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GWAS Reveals Loci Linked to Myeloproliferative Neoplasm Risk

NEW YORK (GenomeWeb) – A new study published online this week in Nature Communications suggests that variants falling in at least three sites in the genome may bump up the risk of developing myeloproliferative neoplasms, blood cell overproduction disorders that can progress to acute myeloid leukemia. 

An international team led by investigators in the UK performed a three-stage genome-wide association study involving more than 13,500 cases with or without myeloproliferative neoplasms to search for inherited variants that contribute to a patient's risk for developing the condition. The search led to variants in and around the JAK2, TERT, and MECOM genes, along with variants in the HBS1L and MYB gene region.

"[O]ur study indicates that genetic variation at multiple loci contributes to the risk of developing [myeloproliferative neoplasms]," senior author Nicholas Cross, a researcher affiliated with the University of Southampton and Salisbury District Hospital, and colleagues wrote. "Further investigation will be needed to understand how genetic variation at JAK2, MECOM, TERT, and other loci predispose to [myeloproliferative neoplasms]."

Myeloproliferative neoplasms include conditions such as polycythemia vera, which involves excess proliferation of red blood cells, the team noted, as well as the platelet overproduction disease essential thrombocythemia or the bone marrow condition primary myelofibrosis.

Past research suggests that myeloproliferative neoplasms can arise due to somatic mutations in genes such as JAK2 or CALR. But the heritability of the diseases hints that inherited variants in JAK2 and other genes may ramp up risk of the myeloproliferative neoplasms, too.

In an effort to more fully define risk factors for the disease, authors of the new analysis did a GWAS that began by looking at 524 individuals with myeloproliferative neoplasms that did not harbor the characterized JAK2 somatic mutation.

When they compared genotyping patterns in these cases with those found in 2,674 unaffected controls, the researchers narrowed in on just over 200 SNPs in 173 suspicious genomic regions for follow-up testing.

During the replication stage of the study, meanwhile, the team considered almost 1,000 more myeloproliferative neoplasm cases from the UK, Germany, Austria, and Greece, alongside thousands of unaffected controls from the UK and Bavaria, uncovering four SNPs that remained significantly linked to myeloproliferative neoplasm risk.

The researchers went on to further validate these disease associations by testing additional cases and controls from the UK and Italy. They also determined the specificity of these risk factors by ruling out similar associations in 406 individuals with conditions that resemble myeloproliferative neoplasms but are diagnostically distinct.

In the multistage GWAS and in a meta-analysis of all of the case-control cohorts, the team saw ties between myeloproliferative disease and variants near the TERT and HBS1L-MYB genes.

Additional variants in JAK2 and MECOM were specifically associated with myeloproliferative neoplasm cases that were negative for a previously described somatic mutation in JAK2.

On the other hand, the risk variant near HBS1L and MYB appeared to have a more pronounced association with JAK2 somatic mutation-positive neoplasms, particularly for individuals with essential thrombocythemia, the platelet proliferation disease.

The team's follow-up studies in normal myeloid cells suggested that this essential thrombocythemia risk might stem, in part, from lower-than-usual expression of a gene called MYB when the HBS1L-MYB variant is present, though more research is needed to explore that possibility.