Alternative titles; symbols
DO: 5844;
Cytogenetic location: 13q12 Genomic coordinates (GRCh38): 13:18,900,001-31,600,000
| Location | Phenotype | Phenotype MIM number |
Inheritance | Phenotype mapping key |
|---|---|---|---|---|
| 13q12 | {Myocardial infarction, susceptibility to, 2} | 608557 | 2 |
For a discussion of the genetic heterogeneity of myocardial infarction, see MCI1 (608446).
In a genomewide scan of 296 multiplex Icelandic families including 713 individuals with myocardial infarction, Helgadottir et al. (2004) found suggestive linkage to chromosome 13q12-q13. By analysis of a candidate gene in the region, ALOX5AP (603700), they identified a 4-SNP haplotype, 'HapA' (defined by SG13S25, SG13S114, SG13S89, and SG13S32), that conferred a nearly 2 times greater risk of myocardial infarction and stroke (see 601367). Another 4-SNP haplotype, 'HapB' (defined by SG13S377, SG13S114, SG13S41, and SG13S35), was associated only with the risk of myocardial infarction. The authors noted that FLAP, encoded by the ALOX5AP gene, is a regulator of a crucial pathway in the genesis of leukotriene inflammatory mediators, which are implicated in atherosclerosis both in a mouse model (Mehrabian et al., 2002) and in human studies (Brezinski et al., 1992; Spanbroek et al., 2003). Males had the strongest association with the at-risk haplotype, and stimulated neutrophils from individuals with myocardial infarction had significantly greater production of leukotriene-B4 (LTB4), supporting the idea that proinflammatory activity has a role in the pathogenesis of myocardial infarction. The association of ALOX5AP with myocardial infarction was confirmed in an independent cohort of British individuals with another haplotype.
In a large case-control sample from Germany that included 3,657 patients with MI and a control group of 1,211 individuals with angiographically normal coronary arteries and who had no clinical signs or symptoms of MI, Koch et al. (2007) failed to replicate the association of polymorphisms in the ALOX5AP gene and myocardial infarction. The negative results included the HapA and HapB haplotypes previously linked with MI in samples from Iceland and the United Kingdom.
Assimes et al. (2008) genotyped 6 SNPs in the ALOX5AP gene in 1,552 patients with 'clinically significant' coronary artery disease (CAD), including a history of myocardial infarction or angina with greater than 50% stenosis of at least 1 coronary artery, and 1,583 controls but found no significant associations between any of the SNPs and CAD.
Assimes, T. L., Knowles, J. W., Priest, J. R., Basu, A., Volcik, K. A., Southwick, A., Tabor, H. K., Hartiala, J., Allayee, H., Grove, M. L., Tabibiazar, R., Sidney, S., Fortmann, S. P., Go, A., Hlatky, M., Iribarren, C., Boerwinkle, E., Myers, R., Risch, N., Quertermous, T. Common polymorphisms of ALOX5 and ALOX5AP and risk of coronary artery disease. Hum. Genet. 123: 399-408, 2008. [PubMed: 18369664] [Full Text: https://doi.org/10.1007/s00439-008-0489-5]
Brezinski, D. A., Nesto, R. W., Serhan, C. N. Angioplasty triggers intracoronary leukotrienes and lipoxin A4: impact of aspirin therapy. Circulation 86: 56-63, 1992. [PubMed: 1617790] [Full Text: https://doi.org/10.1161/01.cir.86.1.56]
Helgadottir, A., Manolescu, A., Thorleifsson, G., Gretarsdottir, S., Jonsdottir, H., Thorsteinsdottir, U., Samani, N. J., Gudmundsson, G., Grant, S. F. A., Thorgeirsson, G., Sveinbjornsdottir, S., Valdimarsson, E. M., and 14 others. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nature Genet. 36: 233-239, 2004. [PubMed: 14770184] [Full Text: https://doi.org/10.1038/ng1311]
Koch, W., Hoppmann, P., Mueller, J. C., Schomig, A., Kastrati, A. No association of polymorphisms in the gene encoding 5-lipoxygenase-activating protein and myocardial infarction in a large central European population. Genet. Med. 9: 123-129, 2007. Note: Erratum: Genet. Med. 9: 187 only, 2007. [PubMed: 17304054] [Full Text: https://doi.org/10.1097/gim.0b013e318030c9c5]
Mehrabian, M., Allayee, H., Wong, J., Shih, W., Wang, X.-P., Shaposhnik, Z., Funk, C. D., Lusis, A. J. Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice. Circ. Res. 91: 120-126, 2002. Note: Erratum: Circ. Res. 91: e27 only, 2002. [PubMed: 12142344] [Full Text: https://doi.org/10.1161/01.res.0000028008.99774.7f]
Spanbroek, R., Grabner, R., Lotzer, K., Hildner, M., Urbach, A., Ruhling, K., Moos, M. P. W., Kaiser, B., Cohnert, T. U., Wahlers, T., Zieske, A., Plenz, G., Robenek, H., Salbach, P., Kuhn, H., Radmark, O., Samuelsson, B., Habenicht, A. J. R. Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis. Proc. Nat. Acad. Sci. 100: 1238-1243, 2003. [PubMed: 12552108] [Full Text: https://doi.org/10.1073/pnas.242716099]