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Genetic overlap exists between Alzheimer’s disease, two CVD risk factors
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Researchers have found genetic overlap between Alzheimer’s disease, high levels of C-reactive protein and plasma lipids.
The findings indicate that high levels of CRP and plasma lipids may play a role in the risk for Alzheimer’s disease and lead to new research to determine whether treating the CVD risk factors delays the onset of Alzheimer’s disease.
Genetic signals found
“For many years we have known that high levels of cholesterol and high levels of inflammation are associated with increased risks for Alzheimer’s disease,” researcher Paul M. Ridker, MD, MPH, the Eugene Braunwald professor of medicine at Harvard Medical School and director of the Center for Cardiovascular Disease Prevention at Brigham & Women’s Hospital, said in a press release. “The current work finds that specific genetic signals explain a part of these relationships. We now need to characterize the function of these genetic signals and see whether they can help us to design better trials evaluating inflammation inhibition as a possible method for Alzheimer’s treatment.”
Paul M. Ridker
The researchers used summary statistics from genomic-wide association studies of more than 200,000 individuals to investigate whether there was overlap in single nucleotide polymorphisms associated with clinically diagnosed Alzheimer’s disease and CRP, triglycerides, HDL and LDL.
For progressively stringent P-value thresholds for Alzheimer’s disease single nucleotide polymorphisms, the researchers found at least 50-fold enrichment using CRP, 30-fold enrichment using triglycerides, 20-fold enrichment using HDL and 40-fold enrichment using LDL.
They conditioned on polymorphisms associated with the four phenotypes and found 55 loci that were associated with increased risk for Alzheimer’s disease.
Subsequently, the researchers performed a meta-analysis of the 55 variants across four independent cohorts from studies of Alzheimer’s disease (29,054 people with Alzheimer’s disease, 114,824 healthy controls).
Two key variants
That meta-analysis revealed two genome-wide significant variants on chromosome 4 (rs13113697, closest gene HS3ST1; OR = 1.07; 95% CI, 1.05-1.11) and on chromosome 10 (rs7920721, closest gene ECHDC3; OR = 1.07; 95% CI, 1.04-1.11).
The gene expression of HS3ST1 and ECHDC3 was altered in brains with Alzheimer’s disease compared with brains without it, according to the researchers. In those with Alzheimer’s disease, transcript expression of HS3ST1 was decreased (standardized beta-coefficient = –0.09201; standard error = 0.01864; P = 9.99 x 10-7) and transcript expression of ECHDC3 was increased (standardized beta-coefficient = 0.12715; standard error = 0.01829; P = 8.32 x 10-12) compared with those without Alzheimer’s disease, they wrote.
“Careful and considerable effort will be required to further characterize the novel candidate genes detected in this study and to detect the functional variants responsible for the association of those loci with Alzheimer’s risk,” Anders M. Dale, PhD, professor of neurosciences and radiology and director of the Center for Translational Imaging and Precision Medicine at the University of California, San Diego, said in the release. “It will also be important to understand whether these genes, in combination with other known markers such as brain imaging, cerebrospinal fluid measurements and APOE E4 status, can improve the prediction of disease risk in [Alzheimer’s disease].” – by Erik Swain
Disclosure: The researchers report no relevant financial disclosures.
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