Genetic variants at the 9p21 locus contribute to atherosclerosis through modulation of ANRIL and CDKN2A/B☆
Section snippets
Study sample
For the genetic association study between the SNPs: rs1333049, rs564398 and rs2811712 (see SNPs in green in Fig. 1), and CAD, patients with documented evidence of angiographically diagnosed coronary stenosis (including acute myocardial infarction, angina pectoris and, silent myocardial ischemia) (subjects characteristics in Supplementary Table 1 and Supplementary Methods).
For peripheral blood RNA expression analysis, we obtained whole blood samples from 57 volunteers (69–72 years old) from Asago
Confirmation of 9p21 association in the Japanese sample
We assessed the possible association of the three SNPs: rs1333049, rs564398, and rs2811712 with CAD. We confirmed the rs1333049 association with CAD in our sample (Controls CC:101; CG:224; GG:122; Cases CC:72; CG:116; GG:43; age adjusted P-value < 0.01) (Fig. 2A); however, we were not able to detect any significant association of CAD with either rs564398 or rs2811712 (see Supplementary Table 4).
Expression analysis of CDKN2A/B and ANRIL in blood
The linkage disequilibrium (LD) map for the SNPs genotyped in this study and a transcriptional
Discussion
Since the GWAs have revealed a CAD association at the 9p21 locus, researchers have hypothesized a potential regulatory role of the associated SNPs in the expression of ANRIL, CDKN2A, and CDKN2B. However, publications demonstrating a correlation between the risk genotypes and the expression of the transcripts in the locus have reported contradictory results [18], [23], [24], highlighting the need to replicate such studies to clarify true associations. Probably, this lack of consistency is due to
Acknowledgements
We would like to express our gratitude to Ms. Yuki Imaizumi and Ms. Takako Baba for their continuous support in this investigation.
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This study was supported in part by grants-in-aid from the Program for Promotion of Fundamental Studies in National Institute of Biomedical Innovation of Japan (HR: 22-2-5), the Ministry of Education, Culture, Sports, Science, and Technology of Japan (KK: 22510211) and NOVARTIS Foundation for Gerontological Research (KK).