| Institution: | 1. Department of Genetics, Yale University School of Medicine, New Haven, CT, USA;2. Cardiovascular Research Institute, University of California, San Francisco, CA, USA;3. Department of Cardiology, The Guangzhou Eighth People''s Hospital, Guangzhou Medical University, Guangzhou, China;4. Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA;5. Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA;6. Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Korea;7. Institute for Human Genetics, University of California, San Francisco, CA, USA;8. Department of Internal Medicine, Istanbul University, Istanbul, Turkey;9. Department of Medicine, University of California, San Francisco, CA, USA;10. Department of Pediatrics, University of California, San Francisco, CA, USA;11. Department of Dermatology, University of California, San Francisco, CA, USA;12. Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA;13. Physiological Nursing, University of California, San Francisco, CA, USA |
| Abstract: | Low levels of high density lipoprotein-cholesterol (HDL-C) are associated with an elevated risk of arteriosclerotic coronary heart disease. Heritability of HDL-C levels is high. In this research discovery study, we used whole-exome sequencing to identify damaging gene variants that may play significant roles in determining HDL-C levels. We studied 204 individuals with a mean HDL-C level of 27.8 ± 6.4 mg/dl (range: 4–36 mg/dl). Data were analyzed by statistical gene burden testing and by filtering against candidate gene lists. We found 120 occurrences of probably damaging variants (116 heterozygous; four homozygous) among 45 of 104 recognized HDL candidate genes. Those with the highest prevalence of damaging variants were ABCA1 (n = 20), STAB1 (n = 9), OSBPL1A (n = 8), CPS1 (n = 8), CD36 (n = 7), LRP1 (n = 6), ABCA8 (n = 6), GOT2 (n = 5), AMPD3 (n = 5), WWOX (n = 4), and IRS1 (n = 4). Binomial analysis for damaging missense or loss-of-function variants identified the ABCA1 and LDLR genes at genome-wide significance. In conclusion, whole-exome sequencing of individuals with low HDL-C showed the burden of damaging rare variants in the ABCA1 and LDLR genes is particularly high and revealed numerous occurrences in HDL candidate genes, including many genes identified in genome-wide association study reports. Many of these genes are involved in cancer biology, which accords with epidemiologic findings of the association of HDL deficiency with increased risk of cancer, thus presenting a new area of interest in HDL genomics. |
