By Dr. David Clark

Results from 11,341 Subjects Enrolled in My Life, Our Future

Many of you signed up to have your factor IX gene sequenced under the My Life, Our Future (MLOF) program. In fact, out of the 11,341 subjects, 2361 have hemophilia B, including three with both A and B. This is about one-fifth (20.8%) of the total number of subjects, which is consistent with the overall prevalence of hemophilia A and B. For hemophilia B, there were 1616 males (68.4%), 742 females (31.4%) and two transgender people who had transitioned from male to female. Ages ranged from less than two years (5.0%) to 65 and over (3.9%), with the largest segment in the 20 - 44 age range (35.5%).

In 2012, only about 20% of hemophilia patients had been genotyped, that is, had the sequences of their factor VIII or IX genes determined. MLOF, which ran from 2013 to 2017, significantly increased that proportion. In 2016, the program was opened to carriers, so a fairly large group of women was also included. Subjects enrolled through their HTCs, giving permission to MLOF to access their medical records and providing a sample for genotyping.

The subjects were also given the opportunity to give a blood sample to the Research Repository for future studies, which about 80% of subjects did. The medical data were connected to the patient’s gene sequence, but all of the data were de-identified to protect patient privacy. All participants had both their factor VIII and factor IX genes sequenced.

The study found 431 unique factor IX gene mutations, 134 of which were novel, that is, they hadn’t been seen before. They found that about 1.9% of Bs did not appear to have any mutation. All of those with no mutation were milds and moderates. Mutations were found in all subjects with severe disease.

The lack of an identifiable mutation suggests that these people’s hemophilia is not caused by an issue with their factor IX. It could be caused by problems in the vitamin K-dependent processing of the factor IX protein, which is essential for clotting activity, or it could be a result of problems with other proteins with which factor IX interacts. For instance, see the article in this issue on Ehlers-Danlos syndrome, where factor IX can’t bind to collagen because of a problem with the collagen, not the factor IX.

More than one mutation was identified in 95 patients, including 36 female patients. Because they sequenced both the factor VIII and IX genes of each subject, they were able to identify a number of benign mutations, mutations that don’t cause disease. For instance, all the Bs had their factor VIII gene sequenced and a number of variants were found in those genes that did not appear to be harmful. Vice versa for the As who had their factor IX genes sequenced.

The study focused a lot on inhibitors, which are a big problem in hemophilia A. Fewer hemophilia B patients develop inhibitors, but when they do, the issues can be more severe. In hemophilia B, about 12% of severes had a history of inhibitors but only 1.9% of milds and moderates. Overall for all severities about 5.7% of Bs developed inhibitors. This is much higher than the UDC study from 1998 to 2011, which found an inhibitor rate of only 1.3% for Bs. The MLOF result is probably more accurate since it came from a much larger sample size.

They also looked at inhibitor development according to ethnicity and race. For hemophilia B, they found that Blacks have the highest incidence with 13.1% developing an inhibitor, while whites have an incidence of 4.9%. They also looked at Asians, American or Alaskan natives, Hawaiians and other Pacific Islanders and mixed races, but the numbers of patients were too small to show significant differences. For ethnicity, they looked at Hispanic (9.9% incidence) versus non-Hispanic (5.1%). The reasons for these differences are unknown.

The complete study article can be downloaded for free https://pubmed.ncbi.nlm.nih.gov/35770352/
If you want to play around with the results yourself, scroll down to the bottom of the web page, where you can download a supplementary Excel file containing all the data. [Johnsen JM, et al., J. Thromb. Haemost., 20:2022-2034 (2022)]