Gene Variant Linked to Chronic Kidney Disease

Two common gene variations are associated with the risk for developing chronic kidney disease, according to a study by researchers at the Johns Hopkins Bloomberg School of Public Health and other institutions. One variant increases risk and the other decreases risk with a similar effect in whites, African-Americans, diabetic and non-diabetic individuals. The study, published in the June 15, 2005, edition of JAMA, is the first large-scale investigation of the role Apolipoprotein E (APOE) alleles play in chronic kidney disease. APOE is known to be associated with risk of Alzheimer’s disease and heart disease but interestingly, the kidney disease association is in the opposite direction.

Results of the study found that a variant of the APOE gene, the e2 allele, was associated with a moderately increased risk for chronic kidney disease. The study also confirmed that the e4 variant offered protection against the development of chronic kidney disease. The e4 allele is also a known risk factor for Alzheimer’s disease and a weaker risk factor for coronary heart disease. The e2 allele is known to be associated with abnormalities in plasma triglycerides, a condition that is also common with kidney disease. Smaller previous studies have suggested that the e2 increased and e4 alleles decreased the risk of kidney disease, but those studies mostly focused on individuals with diabetes.

“Consistency of association across a number of previous studies is important in convincing us this effect is real. However, our large study suggests that the effect of the APOE gene is much weaker than previous smaller studies indicated,” said Josef Coresh, MD, PhD, corresponding author and professor of epidemiology, medicine and biostatistics at the Bloomberg School of Public Health. “Our understanding of the biology and genetics of kidney disease is improved, which may point to directions for future improvements in therapy. However, population screening for kidney disease risk is still best focused on diabetes, hypertension and protein in the urine.”

The study involved 14,520 middle-aged whites and African Americans enrolled in the Atherosclerosis Risk in Communities study. Participants underwent standardized medical exams every 3 years from 1987 to 1999. None had severe renal disease when they entered the study and 1,060 developed some kidney disease, as indicated by laboratory testing, hospitalization or death certificates, by 2003. Most recent estimates indicate that approximately 400,000 U.S. residents undergo dialysis and approximately 8 million adults have lost half or more of their kidney function, a level diagnostic of chronic kidney disease. This study sheds light on susceptibility for developing moderate chronic kidney disease while other studies are increasingly focusing on the consequences and complications of chronic kidney disease, which include an increased risk of developing a heart attack, stroke and bone fractures.

Charles C. Hsu, PhD, lead author of the study and an epidemiologist with the Johns Hopkins University School of Medicine said, “The study points to the potential importance of the effects of APOE on cell-to-cell communication and response to injury in the kidney.”

“From a genetics perspective, the APOE gene is fascinating.  It has several common variants–only half the people have the most common form of the gene. The two other main variants are still quite common and, interestingly, relate to different diseases in different ways. APOE was first appreciated for its role in targeting cholesterol and other fats through the bloodstream. Compared to the most common e3 variant of the gene, the e4 variant clears from the blood more quickly and the e2 clears more slowly,” explained co-author Linda Kao, PhD, of the study, a genetic epidemiologist and assistant professor at the Bloomberg School of Public Health. “It was later appreciated that APOE is a key determinant of Alzheimer’s disease risk. APOE is important in the formation of brain lesions central to Alzheimer’s, but the exact mechanisms still need to be understood. It is intriguing that APOE is now found to relate to chronic kidney disease progression, but its effect on risk is opposite to that of its effect on heart disease and Alzheimer’s disease.”

“Apolipoprotein E and Progression of Chronic Kidney Disease” was written by Charles C. Hsu, PhD; W.H. Linda Kao, PhD; Josef Coresh, MD, PhD; James S. Pankow, PhD; Jane Marsh-Manzi, PhD; Eric Boerwinkle, PhD; and Molly S. Bray, PhD.

Funding was provided by the National Heart, Lung and Blood Institute and grants from the National Institutes of Health, the Centers for Disease Control and Prevention, the American Diabetes Medical Scholar Award and the American Heart Association Established Investigator Award.