- Brunzell J.D.
- Davidson M.
- Furberg C.D.
- Goldberg R.B.
- Howard B.V.
- Stein J.H.
- Witztum J.L.
METHODS
Data sources
In silico predictions
Variant and haplotype frequency analyses
Associations with GWAS data
RESULTS
Overview of the genetic variability profile in human APO genes

Worldwide frequencies of clinically important variants in the human APO gene family
Population frequencies (in %) | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|
Defining variants as RSID (HGVS) | Variant type | EUR | AFR | EAS | SAS | AMR | AJ | Clinical parameters | Effect size or strength of association | Reference |
APOB | ||||||||||
rs5742904 (NC_000002.11:g.21229160C>T) | Missense (R3527Q) | <0.1 | <0.1 | 0 | 0 | <0.1 | 0 | Ischemic heart disease | OR = 7 | ( 17. ) |
rs1042031 (NC_000002.11:g.21225753C>T) | Missense (E4181K) | 18.3 | 15.4 | 4.8 | 10.3 | 12.3 | 14.8 | Ischemic cerebrovascular disease | HR = 0.5 | ( 38. ) |
Ischemic stroke | HR = 0.2 | |||||||||
rs1367117 (NC_000002.11:g.21263900G>A) | Missense (T98I) | 31.9 | 11.2 | 12.7 | 16 | 28.9 | 18.7 | CAD | β=0.035 | ( 40. ) |
LDL-C | β=0.12 | |||||||||
TG | β=0.025 | |||||||||
LDL | β'=4.05 | ( 39. ) | ||||||||
rs1042034 (NC_000002.11:g.21225281C>T) | Missense (S4338N) | 78.4 | 85.2 | 27.3 | 48.6 | 74.2 | 80.5 | TG | β'=−5.99 | ( 39. ) |
rs693 (NC_000002.11:g.21232195G>A) | Synonymous (T2515T) | 50 | 22.1 | 5.6 | 26.7 | 38 | 34.9 | LDL-C | P = 7.1*10−7 | ( 71. ) |
LDL | β=0.123 | ( 72. ) | ||||||||
rs562338 (NC_000002.11:g.21288321A>G) | UTR | 18 | 59.6 | 0.19 | N.A. | 16.5 | 29.8 | LDL-C | P = 5.6*10−22 | ( 73. ) |
rs754523 (NC_000002.11:g.21311691A>G) | UTR | 31.1 | 21.9 | 29.5 | N.A. | 29.1 | 29.1 | LDL-C | P = 8.3*10−12 | ( 73. ) |
rs515135 (NC_000002.11:g.21286057T>C) | UTR | 18.2 | 47.7 | 9.5 | N.A. | 18.8 | 30.1 | CAD | OR = 1.03-1.08 | ( 59. ) |
rs673548 (NC_000002.11:g.21237544G>A) | Intron | 22.7 | 21.1 | 73 | N.A. | 22 | 14.2 | TG | β=−0.081 | ( 72. ) |
APOE | ||||||||||
ε3 | Wild-type | 77.4 | 67.5 | 83.6 | 85.7 | 86.4 | 80.6 | |||
ε2: rs7412 (NC_000019.9:g.45412079C>T) | Missense (R176C) | 7.7 | 10.8 | 7.5 | 4.2 | 3.2 | 7.8 | AD | OR = 0.6-2.6 | ( 41. )
Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997; 278: 1349-1356 |
ε4: rs429358 (NC_000019.9:g.45411941T>C) | Missense (C130R) | 14.9 | 21.7 | 8.9 | 10.1 | 10.4 | 11.6 | AD | OR = 2.2ENTenlineENT33.1 | ( 41. )
Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997; 278: 1349-1356 |
CAD | OR = 1.06 | ( 19. ) | ||||||||
NAFLD | OR = 0.51 | ( 74. ) | ||||||||
rs4420638 (NC_000019.9:g.45422946A>G) | UTR | 18.4 | 20.2 | 11.4 | N.A. | 10.8 | 14.6 | LDL | β'=7.14 | ( 39. ) |
LDL-C | P = 3.4*10−13 | ( 71. ) | ||||||||
β=0.19 | ( 75. ) | |||||||||
rs439401 (NC_000019.9:g.45414451T>C) | UTR | 36.8 | 15.3 | 58.6 | N.A. | 54.9 | 43 | TG | β'=−5.5 | ( 39. ) |
APOA1 | ||||||||||
rs670 (NC_000011.9:g.116708413C>T) | Promoter | 17.3 | 14.8 | 27.8 | N.A. | 27.7 | 15.2 | LDL | OR = 1.66 | ( 76. ) |
TC | OR = 1.77 | |||||||||
APOA2 | ||||||||||
rs5082 (NC_000001.10:g.161193683G>A) | Promoter | 40.6 | 22.5 | 8.2 | N.A. | 23.4 | 35.8 | Obesity | OR = 1.84 | ( 77. ) |
APOA4 | ||||||||||
rs675 (NC_000011.9:g.116691675T>A) | Missense (T367S) | 19.7 | 11.5 | <0.1 | 12.9 | 9.4 | 21.5 | CAD | HR = 2.07 | ( 78. ) |
rs5110 (NC_000011.9:g.116691634C>A) | Missense (Q380H) | 7.8 | 1.5 | <0.1 | 1.9 | 3.6 | 6.7 | TG | P = 0.035 (+) | ( 79. ) |
VLDL | P = 0.035 (+) | |||||||||
HDL | P = 0.0005 (-) | |||||||||
rs1729407 (NC_000011.9:g.116677370C>G) | Intergenic | 50.8 | 12.7 | 30.4 | N.A. | 50.7 | 35.4 | HDL | P = 7.1*10−7 (-) | ( 80. ) |
APOA5 | ||||||||||
*2: rs662799, rs651821, rs2072560, rs2266788 (NC_000011.9:g.116663707G>A, 116662579C>T, 116661826T>C, 116660686G>A), | Promoter, Kozak, Intron and UTR | 8.1 | 0 | 23.8 | 17.7 | 13 | N.A. | TG | 20-30% elevation | ( 44. ) |
*3: rs3135506 (NC_000011.9:g.116662407G>C) | Missense (S19W) | 6.4 | 6.2 | <0.1 | 3.8 | 15.3 | 6.8 | TG | OR = 7.79 | ( 18. , 81. ) |
rs662799 (NC_000011.9:g.116663707G>A) | Promoter | 6.9 | 12.1 | 29.2 | N.A. | 15 | 10.6 | TG | P < 0.001 (+) | ( 82. )
The -1131 T>C and S19W APOA5 gene polymorphisms are associated with high levels of triglycerides and apolipoprotein C–III, but not with coronary artery disease: an angiographic study. Atherosclerosis. 2007; 191: 409-417 |
TG | P = 0.001 (+) | ( 83. ) | ||||||||
HDL | P = 0.008 (-) | |||||||||
rs2266788 (NC_000011.9:g.116660686G>A) | UTR | 7.4 | 1.6 | 21 | N.A. | 13.6 | 10.9 | TG | P = 33*10−5 | ( 71. ) |
CAD | OR = 1.15 | ( 84. )
A functional polymorphism affecting the APOA5 gene expression is causally associated with plasma triglyceride levels conferring coronary atherosclerosis risk in Han Chinese Population. Biochim. Biophys. Acta. 2014; 1842: 2147-2154 | ||||||||
rs2075291 (NC_000011.9:g.116661392C>A) | Missense (G185C) | <0.1 | 0.3 | 6.9 | 0.8 | <0.1 | 0 | TG | OR = 11.73 | ( 45. ) |
CAD | OR = 2.09 | ( 85. ) | ||||||||
APOC1 | ||||||||||
rs11568822 (NC_000019.9:g.45417640_45417641insCGTT) | Promoter | 23 | 35 | N.A. | N.A. | 16.5 | N.A. | AD | OR = 1.84 | ( 86. ) |
APOC3 | ||||||||||
rs5128 NC_000011.9:g.116703640G>C | UTR | 9.5 | 15.5 | 30.3 | 30.3 | 21.2 | 14 | CAD | OR = 1.3 | ( 87. ) |
rs2854116 NC_000011.9:g.116700169C>T | Promoter | 39.1 | 70.7 | 41.6 | N.A. | 34.8 | 47 | Metabolic syndrome | OR = 1.73 | ( 88. ) |
CAD | OR = 1.28 | ( 87. ) | ||||||||
NAFLD | P < 0.001 (+) | ( 89. ) | ||||||||
rs2854117 NC_000011.9:g.116700142T>C | Promoter | 28.9 | 68.3 | 42.4 | N.A. | 30.7 | 35.4 | TG | P = 0.041 (+) | ( 83. ) |
HDL | P = 0.005 (-) | |||||||||
NAFLD | P < 0.001 (+) | ( 89. ) | ||||||||
rs147210663 NC_000011.9:g.116701560G>A | Missense (A43T) | <0.1 | 0.2 | <0.1 | <0.1 | <0.1 | 1.1 | TG | P = 0.01 (-) | ( 47. ) |
HDL | P = 0.004 (+) | |||||||||
rs76353203 NC_000011.9:g.116701353C>G | Stop-gain (R19X) | <0.1 | <0.1 | <0.1 | 0.2 | <0.1 | 0 | CAC | OR = 0.35 | ( 46. ) |
CHD | HR = 0.68 | |||||||||
rs138326449 NC_000011.9:g.116701354G>A | Splice donor | 0.2 | <0.1 | <0.1 | <0.1 | 0 | 0.2 | TG | P = 8*10−8 (-) | ( 90. ) |
APOH | ||||||||||
rs8178847 NC_000017.10:g.64216815C>T | Missense (R154H) | 6.7 | 9.8 | 6.3 | 5.1 | 2.9 | 6.7 | VT | OR = 1.55 | ( 91. ) |
rs1801689 NC_000017.10:g.64210580A>C | Missense (C325G) | 3.3 | 0.5 | <0.1 | 1.6 | 2.4 | 5.8 | LDL | P = 1* 10−11 (+) | ( 31. ) |
rs1801690 NC_000017.10:g.64208285C>G | Missense (W335S) | 5.6 | 0.8 | 6.8 | 4.7 | 1.8 | 3.3 | TG | P = 0.018 (+) | ( 92. ) |
APOA-I levels | P = 0.026 (-) | |||||||||
rs3760291 NC_000017.10:g.64226197G>T | Promoter | 26.1 | 7.2 | 6.3 | N.A. | 10.7 | 11.9 | TC | P = 0.006 (-) | ( 14. ) |
LDL | P = 0.03 (-) | |||||||||
APOB levels | P = 0.001 (-) | |||||||||
APOE levels | P = 0.006 (-) | |||||||||
APOM | ||||||||||
rs707922 NC_000006.11:g.31625507G>T | Missense (G111V) | 5.2 | 31.9 | 15.9 | 7.2 | 12.6 | 18.9 | TC | P = 0.006 (+) | ( 93. ) |
LDL | P = 0.009 (+) | |||||||||
rs805296 NC_000006.11:g.31622893T>C | Promoter | 1.3 | 11.5 | 11.6 | N.A. | 4.5 | 1 | CAD | OR = 1.9 | ( 94. ) |
T2DM | OR = 2.29 | ( 95. ) | ||||||||
rs940494 NC_000007.13:g.56348924A>G | Promoter | 22.4 | 14.1 | 9.4 | N.A. | 27.7 | 17.9 | CAD | OR = 1.82 | ( 96. ) |
- Farrer L.A.
- Cupples L.A.
- Haines J.L.
- Hyman B.
- Kukull W.A.
- Mayeux R.
- Myers R.H.
- Pericak-Vance M.A.
- Risch N.
- van Duijn C.M.
Rare genetic variants are predicted to contribute substantially to the functional variability in human apolipoproteins

Structural variability profiles of APOB and APOE

Population Frequencies (%) | Global Lipid Genetics Consortium | CARDIoGRAM | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Defining Variants as RSID (HGVS) | Variant Type | EUR | AFR | EAS | SAS | AMR | AJ | Effect Size | P | Log_odds | P |
APOB | |||||||||||
rs6752026 (NC_000002.11:g.21260934G>A) | Missense (P145S) | <0.1 | 12.8 | 0 | <0.1 | 0.7 | <0.1 | N.A. | N.A. | N.A. | N.A. |
rs13306198 (NC_000002.11:g.21260084G>A) | Missense (T194M) | <0.1 | <0.1 | 5.5 | 0.2 | 0.3 | 0 | N.A. | N.A. | N.A. | N.A. |
rs13306194 (NC_000002.11:g.21252534G>A) | Missense (R532W) | 0.1 | <0.1 | 13.4 | 0.2 | <0.1 | <0.1 | N.A. | N.A. | N.A. | N.A. |
rs61736761 (NC_000002.11:g.21238007G>T) | Missense (L1212M) | <0.1 | 8.9 | 0 | 0.9 | 0.5 | <0.1 | N.A. | N.A. | N.A. | N.A. |
rs1801699 (NC_000002.11:g.21233999T>C) | Missense (N1914S) | 1.9 | 0.5 | <0.1 | 0.6 | 6.5 | 1.6 | 0.091 | 2.6 × 10−6 | N.A. | N.A. |
rs533617 (NC_000002.11:g.21233972T>C) | Missense (H1923R) | 4 | 0.7 | <0.1 | 3.7 | 0.9 | 2.4 | 0.14 | 9.6 × 10−45 | −0.096 | 0.034 |
rs12713675 (NC_000002.11:g.21232373G>T) | Missense (A2456D) | <0.1 | 5.3 | 0 | <0.1 | 0.3 | 0 | N.A. | N.A. | N.A. | N.A. |
rs676210 (NC_000002.11:g.21231524G>A) | Missense (P2739L) | 21.6 | 14.7 | 72.5 | 50.2 | 25.7 | 19.4 | 0.059 | 4.1 × 10−39 | 0.03 | 0.077 |
rs12720854 (NC_000002.11:g.21229905T>C) | Missense (S3279G) | 0.3 | 1.7 | <0.1 | 0.1 | 0.6 | 1 | N.A. | N.A. | N.A. | N.A. |
rs12720855 (NC_000002.11:g.21229860A>G) | Missense (S3294P) | <0.1 | 5.3 | 0 | <0.1 | 0.3 | 0 | N.A. | N.A. | N.A. | N.A. |
rs1042023 (NC_000002.11:g.21229446G>C) | Missense (Q3432E) | 1.1 | 0.1 | 0 | 0.1 | 0.5 | 0.1 | N.A. | N.A. | N.A. | N.A. |
APOE | |||||||||||
rs533904656 (NC_000019.9:g.45411025G>A) | Missense (A18T) | 0 | 0 | 0.2 | 0 | 0 | 0 | N.A. | N.A. | N.A. | N.A. |
rs769452 (NC_000019.9:g.45411110T>C) | Missense (L46P) | 0.3 | <0.1 | 0 | <0.1 | <0.1 | 0.5 | N.A. | N.A. | N.A. | N.A. |
rs769455 (NC_000019.9:g.45412040C>T) | Missense (R163C) | <0.1 | 2 | 0 | <0.1 | 0.2 | 0 | N.A. | N.A. | N.A. | N.A. |
rs749750245 (NC_000019.9:g.45412172C>T) | Missense (R207C) | 0 | 0 | 0 | 0 | 0.2 | 0 | N.A. | N.A. | N.A. | N.A. |
rs140808909 (NC_000019.9:g.45412337G>A) | Missense (E262K) | 0 | 0 | 0.3 | 0 | 0 | 0 | N.A. | N.A. | N.A. | N.A. |
rs190853081 (NC_000019.9:g.45412340G>A) | Missense (E263K) | 0 | 0 | 0.3 | 0 | 0 | 0 | N.A. | N.A. | N.A. | N.A. |
- Di Filippo M.
- Moulin P.
- Roy P.
- Samson-Bouma M.E.
- Collardeau-Frachon S.
- Chebel-Dumont S.
- Peretti N.
- Dumortier J.
- Zoulim F.
- Fontanges T.
- et al.
Validation of predicted associations using GWAS data

DISCUSSION
- Shen H.
- Damcott C.M.
- Rampersaud E.
- Pollin T.I.
- Horenstein R.B.
- McArdle P.F.
- Peyser P.A.
- Bielak L.F.
- Post W.S.
- Chang Y.-P. C.
- et al.
Acknowledgments
Supplementary Material
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L.M. is supported by Eesti Teadusagentuur (Estonian Research Council) Grant PRG184 and by an Uppsala Universitet Strategic Research Grant as part of the Science for Life Laboratory fellowship program. V.M.L. is supported by Swedish Research Council Grants 2016-01153 and 2016-01154, the Strategic Research Programme in Diabetes at Karolinska Institutet, the Malin and Lennart Philipson Foundation, and the Harald och Greta Jeanssons Stiftelse. V.M.L is a cofounder and owner of HepaPredict AB.
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