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. 2020 Oct 28;10:18434. doi: 10.1038/s41598-020-75612-6

Table 3.

Tentative associations in regions previously associated with blood lipid levels or dyslipidemia associated comorbidities.

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.