X chromosome provides clues to the causes of primary biliary cholangitis

A study by a group of researchers from Milano-Bicocca and Humanitas University, published in “Gastroenterology”, opens up new perspectives on autoimmune diseases and on the reason why they affect women much more than men.

A recent study by an international team of researchers marked an important step towards understanding the causes of primary biliary cholangitis (CBP). The work was coordinated by experts from the Milano-Bicocca University and the Centre for Autoimmune Liver Diseases at the San Gerardo Hospital in Monza, who have been studying this disease for years, and geneticists from the Istituto Clinico Humanitas in Rozzano. The researchers investigated the role the X chromosome has in the genetic architecture of liver disease.

Like most autoimmune diseases, PBC (Primary Biliary Cholangitis) mainly affects females, with a female-to-male ratio of 9:1. Since the 1950s and 1960s, many doctors and scientists have been studying sex hormones, such as estrogen and progesterone, in an attempt to explain female preponderance. As no clear explanation was found, researchers started including also sex chromosomes in their studies.

The study X chromosome contribution to the genetic architecture of primary biliary cholangitis (DOI: 10.1053/j.gastro.2021.02.061) was published in the journal ‘Gastroenterology’. Thanks to the contribution of colleagues from healthcare institutions and research institutes in the UK, Japan, China and Canada, researchers from Milano-Bicocca and Humanitas University collected and examined genetic data from 5,244 cases, including Italian patients. By applying for the first time a method of analysis called XWAS developed to specifically identify possible genetic associations in the X chromosome, researchers found associations with genes such as the ‘FOXP3’ one which, if defective, can alter the normal functions of our immune defences, leading them to “self-aggression” and thus causing PBC and autoimmunity.

«This study was specifically designed to investigate the X chromosome, which, due to its peculiarities (it has two copies in women and a single copy in men), has never been specifically targeted in this kind of research. It is thought that the X chromosome is responsible for up to 5% of the human genome, and mutations in genes located in this chromosome explain about 10% of monogenic diseases. Despite this, studies on the X-chromosome and complex – or multigenic – diseases, such as PBC are still at an early stage, and less than 1% of all genetic associations described so far involve this particular chromosome», explains Professor Rosanna Asselta    of Humanitas University, who adds, «We have shed a light on a topic which has not been explored much to date, but which can now be explored further to understand the involvement of this chromosome in other diseases. More generally, this is a small step towards gender-based medicine, which so far has not been a focus of attention ».

«More than 20 years ago our group pioneered the study of how genetic and epigenetic defects in the X and Y sex chromosomes explain the female predominance in CBP and in autoimmune diseases in general. This study is yet another confirmation that the sex chromosomes are precisely where we can find the main answer to this fundamental problem», says Professor Pietro Invernizzi, gastroenterologist at the University of Milan-Bicocca. «Having understood this, we are now confident we can also understand why we can contract this rare liver disease, as well as the 80 or more autoimmune diseases that together affect 5-6% of the general population, often with very debilitating clinical pictures and insufficient availability of effective therapies as in the case of rheumatoid arthritis, lupus and connective tissue diseases».

«The Italian Federation of Rare Diseases represents several associations of patients with autoimmune diseases (and many of these are formed mainly by women), so we are pleased to know that research has taken a step forward in understanding this disease. In Italy, there is still much to be done within this field to ensure equal access to services and to create a network of experiences in the whole territory. We hope this study will pave the way for more effective, and perhaps even decisive therapies, and will also help to strengthen the concept of centrality of the patient and of personalised treatment» says Annalisa Scopinaro, president of Uniamo F.I.M.R. non-profit organisation. «Scientific research in Italy remains a key contribution to medical knowledge: it is a source of great pride, as well as a good thing for the many Italian patients».


Humanitas is a highly specialized Hospital, Research and Teaching Center. Built around centers for the prevention and treatment of cancer, cardiovascular, neurological and orthopedic disease – together with an Ophthalmic Center and a Fertility Center – Humanitas also operates a highly specialised Emergency Department.