NEW YORK (GenomeWeb) – Mutations in several dilated cardiomyopathy-related genes — particularly one coding for the muscle protein titin — appear to contribute to the risk of heart failure in some women during late in pregnancy or shortly after giving birth, according to a study published online yesterday in the New England Journal of Medicine.
Researchers from the "Intervention in Myocarditis and Acute Cardiomyopathy 2" (IMAC-2) and the "Investigators in Pregnancy Associated Cardiomyopathy" (IPAC) studies collaborated to sequence more than 40 genes that have been linked to another heart condition — dilated cardiomyopathy — in nearly 200 women who developed peripartum cardiomyopathy, which is marked by systolic heart failure in late pregnancy or shortly after birth.
The search unearthed more than two dozen rare, truncating mutations affecting eight of the dilated cardiomyopathy genes. Truncating alterations in these genes turned up in less than 5 percent of control individuals tested, but more than 15 percent in the peripartum cardiomyopathy group carried such mutations. And similar to patterns the team saw in dilated cardiomyopathy cases, truncating mutations were particularly common in TTN, a gene that codes for a sarcomere muscle unit protein called titin.
"Until now, we had very little insight into the cause of peripartum cardiomyopathy," corresponding author Zoltan Arany, an associate professor of cardiovascular medicine at the University of Pennsylvania, said in a statement. "[T]his research shows that a mutation in the TTN gene is the cause of a significant number of peripartum cardiomyopathies, even in women without a family history of the disease."
Peripartum cardiomyopathy affects between one in 1,000 and one in 4,000 pregnant women in the US and Europe, the researchers noted, though rates are far higher in other parts of the world. Prior studies suggest the condition is more common in those with preeclampsia, advanced maternal age, and in women carrying twins, although it has been difficult to pinpoint a precise cause for peripartum cardiomyopathy.
Still, the team suspected it may have a genetic component, given the far higher-than-usual rates of the condition in places such as Haiti or Nigeria, together with findings from studies hinting at risk of peripartum cardiomyopathy and other heart conditions in some families.
For the current study, the researchers used the Illumina HiSeq 2500 to sequence samples from 172 women with peripartum cardiomyopathy, including 61 women with African ancestry, focusing on protein-coding sequences from 43 dilated cardiomyopathy-related genes that were captured with the Agilent SureSelect method.
The same set of genes was sequenced in 332 individuals with dilated cardiomyopathy, using a combination of in-solution hybridization capture and Applied Biosystems SOLiD 5500XL sequencing.
The team then searched for rare, potentially deleterious variants in the two patient groups.
Indeed, the researchers found that 26 of the 172 women — just over 15 percent — had suspicious mutations, each carrying a distinct, rare truncating alteration affecting one of eight genes. Such mutations were also present in 55 of the dilated cardiomyopathy patients, or nearly 17 percent of those tested.
In contrast, they saw similar truncating mutations in just 4.7 percent of unaffected individuals when they scoured 60,706 exomes from the Exome Aggregation Consortium and the Exome Variant Server.
In particular, almost 10 percent of the peripartum cardiomyopathy cohort carried truncating mutations in TTN, while truncating TTN mutations turned up in just 1.4 percent of the reference population group.
"We conclude that peripartum cardiomyopathy shares a genetic predisposition with both familial and sporadic idiopathic dilated cardiomyopathy," Arany and colleagues wrote, noting that TTN truncating mutations were chief among the apparent culprits uncovered in both conditions.