Genome-wide association studies identified novel loci for non-high-density lipoprotein cholesterol and its postprandial lipemic response

Authors: AN, PING - Washington University; STRAKA, ROBERT - University Of Minnesota; POLLIN, TONI - University Of Maryland; FEITOSA, MARY - Washington University; WOJCZYNSKI, MARY - Washington University School Of Medicine; DAW, E. WARWICK - Washington University; O'CONNELL, JEFFREY - University Of Maryland; GIBSON, QUINCE - University Of Maryland; RYAN, KATHLEEN - University Of Maryland; HOPKINS, PAUL - University Of Utah; TSAI, MICHAEL - University Of Minnesota; Lai, Chao Qiang; PROVINCE, MICHAEL - Washington University; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; SHULDINER, ALAN - Va Medical Center; ARNETT, DONNA - University Of Alabama; BORECKI, INGRID - Washington University

Submitted to: Human Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/24/2014
Publication Date: 3/7/2014
Citation: An, P., Straka, R.J., Pollin, T.I., Feitosa, M.F., Wojczynski, M.K., Daw, E., O'Connell, J.R., Gibson, Q., Ryan, K.A., Hopkins, P.N., Tsai, M.Y., Lai, C., Province, M.A., Ordovas, J.M., Shuldiner, A.R., Arnett, D.K., Borecki, I.B. 2014. Genome-wide association studies identified novel loci for non-high-density lipoprotein cholesterol and its postprandial lipemic response. Human Genetics. DOI: 10.1007/s00439-014-1435-3.

Interpretive Summary: Circulating blood lipids are used in clinical practice to identify people at risk for cardiovascular diseases and to decide on preventive and therapeutic approaches. Traditionally the focus has been on total cholesterol, low-density lipoprotein cholesterol (LDL-C or bad cholesterol) and high-density lipoprotein cholesterol (HDL-C or good cholesterol); however, our recent work has shown that triglyceride levels are also important contributors to risk. Therefore, a measure that includes information about the bad cholesterol as well as triglyceride may be more informative than any of those measures assessed separately. We propose that Non-high-density lipoprotein cholesterol (NHDL) is an independent and superior predictor of CVD risk as compared to low-density lipoprotein alone. It represents a spectrum of atherogenic (promotes the formation of fatty plaques in the arteries) lipid fractions and it may also have its own and distinct genomic fingerprint. In order to investigate this important question, we performed genome-wide association studies (GWAS) to identify loci influencing baseline NHDL and its postprandial (after eating) lipemic (PPL) response. We carried out GWAS in 4,241 participants of European descent. Our discovery cohort included 928 subjects from the Genetics of Lipid-Lowering Drugs and Diet Network Study. Our replication cohorts included 3,313 subjects from the Heredity and Phenotype Intervention Heart Study and Family Heart Study. We found the most enticing results in a region containing three genes: RHOQ-PIGF-CRIPT. The association between genetic variants in this region and fasting NHDL was highly significant. Moreover, we found that another common variant in the gene known as CDH13 was associated with NHDL response to dietary high-fat intake challenge. These results provide evidence of the genetic basis of NHDL values and the ability to predict disease risk early in life to facilitate better prevention.

Technical Abstract: Non-high-density lipoprotein cholesterol (NHDL) is an independent and superior predictor of CVD risk as compared to low-density lipoprotein alone. It represents a spectrum of atherogenic lipid fractions with possibly a distinct genomic signature. We performed genome-wide association studies (GWAS) to identify loci influencing baseline NHDL and its postprandial lipemic (PPL) response. We carried out GWAS in 4,241 participants of European descent. Our discovery cohort included 928 subjects from the Genetics of Lipid-Lowering Drugs and Diet Network Study. Our replication cohorts included 3,313 subjects from the Heredity and Phenotype Intervention Heart Study and Family Heart Study. A linear mixed model using the kinship matrix was used for association tests. The best association signal was found in a tri-genic region at RHOQ-PIGF-CRIPT for baseline NHDL (lead SNP rs6544903, discovery p = 7e-7, MAF = 2 %; validation p = 6e-4 at 0.1 kb upstream neighboring SNP rs3768725, and 5e-4 at 0.7 kb downstream neighboring SNP rs6733143, MAF = 10 %). The lead and neighboring SNPs were not perfect surrogate proxies to each other (D' = 1, r**2 = 0.003) but they seemed to be partially dependent (likelihood ration test p = 0.04). Other suggestive loci (discovery p < 1e-6) included LOC100419812 and LOC100288337 for baseline NHDL, and LOC100420502 and CDH13 for NHDL PPL response that were not replicated (p > 0.01). The current and first GWAS of NHDL yielded an interesting common variant in RHOQ-PIGF-CRIPT influencing baseline NHDL levels. Another common variant in CDH13 for NHDL response to dietary high-fat intake challenge was also suggested. Further validations for both loci from large independent studies, especially interventional studies, are warranted.