APOA5 S19W - GET-Evidence

Curation:
Currentness:

APOA5 S19W

(APOA5 Ser19Trp)


Short summary

This variant, also known as APOA5*3, is associated with higher plasma triglyceride concentrations but no significant correlation with coronary artery disease itself has been found.

Variant evidence
Computational 2

NBLOSUM = 4, gene is associated with disease.

See Pennacchio LA et al. 2002 (12417524), Talmud PJ et al. 2002 (12417525), Evans D et al. 2005 (16143024).

Functional
Case/Control 4

Although there isn’t an odds ratio, the data seems to support one around 1.5-2. Significance is pretty strong.

See Pennacchio LA et al. 2002 (12417524), Talmud PJ et al. 2002 (12417525), Evans D et al. 2005 (16143024).

Familial
 
Clinical importance
Severity 3

Unclear what impact triglycerides have on heart disease, Chasman et al. report no correlation with coronary artery disease as diagnosed using imaging (although they confirm the triglyceride association).

See Chasman DI et al. 2008 (19802338).

Treatability 3
Penetrance 2

Unclear, presumably low penetrance for heart attack

 

Impact

Low clinical importance, Likely pathogenic

(The "low clinical importance, likely" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

unknown

Summary of published research, and additional commentary

 

Allele frequency

  • C @ chr11:116662407: 6.5% (695/10756) in EVS
  • C @ chr11:116167616: 3.9% (5/128) in GET-Evidence
  • Frequency shown in summary reports: 6.5% (695/10756)

Publications
 

Pennacchio LA, Olivier M, Hubacek JA, Krauss RM, Rubin EM, Cohen JC. Two independent apolipoprotein A5 haplotypes influence human plasma triglyceride levels. Hum Mol Genet. 2002 Nov 15;11(24):3031-8. PubMed PMID: 12417524.

Comparing low and high triglyceride groups (<10th & >90th percentile), they found a higher incidence of this variant in the high triglyceride group: high men had 19 heterozygous and 63 wild-type and women had 11 heterozygous and 39 wild-type. Low men had one homozygous, 7 heterozygous, and 74 wild-type, and low women had 50 wild-type. Counting chromosomes this is: high+: 30, high-: 228, low+: 9, low-: 248. This has a significance of 2.6 * 10^-4. The authors state that the incidence of the mutation is 8.4% in caucasians, which would imply that this variant has an OR of ~1.4 for high triglycerides.

Talmud PJ, Hawe E, Martin S, Olivier M, Miller GJ, Rubin EM, Pennacchio LA, Humphries SE. Relative contribution of variation within the APOC3/A4/A5 gene cluster in determining plasma triglycerides. Hum Mol Genet. 2002 Nov 15;11(24):3039-46. PubMed PMID: 12417525.

The authors report that the people homozygous for S19W have ~ 50% more triglycerides compared to homozygous wild-type, and that this effect is additive with a -1131 T to C SNP associated with the same gene.

Evans D, Seedorf U, Beil FU. Polymorphisms in the apolipoprotein A5 (APOA5) gene and type III hyperlipidemia. Clin Genet. 2005 Oct;68(4):369-72. PubMed PMID: 16143024.

Looking at patients with type III hyperlipidemia, who are usually homozygous for the ε2 allele of the APOE gene, to see if APOA5 variants contribute. (Only ~10% of homozygotes of the APOE allele develop the disease). Counting chromosomes, case+: 19, case-: 125, control+: 18, control-: 276 — this is a significance of p = .017.

Martinelli N, Trabetti E, Bassi A, Girelli D, Friso S, Pizzolo F, Sandri M, Malerba G, Pignatti PF, Corrocher R, Olivieri O. The -1131 T>C and S19W APOA5 gene polymorphisms are associated with high levels of triglycerides and apolipoprotein C-III, but not with coronary artery disease: an angiographic study. Atherosclerosis. 2007 Apr;191(2):409-17. Epub 2006 May 8. PubMed PMID: 16682041.

Although associated with high triglycerides, not associated with coronary artery disease as study using angiographic imaging.

Chasman DI, Paré G, Zee RY, Parker AN, Cook NR, Buring JE, Kwiatkowski DJ, Rose LM, Smith JD, Williams PT, Rieder MJ, Rotter JI, Nickerson DA, Krauss RM, Miletich JP, Ridker PM. Genetic loci associated with plasma concentration of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein A1, and Apolipoprotein B among 6382 white women in genome-wide analysis with replication. Circ Cardiovasc Genet. 2008 Oct;1(1):21-30. PubMed PMID: 19802338; PubMed Central PMCID: PMC2630707.

 

Genomes
 

hu025CEA - CGI sample GS01669-DNA_D02 from PGP sample 27316983
het C @ chr11:116662407

 

hu04FD18 - CGI sample GS00253-DNA_F01_200_37
het C @ chr11:116662407

 

hu2DBF2D - CGI sample GS01173-DNA_G02 from PGP sample 67180598
het C @ chr11:116662407

 

 

 

hu3CAB43 - CGI sample GS01175-DNA_D03 from PGP sample 27486199
het C @ chr11:116662407

 

hu8229AE - CGI sample GS01173-DNA_A07 from PGP sample 96240009
het C @ chr11:116662407

 

GS18517 - var-GS18517-1100-36-ASM
het C @ chr11:116167617

 

NA12878

 

Other external references
 

    dbSNP
  • rs3135506
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PharmGKB
  • [Cardiovascular Diseases]
    Phenotype: In a GWAS, this SNP was significantly associated with plasma concentrations of triglycerides and apolipoprotein B. Study size:6382. Study population/ethnicity: Caucasian women. Significance metric(s): triglycerides: p = 5.5 x 10(-12); ApoB: p = 8.4 x 10(-8). Type of association: CO; GN
    www.ncbi.nlm.nih.gov/pubmed/19802338
    PolyPhen-2
  • Score: 0.778 (possibly damaging)

Other in silico analyses
 

  • NBLOSUM100 score = 7
  • GET-Evidence autoscore = 2

Edit history
 

Gene search

"GENE" or "GENE A123C":

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