Alternative titles; symbols
SNOMEDCT: 413596002;
Cytogenetic location: 19p13.3-p13.2 Genomic coordinates (GRCh38): 19:1-12,600,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.3-p13.2 | {Atherosclerosis, susceptibility to} | 108725 | Autosomal dominant | 2 |
The atherogenic lipoprotein phenotype (ALP) is a common heritable trait characterized by a preponderance of small, dense low density lipoprotein (LDL) particles (subclass pattern B), increased levels of triglyceride-rich lipoproteins, reduction in high density lipoprotein, and a 3-fold increased risk of myocardial infarction (summary by Nishina et al., 1992).
The so-called atherogenic lipoprotein phenotype was shown by Austin et al. (1988) to be independently associated with an increased risk for coronary artery disease. Allayee et al. (1998) concluded, furthermore, that there is a genetically based association between familial combined hyperlipidemia (FCHL; 144250) and small, dense LDL particles and that the genetic determinants for LDL particle size are shared, at least in part, among FCHL families and the more general population at risk for coronary artery disease. Juo et al. (1998) concluded from a bivariate segregation analysis of small, dense LDL particles and elevated apolipoprotein B levels (APOB; 107730), which are commonly found together in members of FCHL families, that the 2 traits share a common major gene plus individual polygenic components. The common major gene was estimated to explain 37% of the variance of adjusted LDL particle size and 23% of the variance of adjusted apoB levels.
Nishina et al. (1992) found close linkage between the atherogenic lipoprotein phenotype and the LDL receptor locus; maximum lod = 4.07 at theta = 0.04, assuming 100% penetrance of the ALP pattern B, and 4.27 at a recombination fraction of 0.0, assuming 90% penetrance of pattern B. The gene, which may be the same as the LDLR gene (606945), was symbolized ATHS (for atherosclerosis susceptibility). It appeared to be located distal to D19S76 near or at the LDL receptor locus.
Small dense LDL particles carry a 3-fold increased risk for coronary artery disease. By utilizing nonparametric quantitative sib-pair and relative-pair-analysis methods in coronary artery disease families, Rotter et al. (1996) confirmed linkage to the LDLR locus (P = 0.008). No evidence of linkage could be found to 6 candidate gene loci: APOB, APOA2, Lp(a), APOE, lipoprotein lipase, and high-density lipoprotein-binding protein (142695). Significant evidence for linkage was found with the CETP locus on chromosome 16 (118470) and the SOD1 locus on chromosome 6 (147450). A suggestion of linkage was found with the APOA1/APOC3/APOA4 cluster on chromosome 11.
Associations Pending Confirmation
To determine whether genetic variation in the TNFR1 gene contributes to aging-related atherosclerosis, Zhang et al. (2010) performed a case-control association study of coronary artery disease (CAD) with 16 TNFR1 (191190) SNPs in 1,330 subjects from a coronary angiography database. Two TNFR1 SNPs were significantly associated with CAD in subjects older than 55 years, and this association was supported by analysis of a set of 759 independent CAD cases. In multiple linear regression analysis, accounting for TNFR1 SNP rs4149573 significantly altered the relationship between aging and CAD index among 1,811 subjects from the coronary angiography database. In a mouse model of atherosclerosis, Zhang et al. (2010) demonstrated that arterial wall aging-dependent acceleration of atherosclerosis was abrogated when arterial walls lacked TNFR1.
Naggert et al. (1997) followed up on the family study showing tight linkage of the atherogenic lipoprotein phenotype to the LDL receptor locus (LDLR; 606945) on 19p13.2. To test whether a mutation in the structural portion of the LDLR gene could be responsible for the phenotype, they sequenced the exons of the receptor-binding domain for each pair of parents in the 11 pedigrees. For the remaining LDLR coding region, exons as well as cloned LDLR cDNAs were sequenced for selected members of the pedigrees. No mutations that changed the amino acid sequence of the LDLR were found. They concluded that a mutant allele of LDLR is not likely to be responsible for ALP.
Allayee, H., Aouizerat, B. E., Cantor, R. M., Dallinga-Thie, G. M., Krauss, R. M., Lanning, C. D., Rotter, J. I., Lusis, A. J., de Bruin, T. W. A. Families with familial combined hyperlipidemia and families enriched for coronary artery disease share genetic determinants for the atherogenic lipoprotein phenotype. Am. J. Hum. Genet. 63: 577-585, 1998. [PubMed: 9683614] [Full Text: https://doi.org/10.1086/301983]
Austin, M. A., Breslow, J. L., Hennekens, C. H., Buring, J. E., Willett, W. C., Krauss, R. M. Low-density lipoprotein subclass patterns and risk of myocardial infarction. JAMA 260: 1917-1921, 1988. [PubMed: 3418853]
Juo, S.-H. H., Bredie, S. J. H., Kiemeney, L. A., Demacker, P. N. M., Stalenhoef, A. F. H. A common genetic mechanism determines plasma apolipoprotein B levels and dense LDL subfraction distribution in familial combined hyperlipidemia. Am. J. Hum. Genet. 63: 586-594, 1998. [PubMed: 9683593] [Full Text: https://doi.org/10.1086/301962]
Naggert, J. K., Recinos, A., III, Lamerdin, J. E., Krauss, R. M., Nishina, P. M. The atherogenic lipoprotein phenotype is not caused by a mutation in the coding region of the low density lipoprotein receptor gene. Clin. Genet. 51: 236-240, 1997. [PubMed: 9184244] [Full Text: https://doi.org/10.1111/j.1399-0004.1997.tb02461.x]
Nishina, P. M., Johnson, J. P., Naggert, J. K., Krauss, R. M. Linkage of atherogenic lipoprotein phenotype to the low density lipoprotein receptor locus on the short arm of chromosome 19. Proc. Nat. Acad. Sci. 89: 708-712, 1992. [PubMed: 1731344] [Full Text: https://doi.org/10.1073/pnas.89.2.708]
Rotter, J. I., Bu, X., Cantor, R. M., Warden, C. H., Brown, J., Gray, R. J., Blanche, P. J., Krauss, R. M., Lusis, A. J. Multilocus genetic determinants of LDL particle size in coronary artery disease families. Am. J. Hum. Genet. 58: 585-594, 1996. [PubMed: 8644718]
Zhang, L., Connelly, J. J., Peppel, K., Brian, L., Shah, S. H., Nelson, S., Crosslin, D. R., Wang, T., Allen, A., Kraus, W. E., Gregory, S. G., Hauser, E. R., Freedman, N. J. Aging-related atherosclerosis is exacerbated by arterial expression of tumor necrosis factor receptor-1: evidence from mouse models and human association studies. Hum. Molec. Genet. 19: 2754-2766, 2010. [PubMed: 20421368] [Full Text: https://doi.org/10.1093/hmg/ddq172]