Can rare genes increase the risk of heart attack?

In his PhD thesis, Oddgeir Lingaas Holmen looks for low-frequency gene variations that associate with myocardial infarction and serum lipid levels.


MAIN RESULTS:

  1. A genetic variation that can reduce cholesterol levels and the risk of myocardial infarction was found.
  2. No large-effect low-frequency coding variation was found for myocardial infarction.

THESIS DEFENCE:

Thesis: HUNTing for genes: Studies of low-frequency and rare variation in human height, myocardial infarction and serum lipid levels utilizing population-based biobanks
Candidate: Oddgeir Lingaas Holmen
Time: December 7, 2017 at 12:15
Place: HUNT Research Center, Levanger: Auditorium
Link to university website (in Norwegian)


SUMMARY:

Our genes are located on specific loci in our DNA. The order of nucleotides within a locus determines the characteristics of each gene. Different variations of a gene within the same locus are called alleles. A number of different alleles can be found within the same locus in different persons, but normally one allele is dominating – the so-called major allele. A large sample size is needed to find rare alleles that are linked to health and disease. In his research, Oddgeir Lingaas Holmen has studied DNA from about 10,000 participants in the HUNT Study and the Tromsø study, of which about half had a previous myocardial infarction.

(1) In the first article, Lingaas Holmen and several co-workers showed that the gene TM6SF2 is linked to cholesterol profile. Specifically, the minor allele of TM6SF2 seems to cause lower total cholesterol. In an experimental study on mice, high levels of human TM6SF2 increased both total cholesterol, LDL cholesterol and triglycerides, whereas the levels of the good HDL cholesterol were reduced. Furthermore, the rare variant of TM6SF2 was linked to reduced risk of myocardial infarction.

In total, the study identified eleven loci associated with lipid levels. Two of them, including TM6SF2, have previously not been known to affect lipid metabolism. Minor alleles associated with lipid levels were also found in two of the nine genes previously known to affect the levels of blood lipids.

(2) No allele with a low-frequency of 1–5 % in the population was associated with myocardial infarction. Almost 200,000 gene variations were investigated in this study. The study is underpowered to detect associations with alleles found in less than 1 % of the population. However, the results indicate that some of these very rare alleles could be linked to myocardial infarction.


REFERENCES:

(1) Holmen, O. L., Zhang, H., Fan, Y., Hovelson, D. H., Schmidt, E. M., Zhou, W., Guo, Y., Zhang, J., Langhammer, A., Løchen, M.-L., Ganesh, S. K., Vatten, L., Skorpen, F., Dalen, H., Zhang, J., Pannathur, P., Chen, J., Platou, C., Mathiesen, E. B., Wilsgaard, T., Njølstad, I., Boehnke, M., Chen, Y. E., Abecasis, G. R., Hveem, K., & Willer, C. J. (2014). Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction riskNature genetics46(4), 345-351.

(2) Holmen, O. L., Zhang, H., Zhou, W., Schmidt, E., Hovelson, D. H., Langhammer, A., Løchen, M-L., Ganesh, S. K., Mathiesen, E. B., Vatten, L., Platou, C., Wilsgaard, T., Chen, J., Skorpen, F., Dalen, H., Boehnke, M., Abecasis, G. R., Njølstad, I., Hveem, K, & Willer, C. J. (2014). No large-effect low-frequency coding variation found for myocardial infarctionHuman molecular genetics23(17), 4721-4728.

(3) Marouli, E., Graff, M., Medina-Gomez, C., Lo, K. S., Wood, A. R., Kjaer, T. R., Fine, (…), Holmen, O. L., (…), & Lettre, G., (2017). Rare and low-frequency coding variants alter human adult heightNature542(7640), 186-190.