Supplementary Table 1.Primer sequence for PCR amplification of LDLR in this study

Region / Forward primer / Sequence of forward primer (5' to 3') / Reverse primer / Sequence of reverse primer (5' to 3') / Product size (bp)
Exon1 / LDLR_1F / CTTCACCGGAGACCCAAATA / LDLR_1R / TTACCCCACAAGTCTCCCAG / 496
Exon2 / LDLR_2F / GATTCTGGCGTTGAGAGACC / LDLR_2R / CAAAATCCACTGGCCACTTT / 340
Exon3 / LDLR_3F / TCTTGAACCCCTGACCTCAC / LDLR_3R / TCCCCACTTTGTAATGCCTC / 446
Exon4-1 / LDLR_4F / GGCTATAGAATGGGCTGGTG / LDLR_4R / CCCCTTGGAACACGTAAAGA / 334
Exon4-2 / LDLR_5F / AAGTGCATCTCTCGGCAGTT / LDLR_5R / AAATCACTGCATGTCCCACA / 418
Exon5 / LDLR_6F / TCAAGCAGTTGGAACCACAG / LDLR_6R / AGTCACTTGCCCACAGACG / 472
Exon6 / LDLR_7F / TTACAGGTGTGAGCCACTGC / LDLR_7R / TTCCCAAAACCCTACAGCAC / 496
Exon7 / LDLR_8F / AAAATTAGCTGGGCATGGTG / LDLR_8R / CCCAGAGGCAAGAAACTCTG / 470
Exon8 / LDLR_9F / CACCTGGCTGTTTCCTTGAT / LDLR_9R / GCAAGCCCAAGTCCTAACAG / 447
Exon9 / LDLR_10F / GGAGGTCTTTTCCACCCTCT / LDLR_10R / TCTCTGCTGATGACGGTGTC / 457
Exon10 / LDLR_11F / AGCGAGTACACCAGCCTCAT / LDLR_11R / GCCCACTAACCAGTTCCTGA / 499
Exon11 / LDLR_12F / AAGCCACATTTGGAGTTTGG / LDLR_12R / AAGAGGGAAACCTTCAGGGA / 376
Exon12 / LDLR_13F / CCAGGTGCTTTTCTGCTAGG / LDLR_13R / TGGGAAACGAGAGCAAAACT / 449
Exon13 / LDLR_14F / CGAGATTGGGCCACTGTACT / LDLR_14R / GGTGGTCCTCTCACACCAGT / 474
Exon14 / LDLR_15F / CAAGAGGTAAGGGTGGGTCA / LDLR_15R / CCCATTTGACAGATGAGCAG / 377
Exon15 / LDLR_16F / CCTCCCAAGGTCATTTGAGA / LDLR_16R / CTTGCAAAGAGGGCAAGAAC / 472
Exon16 / LDLR_17F / GCCAGGAGTTCAAGACAAGC / LDLR_17R / GAAAAAGTGAACAGGCCCAA / 436
Exon17 / LDLR_18F / CTCCCAAAATGCTGGGATTA / LDLR_18R / CGCACAGAAGCATTCACCTA / 476
Exon18 / LDLR_19F / GAGGGGTAAAAAGGCAGGAG / LDLR_19R / AGAAACCAAAATCCCAACCC / 488

Supplementary Table 2.HWEof LDLRSNPs among populations

SNP ID / Location*/
Variation / Position / Amino acid Change / HWE**
AA / EA / JP / HC / KR
rs17242759 / +85C>A / Intron 1 / - / - / - / - / -
rs6511720 / +2082G>T / Intron 1 / - / - / - / - / -
rs2228671 / +10688G>A / Exon 2 / C27C / - / - / - / - / -
rs72658855 / +10697G>A / Exon 2 / N30N / - / - / - / - / -
rs3745677 / +10853C>T / Intron 3 / 0.455 / - / - / - / -
rs3745678 / +10855G>A / Intron 3 / - / - / - / 0.928 / 0.742
rs77580341 / +10863G>A / Intron 3 / - / - / - / - / -
Published (Fouchier et al. 2005) / +13217G>A / Exon 3 / G98S / - / - / - / - / -
rs10417394 / +15856C>T / Exon 4 / A166A / - / - / - / - / -
Novel / +17716G>A / Intron 5 / - / - / - / - / -
rs12610872 / +17748G>A / Intron 5 / - / - / - / - / -
Novel / +17775A>G / Intron 5 / - / - / - / - / -
rs146651743 / +17854C>T / Exon 6 / C276C / - / - / - / - / -
rs140241383 / +17884C>T / Exon 6 / S286S / - / - / - / - / -
rs17242906 / +17975C>T / Intron 6 / - / - / - / - / -
rs13306513 / +18002G>A / Intron 6 / - / - / 0.481 / - / 0.506
rs72658861 / +21958T>C / Intron 7 / - / - / - / - / -
rs11669576 / +22076G>A / Exon 8 / A391T / 0.096 / - / - / - / -
rs191859969 / +22197G>A / Intron 8 / - / - / - / - / -
rs72658862 / +23705C>T / Intron 8 / - / - / - / - / -
rs13306498 / +23737C>T / Exon 9 / I398I / - / - / 0.069 / - / -
rs5933 / +23866C>T / Exon 9 / I441I / - / - / - / - / -
rs6413505 / +23933C>T / Intron 9 / 0.914 / - / - / - / -
rs1003723 / +23957C>T / Intron 9 / - / 0.170 / 0.421 / 0.728 / -
rs5930 / +24041G>A / Exon 10 / R471R / 0.362 / - / 0.895 / 0.436 / 0.446
rs5929 / +26576C>T / Exon 11 / P539P / - / - / 0.395 / 0.284 / 0.581
rs186896947 / +26682C>A / Intron 11 / - / - / - / - / -
Novel / +26684G>A / Intron 11 / - / - / - / - / -
rs4508523 / +26720C>T / Intron 11 / - / 0.543 / 0.241 / 0.700 / -
rs1799898 / +27330C>T / Exon 12 / L575L / - / 0.094 / - / - / -
rs688 / +27378C>T / Exon 12 / N591N / 0.191 / 0.127 / 0.842 / - / -
rs116959285 / +30466G>C / Intron 12 / - / 0.951 / - / - / -
rs5925 / +30657A>G / Exon 13 / V653V / 0.355 / 0.725 / 0.490 / 0.216 / 0.483
rs5927 / +33717G>A / Exon 15 / R744R / - / 0.420 / - / - / -
Novel / +33838C>T / Intron 15 / - / - / - / - / -
rs17249323 / +33892G>A,C / Intron 15 / - / - / - / - / -
Novel / +33955T>C / Intron 15 / - / - / - / - / -
rs12459476 / +38267A>G / Intron 15 / 0.007 / 0.027 / - / - / -
rs2569538 / +38324G>A / Intron 15 / - / 0.543 / 0.688 / - / 0.912
Novel / +38380G>A / Intron 15 / - / - / - / - / -
rs41306974 / +38413G>A / Intron 15 / - / - / - / - / -
rs113972139 / +38471G>A / Exon 16 / V775I / - / - / - / - / -
rs183255090 / +38506C>T / Exon 16 / S786S / - / - / - / - / -
Novel / +38569A>C / Intron 16 / - / - / - / - / -
rs2738460 / +38583C>T / Intron 16 / 0.972 / - / 0.944 / - / 0.251
rs13306501 / +38584G>A / Intron 16 / - / - / - / - / 0.655
rs145293532 / +38594C>T / Intron 16 / - / - / - / - / -
rs2116899 / +41556G>A / Intron 17 / 0.972 / - / - / - / 0.251
rs2116898 / +41586G>A / Intron 17 / 0.972 / - / - / - / 0.251
Novel / +41636G_del / Intron 17 / - / - / - / - / -
rs2116897 / +41653G>A / Intron 17 / 0.830 / - / - / - / 0.251
rs6413503 / +41680G>A / Intron 17 / - / - / - / - / -
rs6413504 / +41691A>G / Intron 17 / 0.884 / - / 0.604 / 0.637 / 0.644
rs72658870 / +41710C>T / Intron 17 / - / - / - / - / -
rs13306505 / +41764C>T / Exon 18 / A860V / - / - / - / - / -
rs72658871 / +41781A>G / 3'UTR / - / - / - / - / -
rs17243004 / +41817G>A / 3'UTR / - / - / - / - / -
rs14158 / +41820G>A / 3'UTR / 0.830 / - / - / - / 0.341
rs3826810 / +41909G>A / 3'UTR / - / - / - / - / 0.719

*The first base of the transcription start site is denoted as nucleotide +1.

**P-value of deviation fromHardy–Weinberg equilibrium(HWE).

“-” in HWE indicates P-value = 1.000.

AA, African-American; EA, European-American; JP, Japanese; HC, Han Chinese; KR, Korean.

Supplementary Table 3. Frequency analysis of LDLR SNPs investigated in this study

SNP / Minor allele frequency / P-value of Fisher's exact test
AA / EA / HC / JP / KR / KR vs. AA / KR vs. EA / KR vs. HC / KR vs. JP / AA vs. EA / AA vs. HC / AA vs. JP / EA vs. HC / EA vs. JP / HC vs. JP
rs17242759 / 0.021 / - / - / - / - / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1
rs6511720 / 0.096 / 0.085 / - / - / - / 2.56E-05 / 8.85E-05 / 1 / 1 / 1 / 0.001 / 0.001 / 0.003 / 0.003 / 1
rs2228671 / 0.042 / 0.083 / - / - / 0.005 / 0.04 / 6.67E-04 / 1 / 1 / 0.36 / 0.12 / 0.12 / 0.006 / 0.006 / 1
rs72658855 / 0.010 / - / - / - / - / 0.33 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1
rs3745677 / 0.229 / 0.042 / 0.085 / 0.073 / 0.083 / 8.95E-04 / 0.21 / 1 / 0.81 / 1.29E-04 / 0.009 / 0.003 / 0.23 / 0.52 / 0.79
rs3745678 / 0.010 / - / 0.096 / 0.240 / 0.208 / 6.59E-07 / 4.65E-08 / 0.06 / 0.76 / 1 / 0.008 / 8.85E-07 / 0.001 / 5.70E-08 / 0.02
rs77580341 / - / - / - / 0.010 / 0.005 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1
13217G>A / - / - / - / - / 0.005 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1
rs10417394 / 0.031 / - / - / - / - / 0.04 / 1 / 1 / 1 / 0.24 / 0.24 / 0.24 / 1 / 1 / 1
17716G>A (novel) / 0.010 / - / - / - / - / 0.35 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1
rs12610872 / - / - / 0.032 / 0.011 / 0.022 / 0.30 / 0.30 / 0.69 / 0.66 / 1 / 0.12 / 0.49 / 0.12 / 0.49 / 0.62
17775A>G (novel) / 0.010 / - / - / - / - / 0.34 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1
rs146651743 / 0.010 / - / - / - / - / 0.34 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1
rs140241383 / 0.010 / - / - / - / - / 0.34 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1
rs17242906 / 0.010 / - / - / - / - / 0.34 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1
rs13306513 / - / 0.042 / 0.146 / 0.063 / 0.116 / 1.01E-04 / 0.04 / 0.19 / 0.18 / 0.12 / 2.23E-04 / 0.03 / 0.06 / 0.74 / 0.16
rs72658861 / 0.011 / - / - / - / - / 0.32 / 1 / 1 / 1 / 0.49 / 0.49 / 1 / 1 / 1 / 1
rs11669576 / 0.196 / 0.031 / - / - / - / 2.99E-08 / 0.04 / 1 / 1 / 0.00 / 1.38E-05 / 1.28E-04 / 0.24 / 0.25 / 1
rs191859969 / 0.022 / - / - / - / - / 0.10 / 1 / 1 / 1 / 0.24 / 0.24 / 0.50 / 1 / 1 / 1
rs72658862 / 0.010 / - / - / - / - / 0.34 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1
rs13306498 / - / - / 0.034 / 0.011 / 0.005 / 1 / 1 / 0.24 / 0.54 / 1 / 0.23 / 0.48 / 0.23 / 0.49 / 0.74
rs5933 / 0.010 / - / - / - / - / 0.34 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1
rs6413505 / 0.125 / - / - / - / - / 7.34E-07 / 1 / 1 / 1 / 2.23E-04 / 2.27E-04 / 2.36E-04 / 1 / 1 / 1
rs1003723 / 0.094 / 0.468 / 0.196 / 0.144 / 0.116 / 0.89 / 1.24E-08 / 0.12 / 0.59 / 4.70E-07 / 0.13 / 0.33 / 0.002 / 1.62E-05 / 0.36
rs5930 / 0.272 / 0.415 / 0.378 / 0.385 / 0.416 / 0.02 / 0.86 / 0.56 / 0.83 / 0.10 / 0.29 / 0.07 / 0.85 / 0.69 / 0.56
rs5929 / 0.125 / 0.010 / 0.234 / 0.292 / 0.302 / 0.002 / 2.94E-10 / 0.17 / 0.27 / 0.004 / 0.19 / 0.03 / 2.06E-05 / 4.34E-07 / 0.72
rs186896947 / - / - / 0.021 / 0.010 / - / 1 / 1 / 0.11 / 0.33 / 1 / 0.24 / 1 / 0.24 / 1 / 0.62
26684G>A (novel) / 0.010 / - / - / - / - / 0.33 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1
rs4508523 / 0.396 / 0.083 / 0.351 / 0.354 / 0.401 / 1 / 4.20E-08 / 0.32 / 0.62 / 1.48E-06 / 0.42 / 0.70 / 1.79E-04 / 5.10E-05 / 0.85
rs1799898 / 0.065 / 0.102 / 0.012 / - / - / 9.16E-04 / 2.13E-04 / 0.31 / 1 / 0.47 / 0.11 / 0.03 / 0.07 / 0.04 / 1
rs688 / 0.115 / 0.500 / 0.182 / 0.132 / 0.120 / 0.23 / 1.02E-09 / 0.26 / 0.75 / 1.66E-06 / 0.32 / 0.21 / 2.23E-04 / 9.26E-06 / 0.60
rs116959285 / 0.010 / 0.115 / - / - / - / 0.34 / 9.85E-06 / 1 / 1 / 0.01 / 1 / 1 / 0.001 / 0.001 / 1
rs5925 / 0.240 / 0.479 / 0.240 / 0.198 / 0.167 / 0.06 / 1.32E-06 / 0.34 / 0.09 / 0.001 / 0.26 / 0.68 / 0.005 / 5.62E-05 / 0.14
rs5927 / 0.266 / 0.271 / 0.064 / 0.042 / 0.054 / 3.96E-06 / 8.13E-06 / 0.78 / 0.77 / 0.67 / 7.57E-04 / 4.34E-05 / 0.002 / 1.32E-04 / 0.52
33838C>T (novel) / - / 0.010 / - / - / - / 1 / 0.34 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1
rs17249323 / A:0.021, C:- / A:-, C:- / A:-, C:- / A:-, C:- / A:-, C:0.005 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1
33955T>C (novel) / 0.011 / - / - / - / - / 0.34 / 1 / 1 / 1 / 0.49 / 1 / 0.49 / 1 / 1 / 1
rs12459476 / 0.104 / 0.436 / 0.128 / 0.177 / 0.105 / 0.05 / 7.36E-08 / 0.77 / 0.18 / 2.74E-05 / 0.19 / 0.007 / 1.43E-04 / 7.32E-04 / 0.67
rs2569538 / 0.219 / 0.083 / 0.096 / 0.073 / 0.089 / 0.005 / 0.26 / 0.43 / 0.81 / 0.01 / 0.03 / 0.01 / 0.89 / 1 / 0.89
38380G>A (novel) / - / - / - / - / 0.005 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1
rs41306974 / - / 0.021 / - / - / - / 1 / 0.11 / 1 / 1 / 0.49 / 1 / 1 / 0.49 / 0.49 / 1
rs113972139 / - / - / - / - / 0.005 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1
rs183255090 / - / - / 0.011 / 0.010 / 0.005 / 1 / 1 / 1 / 1 / 1 / 0.49 / 1 / 0.49 / 1 / 1
38569A>C (novel) / - / - / - / - / 0.005 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1
rs2738460 / 0.188 / 0.229 / 0.426 / 0.458 / 0.468 / 3.60E-05 / 7.05E-04 / 0.74 / 0.74 / 0.75 / 0.002 / 3.00E-04 / 0.02 / 0.005 / 0.89
rs13306501 / 0.083 / 0.052 / 0.138 / 0.063 / 0.105 / 0.66 / 0.16 / 0.41 / 0.26 / 0.55 / 0.37 / 0.77 / 0.08 / 1 / 0.15
rs145293532 / - / 0.010 / - / - / - / 1 / 0.34 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1
rs2116899 / 0.188 / 0.229 / 0.427 / 0.458 / 0.462 / 5.55E-05 / 9.85E-04 / 0.76 / 0.76 / 0.75 / 0.002 / 0.0003 / 0.02 / 0.005 / 0.93
rs2116898 / 0.188 / 0.229 / 0.427 / 0.458 / 0.462 / 5.55E-05 / 9.85E-04 / 0.76 / 0.76 / 0.75 / 0.002 / 0.0003 / 0.02 / 0.005 / 0.93
41636G_del / - / 0.010 / - / - / - / 1 / 0.33 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1
rs2116897 / 0.198 / 0.229 / 0.427 / 0.458 / 0.462 / 5.55E-05 / 9.85E-04 / 0.76 / 0.76 / 0.75 / 0.003 / 6.47E-04 / 0.02 / 0.005 / 0.93
rs6413503 / 0.115 / - / 0.031 / 0.021 / 0.016 / 4.50E-04 / 0.55 / 0.41 / 1 / 5.12E-04 / 0.04 / 0.01 / 0.24 / 0.49 / 1
rs6413504 / 0.177 / 0.521 / 0.302 / 0.260 / 0.242 / 0.34 / 1.60E-05 / 0.52 / 0.90 / 1.04E-05 / 0.09 / 0.26 / 0.007 / 0.001 / 0.79
rs72658870 / 0.010 / - / - / - / - / 0.34 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1
rs13306505 / - / - / - / 0.010 / - / 1 / 1 / 1 / 0.34 / 1 / 1 / 1 / 1 / 1 / 1
rs72658871 / 0.042 / - / - / - / - / 0.01 / 1 / 1 / 1 / 0.12 / 0.12 / 0.12 / 1 / 1 / 1
rs17243004 / 0.010 / - / - / - / - / 0.34 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1
rs14158 / 0.198 / 0.223 / 0.427 / 0.458 / 0.468 / 7.21E-05 / 6.62E-04 / 0.74 / 0.80 / 0.93 / 0.003 / 6.47E-04 / 0.01 / 0.003 / 0.93
rs3826810 / 0.083 / 0.032 / 0.146 / 0.063 / 0.102 / 0.66 / 0.05 / 0.31 / 0.35 / 0.20 / 0.32 / 0.77 / 0.02 / 0.49 / 0.12

“-” in Minor allele frequency (MAF) indicates MAF = 0.AA, African-American; EA, European-American; HC, Han Chinese; JP, Japanese; KR, Korean.

Supplementary Fig.1

Supplementary Fig.1.In silico analysis of novel SNPs in intronic regions. In silico analysis using the HumanSplicing Finder ( potential branch point sites for alternative splicing. Results of SNPs (A) +17716 G>A and (B) +38569 A>C are shown.

Supplementary Fig.2

Supplementary Fig.2.In silico analysis for SNP +13217G>A (G98S) of LDLR. (A) Motif including G98Sis predicted asthe functional site for N-glycosylation using a prediction program ( (B) Multiple amino acid sequence alignments nearby to nonsynonymous +13217G>A (G98S)using the ClustalW2 program ( show a weak conservation among human and other species.Asterisk (*)indicates the identical residues, whereas colon (:) and period (.) indicate the positions of strong (:) and weak (.)similarity groups, respectively. Human (NP_000518), monkey (NP_001028078), pig (NP_001193283), rat (NP_786938), zebrafish (NP_001025454), and chicken (NP_989783).