Table 3.
Pheno-type | Chr | Lead-SNP BP | MAF | P | B | SE | Genomic region | Candidate gene | Position of functional candidate gene | Functional link | Region in strong LD with lead-SNP, r2 > 0.8 |
---|---|---|---|---|---|---|---|---|---|---|---|
Sste | 1 | 5,288,352 | 0.30 | 7.64E−06 | − 3.20 | 0.72 | Intron, PACRG |
PACRG PRKN |
4,967,800-5,465,157 5,698,508-6,731,132 |
PACRG and PRKN are located head to head and are co-regulated (Entrez gene). PRKN encodes parkin, which is a lipid-responsive regulator of cellular fat uptake48 and has an effect on lipid absorption from the gut49 | 5,288,352-5,288,352 |
TC | 1 | 26,458,317 | 0.12 | 2.56E−06 | 5.29 | 1.12 | Intergenic | TNFAIP3 | 26,473,985-26,489,555 | The product of TNFAIP1 is a suppressor of the ASK1 activation that plays a key role in development of non-alcoholic steatohepatitis50,51 | 26,313,479-26,469,377 |
LDL-C | 1 | 26,864,925 | 0.19 | 6.60E−06 | 4.76 | 1.06 | Intergenic | TNFAIP3 | 26,473,985-26,489,555 | Do | 26,864,925-26,875,955 |
Bsit | 1 | 97,876,982 | 0.01 | 8.22E−06 | − 161.68 | 36.26 | Intron, ZBTB7C | ZBTB7C | 97,610,258-98,018,149 | The product of ZBTB7C changes transcription factor binding dynamics of SREBP-1C in mice52 | 97,872,191-97,877,224 |
HDL-C | 1 | 261,632,218 | 0.10 | 5.24E−06 | − 4.37 | 0.96 | Intergenic | DAB2IP | 261,659,799-261,859,833 | DAB2IP is associated with risk of coronary heart disease in humans53 that is correlated with HDL-C levels54,55 | 261,632,218-261,653,928 |
TC | 2 | 80,066,762 | 0.07 | 2.60E−06 | − 7.83 | 1.67 | Intron, COL23A1 | COL23A1 | 79,766,160-80,137,598 | COL23A1 encode a collagen variant found in lipid rafts in cell membranes56, which are involved in cholesterol transport57 | 80,066,184-80,075,271 |
Sint | 4 | 6,495,094 | 0.08 | 2.29E−06 | 26.14 | 5.53 | Intergenic | MIR30D | 6,948,669-6,948,747 | MIR30D is negatively correlated with HDL-C levels and positively correlated with LDL-C levels58 | 6,198,095-6,774,519 |
Lan | 4 | 39,414,823 | 0.04 | 7.52E−06 | 0.85 | 0.19 | Intergenic | TSPYL5 | 39,362,978-39,367,404 | Down-regulation of TSPYL5 occur concomitantly with a reduction in cellular cholesterol and fatty acid synthesis and a decrease in total cholesterol and free fatty acid levels42,43 | 39,414,823-39,414,823 |
Lat | 4 | 58,499,547 | 0.05 | 5.38E−06 | 14.81 | 3.26 | Intergenic | PEX2 | 59,252,313-59,270,099 | PEX2 controls levels of HDL-C and TC45 | 58,499,547-58,515,494 |
TG | 4 | 108,751,861 | 0.03 | 1.42E−06 | − 34.01 | 7.05 | Upstream variant, RAP1A | RAP1A | 108,673,364-108,694,720 | RAP1A regulates hepatic and plasma PCSK9, plasma TC and LDL-C in mice59 | 108,751,861-108,751,861 |
TC | 4 | 119,813,955 | 0.13 | 9.39E−06 | 5.05 | 1.14 | Intergenic | SNX7 | 119,162,676-119,255,839 | SNX7 is associated with LDL-C levels60 | 119,765,369-119,828,033 |
Csta | 5 | 90,450,047 | 0.14 | 5.80E−06 | − 3.24 | 0.71 | Intergenic | EEA1 | 90,131,742-90,259,208 | EEA1 encodes an early endosome antigen, which is a core component of endosome docking61 and may play a role in transport of lipids between membrane compartments62 | 90,344,197-90,566,508 |
Sste | 5 | 90,450,047 | 0.14 | 9.69E−06 | − 3.63 | 0.82 | Intergenic | EEA1 | 90,131,742-90,259,208 | Do | 90,344,197-90,566,508 |
Sphy | 6 | 71,581,677 | 0.10 | 9.99E−06 | − 136.25 | 30.84 | Upstream variant, DISP3 |
DISP3 UBIAD1 ANGPTL7 MTOR MFN2 |
71,584,051-71,640,673 71,419,574-71,431,237 71,350,921-71,356,683 71,286,991-71,412,884 72,027,996-72,056,434 |
DISP3 encodes a sterol-sensing-domain-containing protein63 UBIAD1 may be involved in cholesterol metabolism (Entrez Gene) ANGPTL7 plays a role in lipid trafficking and metabolism64 MTOR encodes a SREBP1 regulator65 MFN2 plays a role in regulation of cholesterol synthesis66 |
71,549,824-71,591,026 |
TG | 7 | 8,862,047 | 0.29 | 1.31E−06 | 11.88 | 2.46 | Intergenic | EDN1 | 8,752,082-8,758,348 | Endothelin-1 encoded by EDN1 inhibits IRS-1 expression and IRS-1 activity67. IRS-1 is a determinant for HDL-C and TG levels68 | 8,862,047-8,863,301 |
Lan | 7 | 49,354,803 | 0.22 | 4.27E−06 | − 0.41 | 0.09 | Intron, ARNT2 | ARNT2 | 49,259,648-49,450,466 | ARNT2 is associated with blood lipid levels41 | 49,347,252-49,354,803 |
Cste | 7 | 53,150,849 | 0.14 | 6.45E−06 | − 83.75 | 18.57 | Intron, CRTC3 | CRTC3 | CRTC3 is associated with total cholesterol plasma levels69 | 53,038,983-53,169,774 | |
LDL-C | 8 | 131,059,165 | 0.13 | 6.10E−06 | 5.88 | 1.30 | Upstream variant, PKD2 | SPP1 | 131,077,825-131,085,327 | SPP1 regulates CYP7A1, which converts cholesterol to hydroxyl-cholesterol in the first step of bile acid synthesis70 | 131,057,567-131,064,130 |
TG | 9 | 121,527,397 | 0.14 | 8.42E−06 | 16.21 | 3.64 | Intron, TOR1AIP1 | TOR1AIP1 | 121,515,664-121,566,795 | TOR1AIP1 encodes Torsin 1A interacting protein 1, which regulates hepatic VLDL secretion71 | 121,527,397-121,527,397 |
Sint | 12 | 38,331,125 | 0.19 | 3.98E−06 | − 16.31 | 3.54 | Intergenic | LHX1 | 38,461,948-38,563,314 | LHX1 is associated with circulating lipid levels72 | 38,331,125-38,331,452 |
Des | 12 | 38,656,438 | 0.16 | 8.52E−06 | − 10.69 | 2.40 | Intron, ACACA | ACACA | 38,581,541-38,875,025 | ACACA is involved in fatty acid synthesis73 | 38,656,438-38,723,182 |
TG | 12 | 40,823,266 | 0.16 | 5.54E−07 | − 17.69 | 3.53 | Intergenic | CCL2 | 40,740,308-40,799,969 | The CCL2 gene has been associated with TG level, atherosclerosis and myocardial infarction74 and knock-out of CCL2 in mice results in lower levels of cholesterol and TG75 | 40,823,120-40,850,200 |
Sint | 14 | 12,003,949 | 0.27 | 1.02E−06 | − 18.11 | 3.71 | Intergenic | PBK | 11,543,665-11,561,923 | PBK interacts with cholesterol and modulate cell-signaling76 | 12,001,579-12,021,393 |
Des | 14 | 59,484,064 | 0.09 | 3.56E−06 | 13.54 | 2.92 | Intron, TTC13 | ARV1 | 59,397,433-59,408,878 | Decreased expression of ARV1 cause hypercholesterolemia47 | 59,389,882-59,541,999 |
HDL-C | 14 | 64,268,082 | 0.03 | 2.85E−06 | 7.58 | 1.62 | Intergenic | CDK1 | 64,233,839-64,249,546 | CDK1 encodes a kinase, which stabilized SREBP177 | 61,776,948-64,843,717 |
Des | 15 | 45,876,346 | 0.04 | 6.44E−07 | − 21.42 | 4.30 | Intron, ACSL1 | ACSL1 | 45,867,356-45,933,112 | Hepatic ACSL1 depletion causes a hypercholesterolemic phenotype in mice46 | 45,665,239-46,524,879 |
Bsit | 15 | 93,370,432 | 0.02 | 3.23E−06 | − 116.95 | 25.12 | Intergenic | COL3A1 | 93,556,914-93,595,678 | Expression of COL3A1 is affected by plant sterols78 | 93,370,432-93,370,432 |
Lat | 15 | 130,395,782 | 0.12 | 1.29E−06 | 9.42 | 1.95 | Intergenic | PID1 | 130,079,133-130,332,658 | PID1 controls HDL-C level44 | 130,384,947-130,395,782 |
Tentatively significant results of the genome wide association analyses for loci, which has been associated with blood lipid levels and/or dyslipidemia associated comorbidities in previous studies and have a p value < 10E−5 in the present study. All associations are listed in chromosomal and positional order. Chromosome number (Chr) and base-pair (BP) position refer to pig genome assembly Sscrofa 11.1. MAF = minor allele frequency. P = p value. B = regression coefficient. SE = standard error for B. r2 = The squared correlation coefficient between pairs of SNPs as a measure for linkage disequilibrium (LD). Phenotype abbreviations: Serum levels of the following lipids, Lanosterol (Lan), Lathosterol (Lat), Desmosterol (Des), Sum of intermediates in the cholesterol synthesis pathway (Sint) i.e. Lan + Lat + Des, Betasitosterol (Bsit), Campesterol (Cste), Stigmasterol (Stig) Sum of phytosterols (Sphy) i.e. Bsit + Cste + Stig, Coprostanol (Csta), Epicoprostanol (Esta), Sum of microbiota-derived sterols (Sste) i.e. Csta + Esta, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), Triglycerides (TG). The tentative associations with endophenotypes in the present study point towards specific biological mechanisms, which may be the underlying causes for the observed associations with end-point phenotypes in previous studies.