Unraveling an inherited disorder: AATD. (Genetics).

Alpha-1 antitrypsin deficiency (AATD) is an inherited genetic disorder leading in some patients to potentially fatal lung or liver disease. AATD is known to have a particularly strong environmental component; those affected must avoid environmental chemicals, especially cigarette smoke, and all particulates, which accelerate deterioration of lung function. Until recently, AATD was thought to occur mainly in people of northern European descent; it is actually found among many different ethnicities, including African blacks, Arabs, Middle Eastern Jews, Asians, and whites. These and other important facts were presented in a one-day workshop held 19 August 2002, cosponsored by the NIEHS, the NIH Office of Rare Disease Research, and the Alpha-1 Foundation, a patient advocacy group based in Miami, Florida.

The condition has been diagnosed in more than 5,000 people in the United States, but the Alpha-1 Foundation estimates that there are approximately 70,000 U.S. "Alpha-1s." The only current treatment for AATD is weekly infusion with a human serum-derived substitute AAT protein that is in chronically short supply.

NIEHS genetic epidemiologist Frederick de Serres, himself an Alpha-1, outlined his ongoing research into the worldwide racial and ethnic distribution of the gene alleles associated with AATD. In the 58 countries where genetic epidemiological surveys for AATD have been conducted, there are 117 million carriers, 3.4 million of whom carry the two alleles most associated with risk--a much more widespread distribution than previously believed. In the United States alone there are 24.6 million carriers, 600,000 of whom carry the two alleles most associated with risk.

Robert Sandhaus, clinical director of the Alpha-1 Foundation, said studies of the Alpha-1 community may well identify environmental and genetic risk factors that apply to the general population at risk for chronic lung or liver disease. The foundation keeps a research registry of more than 2,000 patients, a subgroup that is well characterized genetically, willing to participate in studies, and especially sensitive to environmental exposures. But disease registries have inherent biases based on socioeconomic, racial, and health status factors, so researchers need to identify a nonbiased population to more effectively validate AATD studies.

As for other future research directions, Sandhaus said the epidemiology of AATD and its natural history still is in need of a great deal of further research. Priority should also be placed on learning more about the role of environmental exposure sensitivities, identifying early biomarkers of disease and exposure sensitivity, and isolating additional genetic factors, such as modifiers that affect the adverse expression of the most common alleles, both in the same family and among different ethnic subgroups. In addition, says de Serres, researchers must find a cure.