Genetics of Familial Idiopathic Interstitial Pneumonia

The Genetics of Familial Idiopathic Interstitial Pneumonia

When two or more members of the same biological family are diagnosed with idiopathic interstitial pneumonia (IIP), it is called “familial IIP”. Researchers have discovered that IIP runs in certain families because of changes in the genetic information passed down in the family. This article explains the basics of disease genetics in familial IIP. It also discusses how understanding genetic risk factors may or may not be useful to your family. 

Understanding genes

The phrase “disease gene” is used quite a bit in news articles about health and medicine. Perhaps a research study is published about a new “cancer gene” that makes the headlines. These terms are not always explained. Many people are, therefore, rightfully confused as to what a “gene” or a “disease gene” really is.

A good place to start is with a short explanation of how human genetic information works.1 Nearly every cell in the human body has 23 pairs of chromosomes. One chromosome from each pair comes from the mother, and the other chromosome in each pair comes from the father.

Each chromosome contains one very long, string-like molecule called DNA. The DNA is wound up tightly around protein molecules. If all of the DNA molecules in a single human cell were unwound and placed end-to-end, they would measure about 6 feet long.

The DNA molecule contains a biological code that tells cells in the body how to function, like the code for a computer program. The DNA code is separated into units called genes. Each gene has the information the cell needs to make a complex molecule that can do work in our bodies. We have many genes, because our bodies require many complex molecules to carry out all the functions of being alive. 

We have two copies of most genes – one copy on the chromosome from our father and one copy on the chromosome from our mother. Genes on the sex chromosomes X and Y are exceptions. In males who have one X and one Y chromosome, some genes are only available in one copy. 

Understanding mutations

Healthy genes tell cells how to make useful molecules that do their jobs well. However, sometimes the DNA code for a gene has errors. These errors are called mutations. 

When a gene has a mutation or more than one mutation in its DNA code, a number of things can happen to the molecule that is made using that gene. Some of these are:

  • The molecule is made and does the work it is supposed to do in a very slow or poor way (partial loss of function)
  • The molecule is made but does nothing at all (complete loss of function)
  • The molecule is made and does way too much of what it is supposed to do (gain of function)
  • The molecule is made but does something new that it is not supposed to do (gain of function)
  • If the code for a given gene is damaged enough, no molecule is made at all (null)

When molecules are not working properly, cells can become unhealthy and even die. 

A disease gene is a gene with a mutation or mutations that cause a person to develop a disease or raise a person’s risk of developing a disease over time. In the first case, having the mutation definitely means the person will get the disease. In the second case, having the mutation raises the risk of getting a disease but it does not guarantee that someone will get the disease. Whether or not someone gets the disease in that case is often decided by a complicated mixture of genes plus overall health, lifestyle, diet, exercise, smoking status, and exposure to environmental toxins, allergens, or infections. 

Disease genes and familial IIP

Disease genes are often passed down from parents to children. That is why sometimes diseases run in families. Familial IIP is one example of this. All of the disease genes in familial IIP are the type that raise the risk of someone getting the disease but do not guarantee that someone will get the disease.

There are currently nine known disease genes for familial IIP that raise a person’s risk by significant amount.2 Three of the genes have to do with how the alveoli (air sacs) in the lungs make surfactant. Six of the genes have to do with telomeres, which are protective “caps” that cover the ends of chromosomes to keep them from unravelling inside cells. 

Unfortunately, research studies still cannot say exactly how much these disease genes raise a person’s risk. This is an active area of research. 

IIP disease genes that play a role in surfactant

Surfactant is a substance that is a mixture of proteins and fats. It is normally made by cells within the alveoli of the lungs. It keeps the alveoli from collapsing when air is exhaled. Surfactant also plays a role in protecting the cells in the lung from infection.3

Mutations in genes that code for proteins that are needed for healthy surfactant seem to run in some families with familial IIP. The names of the three disease genes are2:

  • Surfactant protein C (SFTPC)
  • Surfactant protein A2 (SFTPA2)
  • Adenosine triphosphate–binding cassette subfamily A member 3 (ABCA3)

Although certain mutations in these three genes increase the risk of having IIP, having those mutations does not guarantee that someone will develop IIP. The disease can also develop differently in family members who both have the same mutation in the same disease gene. Sometimes, family members with a surfactant gene mutation develop IIP as infants or young children, but other times they do not develop it until middle or older adulthood. Sometimes they do not develop IIP at all. Doctors cannot yet predict which family members with the disease gene mutations will or will not develop disease. 

IIP disease genes that play a role in telomeres

If we think of chromosomes as shoelaces, the telomeres are like the plastic tips on the ends of shoelaces (aglets). Telomeres are made of a repeated short sequence of DNA code. The short sequence of code can be repeated up to 3,000 times at the ends of chromosomes. This acts like a protective cap to keep the chromosomes from unraveling or from sticking together.4

Telomeres normally become shorter and shorter as cells age, meaning there are fewer and fewer repeats of the short DNA sequence. When telomeres become too short, the chromosome can no longer be copied, and the cell dies.

Studies have found that telomeres seem to become shorter more quickly than average in people who regularly smoke5, have a high level of alcohol use6, or have a poor diet7. Telomeres may also become shorter more quickly in people who experienced hard childhoods (abuse, neglect, poverty, or violence)8, or who have mental health conditions9. On the other hand, studies have found that telomeres seem to become shorter less quickly than average in people who exercise regularly10, eat a healthy diet7, and get more than 6 hours of sleep per night11.

There are six disease genes for familial IIP that have to do with telomeres:

  • Telomerase reverse transcriptase [TERT]
  • Telomerase RNA component [hTR]
  • Dyskerin [DKC1]
  • Telomere repeat binding factor 1–interacting nuclear factor 2 [TINF2]
  • Regulator of telomere elongation helicase [RTEL1]
  • Poly(A)-specific ribonuclease [PARN]

Normally the molecules made by these genes work to repair damage to telomeres and keep them from becoming too short. When there are mutations in one or more of these genes, the molecules do not work properly, and the telomeres age more quickly than average. The person’s risk of developing some kinds of diseases is increased, including liver fibrosis, bone marrow failure, and familial IIP.12

Researchers do not know exactly how much having a mutation or mutations in one or more telomere genes raises the risk of familial IIP. The disease can also develop differently in family members who both have the same mutation in the same disease gene. Ongoing research studies are attempting to answer this question. 

Other disease genes in familial IIP

A number of research studies are looking at other genes which may increase the risk for familial IIP. Two that have been found are MUC5B, which makes molecules that have to do with mucus in the lungs, and TOLLIP, which makes molecules that have to do with how the immune system recognizes and attacks microbes. 

There are many other genes that are being studied in familial IIP as well.5

Who should receive genetic testing for familial IIP?

Some doctors may offer genetic testing of the 9 known familial IIP disease genes to all members of families where two or more members have IIP. Sometimes doctors may suggest testing other, less well known genes that might be disease genes for familial IIP. If you know that two or more members of your family have been diagnosed with IIP, you may want to ask your pulmonologist about genetic testing.

When a family member is shown to have a mutation in one or more disease genes, that person can receive a thorough screening examination via high-resolution computed tomography (HRCT) to look for very early signs of disease. There are medications available that can slow down the lung damage caused by some forms of IIP. Family members with genetic mutations and very early signs of IIP can be treated early. For family members with a genetic mutation but no signs or symptoms of disease, many doctors suggest periodic screening using HRCT to keep watch on the health of the lungs over time. 

Some clinical trials that study genetics in IIP are available. These studies enroll people with a family history of IIP. Talk to your pulmonologist if you are interested in taking part in a clinical study.

As of March 2020, the following studies are enrolling:


  1. U.S. National Library of Medicine Genetics Home Reference. Help Me Understand Genetics. Updated February 11, 2020. 
  2. Kropski JA, Young LR, Cogan JD, et al. Genetic evaluation and testing of patients and families with idiopathic pulmonary fibrosisAm J Respir Crit Care Med. 2017;195(11):1423–1428. 
  3. Veldhuizen EJ, Haagsman HP. Role of pulmonary surfactant components in surface film formation and dynamicsBiochim Biophys Acta. 2000;1467(2):255–270. 
  4. What is a telomere? Updated January 25, 2016. 
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  10. Cherkas LF, Hunkin JL, Kato BS, et al. The association between physical activity in leisure time and leukocyte telomere lengthArch Intern Med. 2008;168(2):154–158. 
  11. Liang G, Schernhammer E, Qi L, Gao X, De Vivo I, Han J. Associations between rotating night shifts, sleep duration, and telomere length in womenPLoS One. 2011;6(8):e23462. 
  12. Martínez P, Blasco MA. Telomere-driven diseases and telomere-targeting therapiesJ Cell Biol. 2017;216(4):875–887. 
  13. van Moorsel CH, Hoffman TW, van Batenburg AA, Klay D, van der Vis JJ, Grutters JC. Understanding idiopathic interstitial pneumonia: a gene-based review of stressed lungsBiomed Res Int. 2015;2015:304186.