{{Rsnum
|rsid=11591147
|Gene=PCSK9
|Chromosome=1
|position=55039974
|Orientation=plus
|ReferenceAllele=G
|MissenseAllele=T
|GMAF=0.008724
|Assembly=GRCh38
|GenomeBuild=38.1
|dbSNPBuild=141
|geno1=(G;G)
|geno2=(G;T)
|geno3=(T;T)
|Gene_s=PCSK9
}}{{ population diversity
| geno1=(G;G)
| geno2=(G;T)
| geno3=(T;T)
| CEU | 98.2 | 1.8 | 0.0
| HCB | 98.5 | 1.5 | 0.0
| JPT | 98.2 | 1.8 | 0.0
| YRI | 100.0 | 0.0 | 0.0
| ASW | 98.2 | 1.8 | 0.0
| CHB | 98.5 | 1.5 | 0.0
| CHD | 99.1 | 0.9 | 0.0
| GIH | 0.0 | 0.0 | 0.0
| LWK | 98.2 | 1.8 | 0.0
| MEX | 93.1 | 6.9 | 0.0
| MKK | 0.0 | 0.0 | 0.0
| TSI | 97.1 | 2.9 | 0.0
| HapMapRevision=28
}}

[[rs11591147]], also known as R46L, is a SNP in the [[PCSK9]] gene. As early as 2006, the minor [[rs11591147]](T) allele was reported to be associated with lower LDL cholesterol levels, and most studies since have found that this also correlates to a two to three fold reduced risk for both early- and late-onset cardiovascular events and disease.

As part of a 9 SNP set studied in a meta-analysis totaling over 300,000 patients, [[rs11591147]] was the SNP with the greatest effect on LDL-C and therefore cardiovascular risk reduction.{{PMID|23083789}} The set of SNPs was as follows, ordered from strongest to least effect on coronary risk, and the allele shown is the one associated with reduced LDL-C levels along with the associated (or nearby) lipid metabolism gene:

* [[rs11591147]](T), [[PCSK9]]
* [[rs4420638]](A), [[APOE]]
* [[rs6511720]](T), [[LDLR]]
* [[rs599839]](G), [[SORT1]]
* [[rs646776]](C), [[SORT1]]
* [[rs2228671]](T), [[LDLR]]
* [[rs11206510]](C), [[PCSK9]]
* [[rs4299376]](T), [[ABCG8]]
* [[rs12916]](T), [[HMGCR]]

[http://blog.23andme.com/2009/07/27/genetic-research-could-lead-to-new-cholesterol-drugs/ 23andMe blog] The T version of [[rs11591147]] and the A version of [[rs28362286]] have both been associated with decreased LDL levels.  Each copy of these variants leads to lower [[LDL cholesterol]].

{{PMID Auto
|PMID=19773416
|Title=A gene score of nine LDL and HDL regulating genes is associated with fluvastatin-induced cholesterol changes in women
|OA=1
}}

{{PMID Auto GWAS
|PMID=22331829
|Trait=None
|Title=Genetic determinants of statin-induced low-density lipoprotein cholesterol reduction: the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial.
|RiskAllele=
|Pval=5E-9
|OR=5.0000
|ORtxt=None
}}
{{ClinVar
|rsid=11591147
|Reversed=0
|FwdREF=G
|FwdALT=T
|REF=G
|ALT=T
|RSPOS=55039974
|CHROM=1
|GMAF=0.0087
|dbSNPBuildID=120
|SSR=0
|SAO=1
|VP=0x050368020a05040517130100
|GENEINFO=PCSK9:255738
|GENE_NAME=PCSK9
|GENE_ID=255738
|WGT=1
|VC=SNV
|CLNALLE=1
|CLNHGVS=NC_000001.11:g.55039974G>T
|CLNORIGIN=1
|CLNSIG=255
|Tags=PM;PMC;S3D;SLO;NSM;REF;R5;ASP;VLD;HD;GNO;KGPhase1;KGPROD;OTHERKG;PH3;LSD;MTP;OM
|CAF=0.9913; 0.008724
|CLNACC=RCV000003012.1
|CLNDBN=Low density lipoprotein cholesterol level quantitative trait locus 1
|CLNSRC=ClinVar; OMIM Allelic Variant
|CLNSRCID=NM_174936.3:c.137G>T; NR_110451.1:n.-248G>T; 607786.0006
|COMMON=1
|Disease=Low density lipoprotein cholesterol level quantitative trait locus 1
}}
{{PMID Auto
|PMID=17903299
|Title=A genome-wide association study for blood lipid phenotypes in the Framingham Heart Study.
|OA=1
}}

{{PMID Auto
|PMID=19060911
|Title=Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.
|OA=1
}}

{{PMID Auto
|PMID=19148283
|Title=Genetic differences between the determinants of lipid profile phenotypes in African and European Americans: the Jackson Heart Study.
|OA=1
}}

{{PMID Auto
|PMID=19336475
|Title=Integrated associations of genotypes with multiple blood biomarkers linked to coronary heart disease risk.
|OA=1
}}

{{PMID Auto
|PMID=19474294
|Title=Potential etiologic and functional implications of genome-wide association loci for human diseases and traits.
|OA=1
}}

{{PMID Auto
|PMID=19913121
|Title=Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.
|OA=1
}}

{{PMID Auto
|PMID=19951432
|Title=Analysis of recently identified dyslipidemia alleles reveals two loci that contribute to risk for carotid artery disease.
|OA=1
}}

{{PMID Auto
|PMID=20018036
|Title=Using a latent growth curve model for an integrative assessment of the effects of genetic and environmental factors on multiple phenotypes.
|OA=1
}}

{{PMID Auto
|PMID=20031607
|Title=Longitudinal association of PCSK9 sequence variations with low-density lipoprotein cholesterol levels: the Coronary Artery Risk Development in Young Adults Study.
|OA=1
}}

{{PMID Auto
|PMID=21285406
|Title=Low-density lipoprotein cholesterol and the risk of cancer: a mendelian randomization study.
}}

{{PMID Auto
|PMID=22065156
|Title=Rosuvastatin, proprotein convertase subtilisin/kexin type 9 concentrations, and LDL cholesterol response: the JUPITER trial.
}}

{{PharmGKB
|RSID=rs11591147
|Name_s=
|Gene_s=PCSK9
|Feature=
|Evidence=PubMed ID:19802338
|Annotation=Phenotype: In a GWAS, this SNP was significantly associated with plasma concentration of apolipoprotein B . Study size:6382. Study population/ethnicity: Caucasian women. Significance metric(s): P value: 1.8 x 10(-10) . Type of association: CO; GN
|Drugs=
|Drug Classes=
|Diseases=Cardiovascular Diseases
|Curation Level=Curated
|PharmGKB Accession ID=PA165111805
}}

{{omim
|id=607786
|rsnum=11591147
|variant=0006
}}

{{GET Evidence
|gene=PCSK9
|aa_change=Arg46Leu
|aa_change_short=R46L
|impact=protective
|qualified_impact=Moderate clinical importance, Likely protective
|inheritance=unknown
|quality_scores=Array
|dbsnp_id=rs11591147
|overall_frequency_n=108
|overall_frequency_d=10652
|overall_frequency=0.0101389
|n_genomes=1
|n_genomes_annotated=0
|n_haplomes=1
|n_articles=1
|n_articles_annotated=1
|qualityscore_in_silico=2
|qualitycomment_in_silico=Y
|qualityscore_case_control=4
|qualitycomment_case_control=Y
|qualityscore_severity=4
|qualitycomment_severity=Y
|qualityscore_treatability=4
|gene_in_genetests=Y
|in_omim=Y
|in_gwas=Y
|pph2_score=0.099
|genetests_testable=Y
|nblosum100=6
|autoscore=3
|webscore=N
|n_web_uneval=10
|variant_evidence=1
|clinical_importance=1
|summary_short=This variant is reported to have a dominant protective effect against coronary heart disease. Carriers of this variant have about half the risk of coronary heart disease compared to non-carriers (6.3% risk in carriers vs. 11.8% risk in non-carriers).
}}

{{PMID Auto
|PMID=23220704
|Title=PCSK9 SNP rs11591147 is associated with low cholesterol levels but not with cognitive performance or non-cardiovascular clinical events in an elderly population
}}
{{PMID Auto GWAS
|PMID=18193044
|Trait=LDL cholesterol
|Title=Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans
|RiskAllele=T
|Pval=1.9999999999999999E-44
|OR=0.47
|ORtxt=[0.41-0.53] % SD lower
|OA=1
}}

{{omim
|id=607786
|desc=PROPROTEIN CONVERTASE, SUBTILISIN/KEXIN-TYPE, 9; PCSK9
|rsnum=11591147
}}

{{PMID Auto
|PMID=23300213
|Title=PCSK9 SNP rs11591147 is associated with low cholesterol levels but not with cognitive performance or noncardiovascular clinical events in an elderly population.
|OA=1
}}

{{on chip | 23andMe v1}}
{{on chip | 23andMe v2}}
{{on chip | 23andMe v3}}
{{on chip | 23andMe v4}}
{{on chip | HumanOmni1Quad}}
{{on chip | Illumina Human 1M}}