Gene variation finding may open door to screenings for SIDS riskBy John Easton
Medical Center Public Affairs
About 5 percent of deaths from SIDS (sudden infant death syndrome) in African Americans can be traced to defects in one gene, and half of those deaths result from a common genetic variation that increases an infant’s risk of developing an abnormal heart rhythm during times of environmental stress. A research team based at the University reported these findings in the February issue of the Journal of Clinical Investigation.
Children with two copies of the common genetic variation have a 24-fold increased risk of sudden death as infants. One out of nine African Americans carries one copy of the common variant. One copy does not appear to increase risk for infants.
“The common polymorphism alone does not cause SIDS,” said Steven Goldstein, Professor and Chairman of Pediatrics and Director of the study. “Our findings suggest, however, that it renders infants vulnerable to environmental challenges — such as a long pause in respiration — that are tolerated by children without the mutation.”
“The hope,” he added, “is that findings like this may one day allow us to intervene. We might screen to identify children at high risk and teach parents how to lessen the likelihood of secondary challenges. We have already begun to evaluate drugs that may mitigate the risk.”
SIDS—the sudden and unanticipated death of an infant with no detectable lethal disorder—is the leading cause of infant deaths in the United States, representing nearly one-third of deaths between one month and one year of age. African Americans have a three times greater risk for SIDS than Caucasians and six times the risk of Hispanics or Asians, suggesting an important role for genetics.
The researchers studied the genes in tissue collected from 133 African-American infants with a diagnosis of SIDS after autopsy. They compared the results with tissue samples from 1,056 African-American adults with no known health problems.
Their search focused on abnormalities in a gene called SCN5A, which has been associated with abnormal heart rhythms. Overall, the team found common and rare changes in this gene in 5 percent of SIDS deaths in African Americans. One specific variation, known as Y1103, was known to confer an eight-fold risk of cardiac arrhythmia in African-American adults with one copy
In this study, the researchers found that having two copies of Y1103 variant gene was more common in infants who had died from SIDS. Three out of the 133 African-American SIDS cases (2.3 percent) had two copies of Y1103, compared to only one individual out of 1,056 controls (0.1 percent). Four other SIDS cases had other damaging mutations in one copy of the gene.
The team’s next step was to explore how this variation might contribute to SIDS. Looking again at the gene associated with abnormal heart rhythms (SCN5A), they found that it codes for a sodium channel, a pore in cardiac muscle cells that controls the passage of sodium ions in and out of the cell.
“This seemed like a good candidate for a genetic difference that could contribute to SIDS,” said Goldstein, “but we had no clear idea how it increased risk since the Y1103 variant did not affect channel operation under normal conditions.”
Cellular activity, particularly that of nerve and muscle cells, is controlled by the flow of ions like sodium and potassium. A change in an ion channel that disrupts ion flow can alter the cell’s activity. So Goldstein’s team concentrated on how Y1103 might change a cell’s behavior.
On first look, it made no difference. Cells with the normal or Y1103 channels “were found to function indistinguishably,” the authors wrote.
But SIDS is not purely genetic; it appears to require multiple “hits,” some from altered genes and some from the environment.
The environment’s role was demonstrated by the “Back to Sleep” campaign, begun in 1994, which cut the prevalence of SIDS in half by teaching parents to put babies to sleep lying on their backs. The campaign was based, in part, on the assumption that babies sleeping on their bellies had more spells of interrupted breathing or apnea.
One of the immediate consequences of apnea is a slight increase in acid levels inside oxygen-hungry muscle cells. When the researchers compared cells with the Y1103 mutation against normal cells in a slightly more acidic environment, the cells with the abnormal channels began to misbehave.
In normal cells, these sodium channels are closed at rest. In response to electrical signals they open briefly, allowing ions to flow though, then rapidly close again. When the pH level falls, however, the mutant sodium ion channels tended to pop back open, delaying the cells’ recovery after a burst of activity. In the heart, changes like this are known to increase the risk for abnormal rhythms and sudden death.
The drug called mexiletine, used to treat patients with arrhythmias, blocks late re-openings of sodium channels at low levels that do not interfere with normal function.
Goldstein and colleagues found that the drug restored normal function in cells with two copies of the Y1103 channels, even under acid conditions.
The authors note that although this study supports a role of Y1103 in SIDS, and the previous use of mexiletine by patients with arrhythmias “suggests a strategy for prophylactic therapy,” they stress that their results “need to be replicated and the risks and benefits of treatment assessed” before screening programs are designed or drugs given to infants at risk to prevent SIDS.
Repetition of the findings would “lead us to consider genetic screening in African Americans in at least three situations,” the authors reported: “Infants with acute life-threatening events, siblings of SIDS victims and couples who experience infertility or fetal demise.”
Additional authors of the paper include Leigh Plant, Qianyong Liu and Tingting Zhang of the University; Peter Bowers, Thomas Morgan and Matthew State of Yale University; Weidong Chen of Howard University; and Rick Kittles from Ohio State University. The National Institutes of Health and the Doris Duke Foundation supported the research.