OMIA:000499-9823 : Hypercholesterolaemia in Sus scrofa (pig)

In other species: crab-eating macaque , Rhesus monkey , dog , rabbit , golden hamster

Categories: Homeostasis / metabolism phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 143890 (trait) , 606945 (gene)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 1998

Cross-species summary: Hypercholesterolemia; see also OMIA:001160: Hyperlipidaemia

Species-specific name: familial hypercholesterolemia, recessive

Species-specific symbol: FH-r

Species-specific description: In addition to the occurrence of natural variants for this trait, variants have been created artificially: Genetically-modifed organism; GMO.

History: The paper by Hasler-Rapacz et al. (1998) was the first in any non-laboratory animal species to report the mapping of a disorder via a genome scan of microsatellites and the subsequent identification of a causal mutation via the positional comparative candidate gene strategy. This disorder was the first in non-laboratory animals to be investigated via the use of Transcription Activator-Like Effector Nucleases (TALENs) (Carlson et al., 2012) to create knockouts of the key gene (in this case, LDLR) (Carlson et al., 2012).

Mapping: A genome scan with microsatellites evenly spaced throughout the genome at around 20cM, conducted by Hasler-Rapacz et al. (1998) on 65 backcross pigs segregating for this disorder, showed that the gene for this disorder in pigs maps near to the centromere of chromosome 2, which is homologous to the region of human chromosome 19 containing the gene for low-density lipoprotein receptor (LDLR), a strong candidate for involvement in this disorder.

Molecular basis: Sequence analysis of the positional candidate LDLR gene by Hasler-Rapacz et al. (1998) in homozygous normal and affected pigs showed that the disorder is due to a single missense mutation (resulting in the amino-acid substitution Arg84Cys). The causal mutation was thus identified via the comparative positional candidate gene approach. Grunwald et al. (1999) confirmed the above likely causal variant. In a proof-of-principle study, Carlson et al. (2012) used Transcription Activator-Like Effector Nucleases (TALENs) to create cloned pigs with a range of mutations in the porcine LDLR gene, namely 289_290ins34, 285_287delATG, 211_292del128, 289_290del10 and 289_290insA. The phenotypes of these mutant pigs were not reported in this paper. Using homologous recombination to insert a premature stop codon and a neomycin-resistance casette into exon 4 of the LDLR gene in Yucatan miniature pigs, followed by somatic cell nuclear transfer and the mating of heterozygotes, Davis et al. (2014) created Yucatan miniature pigs completely lacking any functional LDLR. The authors report that this "new model of cardiovascular disease could be an important resource for developing and testing novel detection and treatment strategies for coronary and aortic atherosclerosis and its complications."

Genetic engineering: Yes - in addition to the occurrence of natural variants, variants have been created artificially, e.g. by genetic engineering or gene editing
Have human generated variants been created, e.g. through genetic engineering and gene editing

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
LDLR low density lipoprotein receptor Sus scrofa 2 NC_010444.4 (69828348..69864823) LDLR Homologene, Ensembl , NCBI gene


By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.

OMIA Variant ID Breed(s) Variant Phenotype Gene Allele Type of Variant Source of Genetic Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Inferred EVA rsID Year Published PubMed ID(s) Acknowledgements
987 Hypercholesterolaemia LDLR missense Naturally occurring variant Sscrofa11.1 2 g.69841413C>T c.250C>T p.(R84C) rs701604154 rs701604154 1998 9556295 The genomic location on Sscrofa11.1 was determined and the effect was confirmed with Ensembl VEP in the following transcripts: XM_021080444.1, XM_021080449.1, XM_021080452.1, XM_021080457.1 by Stephanie Shields (27/05/2020)

Cite this entry

Nicholas, F. W., Tammen, I., & Sydney Informatics Hub. (2024). OMIA:000499-9823: Online Mendelian Inheritance in Animals (OMIA) [dataset].


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.

2023 Namous, H., Strillacci, M.G., Braz, C.U., Shanmuganayagam, D., Krueger, C., Peppas, A., Soffregen, W.C., Reed, J., Granada, J.F., Khatib, H. :
ITGB2 is a central hub-gene associated with inflammation and early fibro-atheroma development in a swine model of atherosclerosis. Atheroscler Plus 54:30-41, 2023. Pubmed reference: 38116576. DOI: 10.1016/j.athplu.2023.11.001.
2021 Tanihara, F., Hirata, M., Otoi, T. :
Current status of the application of gene editing in pigs. J Reprod Dev 67:177-187, 2021. Pubmed reference: 33840678. DOI: 10.1262/jrd.2021-025.
Zhang, J., Khazalwa, E.M., Abkallo, H.M., Zhou, Y., Nie, X., Ruan, J., Zhao, C., Wang, J., Xu, J., Li, X., Zhao, S., Zuo, E., Steinaa, L., Xie, S. :
The advancements, challenges, and future implications of the CRISPR/Cas9 system in swine research. J Genet Genomics 48:347-360, 2021. Pubmed reference: 34144928. DOI: 10.1016/j.jgg.2021.03.015.
2019 Hoogendoorn, A., den Hoedt, S., Hartman, E.M.J., Krabbendam-Peters, I., Te Lintel Hekkert, M., van der Zee, L., van Gaalen, K., Witberg, K.T., Dorst, K., Ligthart, J.M.R., Drouet, L., Van der Heiden, K., van Lennep, J.R., van der Steen, A.F.W., Duncker, D.J., Mulder, M.T., Wentzel, J.J. :
Variation in coronary atherosclerosis severity related to a distinct LDL (Low-Density Lipoprotein) profile: Findings from a familial hypercholesterolemia pig model. Arterioscler Thromb Vasc Biol 39:2338-2352, 2019. Pubmed reference: 31554418. DOI: 10.1161/ATVBAHA.119.313246.
2017 Huang, L., Hua, Z., Xiao, H., Cheng, Y., Xu, K., Gao, Q., Xia, Y., Liu, Y., Zhang, X., Zheng, X., Mu, Y., Li, K. :
CRISPR/Cas9-mediated ApoE-/- and LDLR-/- double gene knockout in pigs elevates serum LDL-C and TC levels. Oncotarget 8:37751-37760, 2017. Pubmed reference: 28465483. DOI: 10.18632/oncotarget.17154.
2016 Leroy, G., Besbes, B., Boettcher, P., Hoffmann, I., Capitan, A., Baumung, R. :
Rare phenotypes in domestic animals: unique resources for multiple applications. Anim Genet 47:141-53, 2016. Pubmed reference: 26662214. DOI: 10.1111/age.12393.
2014 Davis, B.T., Wang, X.J., Rohret, J.A., Struzynski, J.T., Merricks, E.P., Bellinger, D.A., Rohret, F.A., Nichols, T.C., Rogers, C.S. :
Targeted disruption of LDLR causes hypercholesterolemia and atherosclerosis in Yucatan miniature pigs. PLoS One 9:e93457, 2014. Pubmed reference: 24691380. DOI: 10.1371/journal.pone.0093457.
2013 Bahls, M., Bidwell, C.A., Hu, J., Tellez, A., Kaluza, G.L., Granada, J.F., Krueger, C.G., Reed, J.D., Laughlin, M.H., Van Alstine, W.G., Newcomer, S.C. :
Gene expression differences during the heterogeneous progression of peripheral atherosclerosis in familial hypercholesterolemic swine. BMC Genomics 14:443, 2013. Pubmed reference: 23822099. DOI: 10.1186/1471-2164-14-443.
Hamamdzic, D., Wilensky, R.L. :
Porcine models of accelerated coronary atherosclerosis: role of diabetes mellitus and hypercholesterolemia. J Diabetes Res 2013:761415, 2013. Pubmed reference: 23844374. DOI: 10.1155/2013/761415.
2012 Carlson, D.F., Tan, W., Lillico, S.G., Stverakova, D., Proudfoot, C., Christian, M., Voytas, D.F., Long, C.R., Whitelaw, C.B., Fahrenkrug, S.C. :
Efficient TALEN-mediated gene knockout in livestock. Proc Natl Acad Sci U S A 109:17382-7, 2012. Pubmed reference: 23027955. DOI: 10.1073/pnas.1211446109.
2010 Thim, T., Hagensen, M.K., Drouet, L., Bal Dit Sollier, C., Bonneau, M., Granada, J.F., Nielsen, L.B., Paaske, W.P., Bøtker, H.E., Falk, E. :
Familial hypercholesterolaemic downsized pig with human-like coronary atherosclerosis: a model for preclinical studies. EuroIntervention 6:261-8, 2010. Pubmed reference: 20562079. DOI: 10.4244/.
2009 Pena, R.N., Cánovas, A., Varona, L., Díaz, I., Gallardo, D., Ramírez, O., Noguera, J.L., Quintanilla, R. :
Nucleotide sequence and association analysis of pig apolipoprotein-B and LDL-receptor genes. Anim Biotechnol 20:110-23, 2009. Pubmed reference: 19544207. DOI: 10.1080/10495390902892518.
2002 Krier, J.D., Rodriguez-Porcel, M., Best, P.J.M., Romero, J.C., Lerman, A., Lerman, L.O. :
Vascular responses in vivo to 8-epi PGF(2 alpha) in normal and hypercholesterolemic pigs American Journal of Physiology - Regulatory Integrative & Comparative Physiology 283:R303-R308, 2002.
2001 Martinez-Gonzalez, J., Alfon, J., Berrozpe, M., Badimon, L. :
HMG-CoA reductase inhibitors reduce vascular monocyte chemotactic protein-1 expression in early lesions from hypercholesterolemic swine independently of their effect on plasma cholesterol levels Atherosclerosis 159:27-33, 2001. Pubmed reference: 11689203.
1999 Grunwald, K.A.A., Schueler, K., Uelmen, P.J., Lipton, B.A., Kaiser, M., Buhman, K., Attie, A.D. :
Identification of a novel Arg -> Cys mutation in the LDL receptor that contributes to spontaneous hypercholesterolemia in pigs Journal of Lipid Research 40:475-485, 1999. Pubmed reference: 10064736.
1998 Hasler-Rapacz, J., Ellegren, H., Fridolfsson, A.K., Kirkpatrick, B., Kirk, S., Andersson, L., Rapacz, J. :
Identification of a mutation in the low density lipoprotein receptor gene associated with recessive familial hypercholesterolaemia in swine American Journal of Medical Genetics 76:379-386, 1998. Pubmed reference: 9556295.
1995 Hasler-Rapacz, J., Prescott, M.F., Vonlindenreed, J., Rapacz, J.M., Hu, Z.L., Rapacz, J. :
Elevated concentrations of plasma lipids and apolipoproteins B, C-III, and E are associated with the progression of coronary artery disease in familial hypercholesterolemic swine Arteriosclerosis Thrombosis and Vascular Biology 15:583-592, 1995.
Smith, M.J., Allen, K.G.D., Norman, J.F., Harris, M.A., Miller, C.W. :
Low-dose aspirin does not attenuate platelet aggregation or atherosclerosis in miniature swine but decreases production of aortic wall prostacyclin Prostaglandins Leukotrienes & Essential Fatty Acids 53:331-340, 1995.
1994 Aiello, R.J., Nevin, D.N., Ebert, D.L., Uelmen, P.J., Kaiser, M.E., MacCluer, J.W., Blangero, J., Dyer, T.D., Attie, A.D. :
Apolipoprotein B and a second major gene locus contribute to phenotypic variation of spontaneous hypercholesterolemia in pigs. Arterioscler Thromb 14:409-19, 1994. Pubmed reference: 8123646. DOI: 10.1161/01.atv.14.3.409.
Hasler-Rapacz, J.O., Nichols, T.C., Griggs, T.R., Bellinger, D.A., Rapacz, J. :
Familial and diet-induced hypercholesterolemia in swine - Lipid, ApoB, and ApoA-I concentrations and distributions in plasma and lipoprotein subfractions Arteriosclerosis and Thrombosis 14:923-930, 1994. Pubmed reference: 8199183.
1993 Davis, AM., White, BA., Wheeler, MB. :
A TaqI RFLP at the porcine low density lipoprotein receptor (LDLR) locus. Anim Genet 24:330, 1993. Pubmed reference: 7902045.
Purtell, C., Maeda, N., Ebert, D.L., Kaiser, M., Lundkatz, S., Sturley, S.L., Kodoyianni, V., Grunwald, K., Nevin, D.N., Aiello, R.J., Attie, A.D. :
Nucleotide sequence encoding the carboxyl-terminal half of apolipoprotein-B from spontaneously hypercholesterolemic pigs. Journal of Lipid Research 34:1323-1335, 1993. Pubmed reference: 8409766.
1992 Cooper, S.T., Aiello, R.J., Checovich, W.J., Attie, A.D. :
Low density lipoprotein heterogeneity in spontaneously hypercholesterolemic pigs. Mol Cell Biochem 113:133-40, 1992. Pubmed reference: 1518504. DOI: 10.1007/BF00231533.
Lacko, A.G., Lee, S.M., Mirshahi, I., Hasler-Rapacz, J., Kudchodkar, B.J., Rapacz, J. :
Decreased lecithin:cholesterol acyltransferase activity in the plasma of hypercholesterolemic pigs. Lipids 27:266-9, 1992. Pubmed reference: 1518383. DOI: 10.1007/BF02536473.
1991 Checovich, W.J., Aiello, R.J., Attie, A.D. :
Overproduction of a buoyant low density lipoprotein subspecies in spontaneously hypercholesterolemic mutant pigs. Arterioscler Thromb 11:351-61, 1991. Pubmed reference: 1998653. DOI: 10.1161/01.atv.11.2.351.
Prescott, M.F., McBride, C.H., Hasler-Rapacz, J., Von Linden, J., Rapacz, J. :
Development of complex atherosclerotic lesions in pigs with inherited hyper-LDL cholesterolemia bearing mutant alleles for apolipoprotein B. Am J Pathol 139:139-47, 1991. Pubmed reference: 1853929.
1990 Lee, D.M., Mok, T., Hasler-Rapacz, J., Rapacz, J. :
Concentrations and compositions of plasma lipoprotein subfractions of Lpb5-Lpu1 homozygous and heterozygous swine with hypercholesterolemia. J Lipid Res 31:839-47, 1990. Pubmed reference: 2380632.

Edit History

  • Created by Frank Nicholas on 01 Dec 2009
  • Changed by Frank Nicholas on 08 Oct 2011
  • Changed by Frank Nicholas on 09 Dec 2011
  • Changed by Frank Nicholas on 04 Sep 2012
  • Changed by Frank Nicholas on 09 Jan 2013
  • Changed by Frank Nicholas on 01 Jul 2013
  • Changed by Frank Nicholas on 09 Apr 2014
  • Changed by Frank Nicholas on 29 Sep 2016
  • Changed by Frank Nicholas on 19 Apr 2018
  • Changed by Imke Tammen2 on 25 Jun 2021
  • Changed by Imke Tammen2 on 10 Sep 2021
  • Changed by Imke Tammen2 on 25 Dec 2021
  • Changed by Imke Tammen2 on 10 Dec 2023
  • Changed by Imke Tammen2 on 17 Jan 2024