Perhaps the most significant advance in kidney disease in the past few years was the use of genome-wide association studies (GWAS) in various kidney disorders. In these types of studies, various kidney diseases were linked to certain variants in the genetic code. This blog is an introduction into a series of blogs discussing the genetics of chronic kidney disease (CKD).

The basics

As you may remember, each person inherits 46 chromosomes, 23 from each parent. These chromosomes house the genetic code that determine the characteristics of each person. They are composed of DNA which is a long and windy spiral made up of millions of nucleotides. There are 4 nucleotide bases (adenine, cytosine, guanine, thymine), the sequence of which determines how genetic traits are expressed.
This nucleotide sequence forms the foundation of about 22,000 genes. Our cells read the genetic sequence and use it to make thousands of proteins which are essential for carrying out biological functions that maintain life. In other words, you can think of the cells as protein factories. The DNA code provides the blueprint for all the workers to create proteins. These proteins can function as enzymes, receptors, or other structures that are important for sustaining life.

Genetics of Chronic Kidney Disease

Errors in the code

Alterations in the sequence of nucleotide bases cause errors in the code and affect the efficiency of the protein production process. These may sometimes lead to disease or increased risk for disease. Interestingly, on occasion they may have no effect on risk and may even be protective against disease. There are three major changes that can occur in the code:

  1. Single-nucleotide substitution: this is also called single-nucleotide polymorphism or SNPs. These are common.
  2. Insertion or deletions (indels): a small stretch of DNA can be inserted or deleted from the code.
  3. Structural variation: a large-scale change or rearrangement in the DNA.

It is fascinating that a single variation in one nucleotide among the set of 3 billion in our DNA can sometimes cause a severe and deadly disease and other times have no effect whatsoever.

Why genetics are important?

Genetics play an essential role in many functions in the human body. Genetic changes can affect the type of food that a person prefers to eat. For example, genetic variants in bitter taste receptors in the tongue have been associated with decreased intake of vegetables and increased obesity. Genetic changes can also affect digestion, and absorption of food. They can modify the way we metabolize drugs, and toxins. They can alter the function of vitamins and other nutrients and their interactions.

The genetics of disease risk

For a long time, scientists have been trying to study how variations in genes lead to diseases. Past efforts focused on identifying inherited diseases in the so-called Mendelian patterns. However, recent advances in GWAS studies are making it more possible to identify genetic changes that can be associated with increased risk of a disease. Genetic variations in one or several genes can lead to minor changes that collectively may increase the susceptibility for certain common diseases such as diabetes and high blood pressure. This is an evolving field of study and we will continue to learn about it every day.

Genetics of kidney disease

There are well known and relatively common genetic disorders such polycystic kidney disease, Alport’s Syndrome and Fabry’s disease. GWAS studies has identified more than 500 genes that are associated with kidney diseases. Current evidence suggests that a significant genetic component plays a role in the development of kidney disease. These are evident from the ethnic variabilities in certain diseases such as the higher incidence of IgA nephropathy among Asians
Genetics can also determine the severity of a kidney disease, the age of onset and the likelihood of ending up with End-Stage Kidney Disease. For example, different gene mutations that can cause polycystic kidney disease can have different outcomes.
In addition, genetic variations can explain the differences in susceptibility of the kidneys to systemic disease such as diabetes and lupus. These variations may explain why some people with diabetes get severe kidney disease while others don’t.
Finally, alterations in several genes have been associated with increased risk for CKD. There are several candidate genes. Mutations in the UMOD that encodes uromodulin is one of these candidates. Uromodulin, which used to be called Tamm-Horsfall protein, is excreted in certain portions of tubules and protects from urinary tract infections. The Shroom3 gene is another candidate that has been associated with increased risk for CKD. 

Next generation sequencing

Various methods for identifying genetic variants have been used in the past. Next generation sequencing is a state-of-the-art technology that allows DNA sequencing of the entire human genome within a single day. It also captures a broader spectrum of variations that can affect the genetic code. This revolutionary technology is now available for kidney disease patients and can identify various mutations that are associated with CKD or can increase the risk or severity of CKD.

The Bottom Line

Genetics are one of the factors that lead to the development of kidney disease. For genes and their variants to contribute to a disease, we need to understand all of the factors that explain why people with the same variant may have different outcomes. Understanding the interaction between genetics, epigenetics and environment are crucial in this regard. Ongoing research in this field will not only increase our understanding of kidney disease risk but our ability to find various lifestyle modifications and therapies that can help decrease the burden of CKD worldwide.
Professionals: You can get free CME and learn more about genetics of kidney disease here.