Meta-analyses find no genetic link between diabetes and development of CAD
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Type 2 diabetes has an established causal association to CAD, but researchers observed no apparent genetic link between diabetes and risk for CAD, according to a study published in Circulation: Genomic and Precision Medicine.
Investigators performed two meta-analyses that systematically assessed any genetic overlap between CAD and diabetes among 66,643 individuals (27,708 with CAD; 24,259 with diabetes). The first analysis compared CAD cases with controls without reference to diabetes status and the second repeated the analysis and adjusted for diabetes.
“This study shows that difference in risk of CAD between subjects with and without type 2 diabetes cannot be explained by variants of large effect or differences in the genetic variation contributing to known risk factors of either type 2 diabetes or CAD,” Natalie R. van Zuydam, PhD, researcher in the department of immunology, genetics and pathology at Uppsala University, Sweden, and colleagues wrote.
The investigators confirmed that many previously reported loci associated with CAD had genome-wide significance (P 5×10-8), which included SORT1/CELSR2, WDR12, PHACTR1, TCF21, 9p21.3, CXCL12 and ADAMTS7. This list was expanded to 13 loci in a joint analysis.
For established variants of these loci associated with CAD, the risk allele identified in this meta-analysis was the same as the published risk allele for variants associated with CAD (P 1×10-3), which reflects an overlap of samples included in the analyses, according to the study.
In the second meta-analysis, investigators reported that three CAD loci reached genome-wide significance, ADAMTS7 in patients with diabetes and 9p21.3 and PHACTR1 in the patients without diabetes, but these did not show any systematic difference according to diabetes status.
Researchers found no novel CAD-risk signals in either stratum and the three loci associated with CAD in patients with diabetes overlapped with loci associated with CAD in patients without diabetes.
“There are several other mechanisms, outside the scope of the current study, that could explain some of the increased risk of CAD in subjects with type 2 diabetes,” van Zuydam and colleagues wrote. “There could be epigenetic changes induced by some feature of the type 2 diabetes state. For example, hyperglycemia has been shown to cause epigenetic changes altering gene expression in vascular cells leading to endothelial dysfunction, a hallmark of atherosclerosis.”
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