Functional characterization of genetic loci identified in a genome-wide association study of blood lipid levels

Abstract

Blood lipid levels are linked to the development of many metabolic and cardiovascular disease phenotypes, such as coronary heart disease and diabetes mellitus. Acquiring an understanding of the genetic variation that regulates lipid levels is important to elucidate the underlying biological pathways.

In the present study, we performed a functional characterization for 103 independent SNPs that reached genomewide significance for association with HDL-C, LDL-C, or TG levels in a genome-wide association study. The aim of the characterization was to localize the most likely causal genes in the identified lipid loci, and to characterize their biological functions based on a thorough review of the literature and publicly available bioinformatics databases.

Of the 103 genome-wide significant lipid-associated variants, seven (rs13107325, rs11591147, rs174568, rs235314, rs1800961, rs58542926, rs1260326) were located in coding sequences (protein coding) of the genome. Of these, the rs1800961 T allele was found to have a polyphen score of 0.99, which categorizes it as most likely to have a pathogenic effect. The rs1310732 A allele and rs58542926 T allele were categorized as ‘possibly damaging’ with polyphen scores of 0.79 and 0.55 respectively.

Of the 96 variants that were located in non-coding regions of the human genome, 67 (72%) overlapped with regulatory elements. Pleiotropy was observed for 63 (61%) of the 103 analysed variants. These variants showed associations with one or more complex phenotypic or disease traits, in addition to their association with blood lipid levels.

The majority of the identified SNPs were associated with regulatory elements and transcription factors relating to key players in three important biological process: lipolysis, lipogenesis, and adipogenesis. Thus, we conclude that these processes may be the key determinants of blood lipid level modulation in humans.

Popular Abstract

Determining how different forms of genes affect blood lipid levels

Recently there has been some success in understanding the genetic bases of diseases such as familial hypercholesterolemia and dyslipidemia by looking at tiny differences in the genes of individuals in a chosen population. But discovering where and what these differences are is not enough to provide a complete picture of how complex diseases develop, so this study attempts to give a clearer picture of how these minute differences in genes across a population eventually translates to diseases that are associated with varying levels of fats (lipids) in the blood.

Information about the complete genetic components of 118,736 individuals of European, African, Asian, and Hispanic ancestry associated with specific lipids transported in the blood such as HDL-C, LDL-C, and TG were collated. By using information gleaned from online tools and databases, probable biological processes by which these tiny genetic differences causes’ imbalances in the amounts of lipids in the blood were mapped out by first finding what part of the genes these differences where, and in which tissues these genes were most active.

Gene forms affect blood lipids by changing the proteins that regulate biological processes

For the appropriate amount of lipid in the blood to be maintained, a lot of intricately intertwined processes have to occur. This thesis shows that about 72% of the genes studied indirectly controlled three major biological processes namely Adipogenesis, Lipogenesis, and Lipolysis. There were a few genes (7%) where the tiny differences actually affected the structure of the proteins that was made from information found within the genes.

Furthermore, the study discovered that with 3 of the altered genes, the change in structure was actually detrimental to the proper functioning of the resulting protein and thus inadvertently affected the biological processes that they were involved in.

If we are to properly understand how alterations in genes lead to diseases, it’s important to know how exactly these alterations affect the proper functioning of proteins that are formed from different forms of the genes found in populations. This would help in the future development of drugs or other medicinal therapies.

Master´s Degree Project in Molecular Biology 45 credits 2019
Department of Biology, Lund University

Advisor: Tuomas Oskari Kilpelainen
NNF Center for Basic Metabolic Research, University of Copenhagen

• author: Nwuba, Chiamaka Vivian
• supervisor: Tuomas Oskari Kilpeläinen
• organization: Degree Projects in Molecular Biology
• course: MOBN01 20172
• year: 2019
• type: H2 - Master's Degree (Two Years)
• subject: Biology and Life Sciences
• language: English
• id: 8973197
• date added to LUP: 2019-03-19 14:34:31
• date last changed: 2019-03-19 14:34:31