficits in cognition and memory function that are highly correlated with activity in nerve pathways.Citation30 In a previous GWAS from our research group,Citation18 BRAP and PRMT8 affected neurodevelopment in brain regions that were identified as having potential susceptibility loci for AD (P=4.65×10−6 at BRAP rs3782886 and P=1.77×10−5 at PRMT8 rs876594). Thus, BRAP and PRMT8 were proposed as novel candidate genes for controlling the amount of alcohol consumption.

BRAP is a regulatory protein that binds to several translocation signal proteins in the cytoplasmCitation31 and, based on its functions, can modulate several intracellular signaling pathways. First, BRAP regulates the mitogen-activated protein kinase (MAPK) signaling pathway during CNS development through its function as a ubiquitin ligase.Citation32 MAPK signaling is a known regulator of cell survival, proliferation, and differentiation as well as the production of proinflammatory cytokines. It has also been suggested that activation of the MAPK signaling pathway contributes to the neurotropic factor-mediated regulation of alcohol consumption.Citation33 Second, BRAP acts as a primary mediator of inflammatory cascades by regulating the nuclear translocation of nuclear factor kappa B (NF-κB).Citation34,Citation35 A postmortem study in humans showed that NF-κB is downregulated in the brains of alcoholic patients.Citation36 Similarly, other studies have shown that BRAP silencing via RNA interference inhibits NF-κB activation and that BRAP expression is ~twofold higher due to the genetic variant rs11066001, which is a tagging SNP of rs3782886 that has a high correlation value (r2=0.81).Citation31,Citation37,Citation38 Taken together, these findings suggest that changes in BRAP expression induced by genetic variants might affect the NF-κB inflammatory cascade and may be a mechanism by which BRAP affects the risk level of AD. However, the direct and/or indirect functional impacts of BRAP on AD remain to be tested because the direct functional impacts of BRAP on several human disorders, including schizophrenia,Citation31 myocardial infarction,Citation39 carotid atherosclerosis,Citation37 and metabolic syndrome,Citation40 are not yet fully understood. However, the function of BRAP as a mediator of the translocation of signaling proteins might be a plausible explanation for the association between BRAP and human diseases with distinct pathophysiologies. Taken together, these data support the notion that BRAP has a genetic effect on alcohol-related disorders via the control of various signaling pathways.

PRMT8 is a member of the arginine methyltransferase gene family that influences several cellular processes, such as DNA repair, RNA transcription, and signal transduction, by methylating target regions.Citation41 Of this protein family, only PRMT8 has an expression that is highly restricted to the CNS.Citation42 Several studies have reported that arginine methylation is important for neurogenesis, which is essential for neurologic function.Citation41,Citation43 Although PRMT8 genetic variants showed nominal association signals with the risk of AD, genetic variants of PRMT8 might be implicated in the neuronal differentiation in the brain region.

Interestingly, the strength of the association between BRAP and alcohol use disorders was greater in nonalcoholic subjects than alcoholic subjects in the present study. BRAP is located a short distance from, and is affected by, the concomitant activity of ALDH2, which is highly related to AD. Thus, their association may be more prominent in nonalcoholic subjects because when ALDH2 induces lower rates of ALDH2 catalytic activity, even a small amount of alcohol consumption can cause a dramatic enhancement in acetaldehyde levels that triggers a highly aversion reaction. Therefore, these subjects may be classified as nonalcoholics even though there is an association between BRAP and alcohol use disorders. BRAP may also be a common gene associated with the characteristic patterns of alcohol use among nonalcoholic subjects. Taken together, these findings suggest that the effects of BRAP in nonalcoholics are very complicated and, as a result, interpretations of the present results should be made cautiously.

Although some evidence supports an association between BRAP and AD, it is also important to discuss the independent effects of this gene. There are strong LD values between BRAP rs3782886 and ALDH2 rs671Citation44 and it will be difficult to identify strong genetic influences on AD pathophysiology that arise from only a single or several genes. On the other hand, AD pathophysiology is associated with several unexplained effects from single or several genes, that is, the roles that ADH and ALDH2 play in alcohol metabolism. Despite the fact that these effects are relatively small, many genes with limited effects may be involved in the pathophysiology of AD. Based on the polygenic hypothesis of AD pathophysiology, it is possible that multiple genetic loci in genes related to neurobiologic pathways could be associated with the risk of AD. Although BRAP has fewer independent effects in AD pathophysiology than ALDH2, BRAP may be involved in this process via the summation of many genes with small effects. The present findings suggest that BRAP may contribute to AD pathophysiology via contributions following the summation of its effects with the well-known effects of ALDH2.

Conclusion

Based on findings from a GWAS and a replication study of a Korean AD cohort, the present study was the first to propose that a BRAP SNP (rs3782886) was associated with AD. A future follow-up replication study using an independent sample may strengthen the present results and provide substantiation of the proposed polygenetic influences. Nevertheless, these novel findings provide important evidence that will contribute to the current understanding of the genetic etiology of AD as well as the development of assessments of AD risk that can be used in conjunction with conventional causal markers.

Acknowledgments

This study was supported by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (grant number A084589) and a grant from Hallym University Research Fund 2015, Republic of Korea (HRF-2015–28). This paper was presented at the 16th World Congress of Psychiatry, Madrid, Spain, as an abstract presentation with interim findings on September 15, 2014.

Supplementary materials

Figure S1 Haplotypes and LD structures of BRAP and PRMT8.

Notes: (A) Haplotypes of and (B) LDs among BRAP polymorphisms. (C) Haplotypes of and (D) LDs among PRMT8 polymorphisms.

Abbreviations: BRAP, BRCA1-associated protein; LD, linkage disequilibrium; PRMT8, protein arginine methyltransferase.

Figure S1 Haplotypes and LD structures of BRAP and PRMT8.Notes: (A) Haplotypes of and (B) LDs among BRAP polymorphisms. (C) Haplotypes of and (D) LDs among PRMT8 polymorphisms.Abbreviations: BRAP, BRCA1-associated protein; LD, linkage disequilibrium; PRMT8, protein arginine methyltransferase.
Figure S1 Haplotypes and LD structures of BRAP and PRMT8.Notes: (A) Haplotypes of and (B) LDs among BRAP polymorphisms. (C) Haplotypes of and (D) LDs among PRMT8 polymorphisms.Abbreviations: BRAP, BRCA1-associated protein; LD, linkage disequilibrium; PRMT8, protein arginine methyltransferase.

Table S1 Association analysis between PRMT8 SNPS and alcohol dependence subjects (n=914)

Table S2 Association analysis of PRMT8 SNPs with the AUDIT score in all study subjects (n=914)

Disclosure

Byung Lae Park is an employee and Hyung Doo Shin is the CEO of SNP Genetics, Inc., which is located at #TE1007, Teilhard Hall, Sogang University, Shinsu-dong, Mapo-gu, Seoul, 121-742, Republic of Korea. This company provided the iScan scanner instrument and BeadStudio 3.0 software used in the research. They were also involved in the study design, data collection and analysis, decision to publish, and preparation of the manuscript. However, these competing interests did not alter the authors’ adherence to all policies of Neuropsychiatric Disease and Treatment. The others authors report no conflicts of interest in this work.

References

  • Prom-WormleyECEbejerJDickDMBowersMSThe genetic epidemiology of substance use disorder: a reviewDrug Alcohol Depend201718024125928938182
  • ZollanvariAAlterovitzGSNP by SNP by environment interaction network of alcoholismBMC Syst Biol201711Suppl 31928361705
  • GordisEGenes and the environment in complex diseases: a focus on alcoholismMol Psychiatry1997242822869246664
  • KendlerKSHeathACNealeMCKesslerRCEavesLJA population-based twin study of alcoholism in womenJAMA199226814187718821404711
  • PrescottCAKendlerKSGenetic and environmental contributions to alcohol abuse and dependence in a population-based sample of male twinsAm J Psychiatry1999156134409892295
  • BohmanMSigvardssonSCloningerCRMaternal inheritance of alcohol abuse. Cross-fostering analysis of adopted womenArch Gen Psychiatry19813899659697283667
  • SigvardssonSBohmanMCloningerCRReplication of the stockholm adoption study of alcoholism. Confirmatory cross-fostering analysisArch Gen Psychiatry19965386816878694681
  • KendlerKSNealeMCHeathACKesslerRCEavesLJA twin-family study of alcoholism in womenAm J Psychiatry199415157077158166312
  • ChoiIGSonHGYangBHScanning of genetic effects of alcohol metabolism gene (ADH1B and ADH1C) polymorphisms on the risk of alcoholismHum Mutat200526322423416086315
  • EdenbergHJXueiXChenHJAssociation of alcohol dehydrogenase genes with alcohol dependence: a comprehensive analysisHum Mol Genet20061591539154916571603
  • KimDJChoiIGParkBLMajor genetic components underlying alcoholism in Korean populationHum Mol Genet200817685485818056758
  • SamochowiecJSamochowiecAPulsIBienkowskiPSchottBHGenetics of alcohol dependence: a review of clinical studiesNeuropsychobiology2014702779425359488
  • ThompsonMDKennaGAVariation in the serotonin transporter gene and alcoholism: risk and response to pharmacotherapyAlcohol Alcohol201651216417126311211
  • BierutLJAgrawalABucholzKKGene, Environment Association Studies ConsortiumA genome-wide association study of alcohol dependenceProc Natl Acad Sci U S A2010107115082508720202923
  • LindPAMacgregorSVinkJMA genomewide association study of nicotine and alcohol dependence in Australian and Dutch populationsTwin Res Hum Genet2010131102920158304
  • ZuoLZhangXYWangFGenome-wide significant association signals in IPO11-HTR1A region specific for alcohol and nicotine codependenceAlcohol Clin Exp Res201337573073923216389
  • BaikIChoNHKimSHHanBGShinCGenome-wide association studies identify genetic loci related to alcohol consumption in Korean menAm J Clin Nutr201193480981621270382
  • ParkBLKimJWCheongHSExtended genetic effects of ADH cluster genes on the risk of alcohol dependence: from GWAS to replicationHum Genet2013132665766823456092
  • JoeKHKimDJParkBLGenetic association of DRD2 polymorphisms with anxiety scores among alcohol-dependent patientsBiochem Biophys Res Commun2008371459159518307984
  • American Psychiatric AssociationAmerican Psychiatric Association. Task Force on DSM-IV. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV4th edWashington, DCAmerican Psychiatric Association1994
  • SaundersJBAaslandOGBaborTFde la FuenteJRGrantMDevelopment of the Alcohol Use Disorders Identification Test (AUDIT): WHO collaborative project on early detection of persons with harmful alcohol consumption – IIAddiction19938867918048329970
  • SungJLeeKSongYMHeritabilities of Alcohol Use Disorders Identification Test (AUDIT) scores and alcohol biomarkers in Koreans: the KoGES (Korean Genome Epi Study) and Healthy Twin StudyDrug Alcohol Depend20111132–310410920729011
  • TsaiMCTsaiYFChenCYLiuCYAlcohol Use Disorders Identification Test (AUDIT): establishment of cut-off scores in a hospitalized Chinese populationAlcohol Clin Exp Res2005291535715654291
  • OliphantABarkerDLStuelpnagelJRCheeMSBeadArray technology: enabling an accurate, cost-effective approach to high-throughput genotypingBiotechniques2002SupplS56S61
  • BarrettJCFryBMallerJDalyMJHaploview: analysis and visualization of LD and haplotype mapsBioinformatics200521226326515297300
  • StephensMSmithNJDonnellyPA new statistical method for haplotype reconstruction from population dataAm J Hum Genet200168497898911254454
  • MenasheIRosenbergPSChenBEPGA: power calculator for case-control genetic association analysesBMC Genet200893618477402
  • EzzatiMLopezADRodgersAvander HoornSMurrayCJComparative Risk Assessment Collaborating GroupSelected major risk factors and global and regional burden of diseaseLancet200236093431347136012423980
  • CollinsPYPatelVJoestlSSGrand challenges in global mental healthNature20114757354273021734685
  • KimJWLeeDYLeeBCAlcohol and cognition in the elderly: a reviewPsychiatry Investig201291816
  • ZhangFLiuCXuYA two-stage association study suggests BRAP as a susceptibility gene for schizophreniaPLoS One201491e8603724454952
  • LanctotAAPengCYPawliszASJoksimovicMFengYSpatially dependent dynamic MAPK modulation by the Nde1-Lis1-Brap complex patterns mammalian CNSDev Cell201325324125523673330
  • JeanblancJLogripMLJanakPHRonDBDNF-mediated regulation of ethanol consumption requires the activation of the MAP kinase pathway and protein synthesisEur J Neurosci201337460761223189980
  • TakashimaOTsurutaFKigoshiYBrap2 regulates temporal control of NF-κB localization mediated by inflammatory responsePLoS One201383e5891123554956
  • PlestantCAntonESScaling the MAPK signaling threshold during CNS patterningDev Cell201325322122223673327
  • OkvistAJohanssonSKuzminANeuroadaptations in human chronic alcoholics: dysregulation of the NF-kappaB systemPLoS One200729e93017895971
  • LiaoYCWangYSGuoYCBRAP Activates inflammatory cascades and increases the risk for carotid atherosclerosisMol Med2011179–101065107421670849
  • TsaiPCLiaoYCLinTHHsiEYangYHJuoSHAdditive effect of ANRIL and BRAP polymorphisms on ankle-brachial index in a Taiwanese populationCirc J201276244645222122968
  • OzakiKSatoHInoueKSNPs in BRAP associated with risk of myocardial infarction in Asian populationsNat Genet200941332933319198608
  • AveryCLHeQNorthKEA phenomics-based strategy identifies loci on APOC1, BRAP, and PLCG1 associated with metabolic syndrome phenotype domainsPLoS Genet2011710e100232222022282
  • DillonMBRustHLThompsonPRMowenKAAutomethylation of protein arginine methyltransferase 8 (PRMT8) regulates activity by impeding S-adenosylmethionine sensitivityJ Biol Chem201328839278722788023946480
  • LeeJSayeghJDanielJClarkeSBedfordMTPRMT8, a new membrane-bound tissue-specific member of the protein arginine methyltransferase familyJ Biol Chem200528038328903289616051612
  • KimSParksCGXuZAssociation between genetic variants in DNA and histone methylation and telomere lengthPLoS One201277e4050422792358
  • KamataniYMatsudaKOkadaYGenome-wide association study of hematological and biochemical traits in a Japanese populationNat Genet20104221021520139978