Researchers at The University of Texas Health Science Center at Houston (UTHealth) identified gene variants associated with loss of function (LOF) in genes related to chronic diseases. The study entitled “Analysis of loss-of-function variants and 20 risk factor phenotypes in 8,554 individuals identifies loci influencing chronic disease” was published in Nature Genetics.
UTHealth researchers looked for LOF variants in genes affecting risk factors and the onset of chronic diseases, including cardiovascular disease and diabetes. They sequenced the whole exome (genome DNA that codes for proteins) of 8,554 African American and European American individuals in the United States and identified LOF gene variants that could affect chronic disease risk factors and health.
The study participants were screened for 20 factors affected in chronic diseases, such as serum magnesium levels, triglyceride levels, blood pressure and cholesterol. They found a LOF variant in PCSK9 and APOC3 genes that lowered blood cholesterol and triglycerides, respectively, reducing heart disease risk. These data confirmed a previously association between the PCK9 gene and heart disease made by the same research team. “Years ago, we found a mutation that knocks out a gene that lowers your cholesterol. That turned into drugs that can help with cholesterol. That was with one gene. We are now sequencing lots of people and looking at where people are losing function from every gene in their body,” said Eric Boerwinkle, senior author of this study.
The other LOF variants found are thought to be associated with increasing risk of disease. Those affecting the TXNDC5 gene lead to increased blood glucose levels during fasting. This gene has previously been associated with increased risk of type 1 diabetes risk. “Loss-of-function variation in certain genes, such as TXNDC5, may predispose individuals to develop disease. More research is needed to determine the exact mechanisms of these newly discovered relationships,” said Boerwinkle.
Researchers also found LOF mutations in the C1QTNF8 gene related to elevated serum magnesium levels. A LOF mutation in SEPT10 gene was present in five study participants who also had significantly reduced lung function. This gene has been previously associated with nicotine dependence.
Overall, this study proved the utility of identifying gene functional variants within a large sample of participants whose disease risk factors are fully characterized.