The most common cause of death by disease is heart failure. The second most common cause of heart failure worldwide is patent ductus arteriosus - PDA for short. It occurs as a prenatal glitch.
"We were interested in PDA because it's a spectacular example of rapid vascular remodeling," observed molecular geneticist Richard Lifton at Yale University. "In fetal life, the lungs of the fetus aren't necessary for oxygenating blood, because the unborn baby isn't breathing air. Oxygenated blood instead reaches the fetus by exchange across the placenta from mother's blood to fetal blood.
Then, rather than being pumped out of the heart to the lungs, as occurs in adult life, an artery called the ductus arteriosus shunts the blood onward for circulating to the prenatal organs and tissues. But once the infant is born, there comes an abrupt transition. Within the first day of life, a complete remodeling of the ductus arteriosus takes place, completely closing off this artery. In a very short time, this is completely remodeled into a ligament that bars passage of any blood whatsoever. So now the entire output of the heart's right side goes to the lungs. That's the normal event. The closure typically happens on the first day of life, and remodeling occurs within 48 hours. It's a really dramatic event.
"In this sporadic PDA disease," Lifton continued, "that remodeling process fails to happen, and the ductus arteriosus remains open - patent - after birth. In consequence, the blood in the newborn's circulation is under so much higher pressure than the blood in the cardiac and pulmonary circulation that the baby ends up getting a shunt where oxygenated blood is going back into the pulmonary circulation under high pressure. These children can incur congestive heart failure and pulmonary hypertension. PDA is a serious congenital heart disorder that needs to be corrected."
Preemies Have It Easy; Full-Termers, Tough
"There are two main forms of PDA," Lifton recounted, "one that occurs in premature infants, because their physiologic program says it's not time to be closing off their ductus. Those preemies can be treated easily with medications that close off the ductus quickly. But among full-term births - kids who have gone to 39 weeks and are born normally, but their ductus nonetheless stays open - they never react to these drugs. They must always have surgical closure of the ductus to prevent these complications of congestive heart failure."
Lifton is senior author of a paper in the Proceedings of the National Academy of Sciences (PNAS) released online Oct. 30, 2002. Its title: "Finding genetic contributions to sporadic disease: A recessive locus at [chromosome] 12q24 commonly contributes to patent ductus arteriosus."
"The broad message in this paper," Lifton told BioWorld Today, "is that some diseases we now regard as sporadic - such as PDA - can be largely genetic, with recessive genes and reduced penetrance."
(Recessive genes don't manifest themselves unless mutant alleles are present on both homologous chromosomes of a pair. If only some of the individuals carrying the mutant allele display the abnormal phenotype, the trait shows incomplete penetrance. If all of them do, the trait has complete or full penetrance.)
"The approach that we took," Lifton continued, "is, I think, unique. Our basic idea was that we should be able to recognize these diseases by finding that they are more common in populations with high degrees of consanguinity - marriage between related individuals. And then we did genetic mapping to prove that there are large recessive components to the disease. This is the first time this strategy has been taken," he went on, "from initial population study to proof by gene-linkage mapping in a general population, rather than a small inbred population. In the Iranian population, which we studied, at least a third, and as many as two-thirds, of all PDA patients share a large contribution from a single recessive gene. In the Teheran area of Iran that we investigated, marriage between first or second cousins constitutes about 25 percent of all marriages.
"So we wondered," Lifton recalled, "how could we recognize sporadic diseases where there were large contributions from recessive genes? That led on to the idea that we send clinically trained physicians from the U.S. to Iran, put them in a referral hospital where there's a lot of consanguinity, and ask them to look for diseases that seem much more prevalent in that inbred environment than in the U.S. Then see whether the affected cases were more commonly the offspring of consanguineous unions than the surrounding population. If so, those ought to be recessive diseases with reduced penetrance. Then we could bring those patients back to our laboratory, and prove by genetic linkage studies that this was in fact the case."
Tribal Inbreeding Cultural, Not Faith-Based
Lifton made the point that the Iranian custom of inbreeding with first and second cousins is not religious, but cultural. "Throughout much of the Middle East," he observed, "including Saudi Arabia, Iran and many neighboring states, consanguinity is a consequence of nomadic heritage, where wandering tribes found it was desirable to wed within the tribe, because its population was small. So it became customary in many of these societies to marry first cousins.
"The PDA gene or genes involved in our Iranian survey have yet to be located," he said. "We've mapped that candidate gene to about a 30 million base pair segment of the chromosome 12 locus, and we're cranking through them by sequence to look for the gene responsible. Meanwhile, we're continuing to collaborate with the Iranians to recruit additional PDA families. It's been a very interesting cultural experience for us," Lifton added, "because in the West we tend not to recognize what a sophisticated medical culture Iran has.
"The first author of the PNAS paper, Arya Mani, is an Iranian-born physician now a U.S. citizen," Lifton noted. "Trained as a clinical cardiologist in the U.S., he went to Iran and found that the collaboration with Iranian investigators to recognize PDA was a terrific experience. They did all the epidemiology and case-finding, then Mani returned to the lab at Yale, and is continuing with the molecular studies."