Ze Yang, Jan Dorman

1
?????????????

• Ze Yang, Jan Dorman Ron LaPorte

?????? ???? ?
2
??

• ??????????????
• 1997?,????????4???????,?????????3.21
• ?40?????????,????????????(IGT)???????11?10
• ?????????98?2????,????????1????(??0.5/100000??)

3
??? ?????? ?????? (??)

• ??????????????
• ??????????????????
• ??????????????????
• ?????????????????????

4
??????????

• ???????????????????????
• ??????????????????(LPL)?????????(CETP)????(a)(Lp(a
  ))?????E(apoE)?????B(apoB)??????????????????

5
??????????(?)

• ?????????????????????????
• ??,???????????????????????????????
• ????????????

6
??????????(?)

• ??????????????????????????
• ??????????????????????????????????????????????????
  ??
• ??????????????????????????????????????????????????
  ???????????????????????????

7
????????(CETP)

• ????????,??????-C??????????????????????
• ?????????????????-C??????????
• ???????????????-C??B?????????????????
• ?????????????
• ?????????????????????????,??????????????

8
????????(CETP)(?)

• ?1????????,????????????????
• ???2????????,???????????????
• ???????,????????????????????????????

9
????????(CETP)(?)

• ????????????16????(?????32250??????),????25000???
  ?
• ???????????????????????????????-C?????????????????
  ??

10
????????(CETP)(?)

• ?????????????????????????????????????,????????????
  ????
• ???,????????????????????????,???????????????

11
????????(CETP)(?)

• ??????,???????????????????????-C??????????????????
  ????14????????????????????????15???????????(442???
  ????????????)

12
????????(CETP)(?)

• Akita???1994???,???????,??14???????????????15?????
  ?????????0.81?4.62(?14????????????????,??????-C?
  ???3.85mmol/L,????????????0?15???????????????,??
  ????-C????2.13mmol/L,????????????10.7)
• ???????????0.02,????????-C???????(3.10mmol/L),???
  ????????????(1)

13
????????(CETP)(?)

• ????????, 15????????????2.1,????????????-C???????
  ?
• ???????????,???????????1????????(B1B2??TaqIB????
  ?)??????????-C?????,???????????????

14
????????(CETP)(?)

• ???,Dullaart ???1997???,?1???????,???????????TaqIB
  ???????????-C???????????????
• ?????B1B1????????????-C???????B2B2?????0.39mmol/L

15
????????(CETP)(?)

• ???,???????????16?????????????-C??????????????????
  ?,????????????(CHD),?????????????????3?????1696??
  ????????????????????

16
????????(CETP)(?)

• ????????????????92????????????????????,???????????
  ???????????(???100nmol/h/ml?71nmol/h/ml)???????-C?
  ????(???0.92mmol/ml?1.01mmol/ml)?

17
????????(CETP)(?)

• ???????????16??????????????????????????,??????????
  ?????????????????????,????????????????2???????????
  ????

18
???????????????

• Gordon D, Rifkind BM High density lipoprotein.
  The clinical implications of recent studies. N
  Engl Med 1989, 3211311-1316
• Tall AR. Metabolic and genetic control of HDL
  cholesterol levels. J Intern Med 1992231661
• Brown ML, Hesler C, Tall AR. Plasma enzymes and
  transfer proteins in cholesterol metabolism, Curr
  Opin Lipidol 19901122
• Swenson TL. The role of the cholesteryl ester
  transfer protein in lipoprotein metabolism.
  Diabetes Metab Rev 19917139
• Hesler CB, Swenson TL, Tall AR purification and
  characterization of a human plasma cholesteryl
  ester transfer protein. J Biol Chem 19872622275
  
• Ritter MC, Bagdade JD Contribution of glyucaemic
  control, endogenous lipoproteins and cholesteryl
  ester transfer protein to accelerated cholesteryl
  ester transfer in IDDM. Eur J Clin Invest 1994
  24607-614

19
???????????????(?)

• Kahri J, Syvanne M, Taskinen M_R Plasma
  cholesteryl ester transfer protein activity in
  non-insulin-dependent diabetic patients with and
  without coronary artery disease. Metabolism
  1994431498-1502 8. Richard J. Jones, Daphne
  Owens,
• Cara Brennan, Patrick B. Collins, Alan H.
  Johnson, Gerald H. Tomkin Increased
  esterification of cholesterol and transfer of
  cholesteryl ester to apo B-containing
  lipoproteins in Type 2 diabetes relationship to
  serum lipoproteins A-I and A-II. Atherosclerosis
  1996 119151-157
• Dennis Drayna, Alisha Stephens Jarnagin, John
  Mclean, William Henzel, William
• Kohr, Christopher Fielding Richard Lawn.
  Cloning and sequencing of human
• cholesteryl ester transfer protein cDNA. Nature
  1987327632-634
• Luis B Agellon, Elaine M Quinet, Thomas G
  Gillette, Dennis T Drayna, Maryanne L Brown, Alan
  R Tail. Organization of the human cholesteryl
  ester transfer protein gene. Biochemistry
  1990291372-1376

20
???????????????(?)

• Omar L Francone, Lori Royer, Mehrdad Haghpassand.
  Increased pre-HSL levels, cholesterol efflux,
  and LCAT-mediated esterification in mice
  expressing the human cholesteryl ester transfer
  protein and human apolipoprotein A-I transgenes.
  J Lipid Res 1996371268-1277
• Jan Albert Kuivenhoven, Peter de Knijff, Jolanda
  MA Boer, Harold A Smalheer, Gert-Jan Botma, Jaap
  C Seidell, John JP Kastelein, P Haydn Pritchard.
  Heterogeneity at the CETP gene locus influence on
  plasma CETP concentrations and HDL cholesterol
  levels. Arterioscler Thromb Vasc Biol
  199717560-568
• Harukuni Akita, Hitoshi Chiba, Keiko Tsuchihashi,
  Masahiro Tsuji, Mitsuru Kumagai, Kazuhiko
  Matsuno, Kunihiko Kobayashi. Cholesteryl ester
  transfer protein gene two common mutations and
  their effect on plasma high-density lipoprotein
  cholesterol content. J Clin Endocrinol Metab
  1994791615-1618
• Harukuni Akita, Hitoshi Chiba, Shu-Ping Hui,
  Yukihiro Takahashi, Kazuhiko Matsuno, Kunihiko
  Kobayashi. Cholesteryl ester transfer protein
  deficiency identification in the Chinese. Am J
  Med Genet 199559399-400

21
???????????????(?)

• Shu-Ping Hui. Frequency and effect on plasma
  lipoprotein metabolism of a mutation in the
  cholesteryl ester transfer protein gene in the
  Chinese. ????? 199772319-327
• Robin PF Dullaart, Klaas Hoogenberg, Stephen C
  Riemens, Johanna EM Groener, Arie van Tol, Wim J
  Sluiter, Ben K Stulp. Cholesteryl ester transfer
  protein gene polymorphism is a determinant of HDL
  cholesterol and of the lipoprotein response to a
  lipid-lowering diet in type 1 diabetes. Diabetes
  1997462082-2087
• Minna Tamminen, Sakari Kakko, Y Antero Kesaniemi,
  Markku J Savolainen. A polymorphic site in the 3
  untranslated region of the cholesteryl ester
  transfer protein gene is associated with low CETP
  activity. Atherosclerosis 1996124237-247
• Ukkola O, Savolainen Mj, Salmela PI, von Dickhoff
  K, Kesaniemi YA DNA polymorphism at the locus
  for human cholesteryl ester transfer protein are
  associated with macro- and microangiopathy in
  non-insulin-dependent diabetes mellitus. Clin
  Genetics 199446217-227

22
???(a)(Lp(a))

• ???(a)?????????????????????
• ???(a)?????(a)(apo(a))?????(B100)????????
• ??????(a)????????????,?????(a)?????????
• ?????????????(a)????20mg/dl,2??????????????

23
?????(a)?????

• Armstrong VW, Cremer P, Eberle E, Manke A, Shulze
  F, Wieland H, Kreuzer H, Seidel D. The
  association between serum Lp(a) concentrations
  and angiographically assessed coronary
  atherosclerosis. Atherosclerosis 198662249
• Fless GM, Zummallen ME, Scanu AM. Isolation of
  apolipoprotein (a) from lipoprotein (a). J Lipid
  Res 1985261224-1229
• Rath M, Neindorf A, Reblin T, Dietel M, Krebber
  H-J, Beisiegel U. Detection and quantification of
  lipoprotein(a) in the arterial wall of 107
  coronary bypass patients. Arteriosclerosis
  19899579

24
?????(a)?????(?)

• Mclean JW, cDNA sequence of human
  apolioprotein(a) is homologous to plasminogen.
  Nature. 1987330132-137
• Kennel WB,DAgostin RB, Wilson PW, Belanger AJ,
  Gagnon DR. Diabetes, fibrinogen, risk of
  cardiovascular disease the Framingham
  experience. Am Heart J 1990120672
• Eriko Morishita, Hidesaku Asakura, Hiroshi
  Jokaji, Masanori Saito, Chika Uotani, Ichiro
  Kumabashiri, Masahide Yamazaki, Keiji Aoshima,
  Takuma Hashimoto, Tamotsu Matsuda.
  Hypercoagulability and high lipoprotein(a) levels
  in patients with type II diabetes mellitus.
  Atherosclerosis 19961207-14

25
????????2??????????(a)???????

• ????(a)???????6q26-27,?????141000????
• ??????????(a)???????????????
• ????????????????????????????

26
????????????2??????????(a)???????
?????????????????????0.05?0.01,???????????????
?
27
?????(LPL)

• ??????????????,???????????????
• ????????????????,???????????????????????-C????
• ?????????????8p22,??10?????9????
• ???????????????????????????????

28
??????(LPL)(?)

• ????????102???????62????????????,?????????8????(Hi
  nd?)???????????
• ???????????,?????(H1H2??Hind?????)????????H1
  80?81,H2 20?19

29
??????(LPL)(?)

• ???????????,????????????H1H1 63.7?67.7,H1H2
  34.3?27.4,H2H2 2?4.9
• ??H1H1????????????????????(1.77mmol/L)??????????(1
  .45mmol/L)??,??????-C??(0.97mmol/L)????????????(1.
  03mmol/L)

30
????????(LPL)?????

• Ahn YI, Hamman RF, Ferrell RE. Association of
  lipoproteinlipase gene variation with the
  physiological components of the insulin
  resistance syndrome in the population of the San
  Luis Valley, Colorado. Diabetes Care 1993161502
  
• Seip RL, Angelopoulos TJ, Semenkovich CF.
  Exercise induces human lopoprotein lipase gene
  expression in skeletal muscle but not adipose
  tissue. Am J Physiol 1995268 E229-E236
• Ahn YI, Kamboh MI, Hamman RF. Two DNA
  polumorphisms in the lipoprotein lipase gene and
  their associations with factors related to
  cardiovascular disease. J Lipid Res 199334421
• Wion KL, Kirchgessner TG. Human lipoprotein
  lipase complementary DNA sequence. Science
  19872351638-1641
• Renier G, Skamene E, DeSanctis JB, Radzioch D.
  High macrophage lipoprootein lipase expression
  and secretion are associated in inbred murine
  strains with susceptibility to atherosclerosis.
  Arterioscler Thromb 199213190-196
• Zhu Hongda, Sun Rong, Gao Mei. Polymorphism in
  the lipoprotein lipase gene in patients with
  NIDDM. ????????? 19971373-76

31
????E(ApoE)

• ????E????????????????
• ????E?????????????????????
• ????E?????????????????????????????????
• ????E???????,??E2?E3?E4?????????

32
????E(ApoE)(?)

• ????E?????19?????,??4?????3????,???3597????
• ??????,?3????(E2/2,E3/3,E4/4)?3????(E2/3,E2/4,E3/4
  )

33
????E(ApoE)(?)

• ?????????????????E4?????????????
• ???????E4???????????????????????????????

34
??????E(ApoE)?????

• Hixson JE, Vernier DT. Restriction isotyping of
  human polipoprotein E by gene amplification and
  cleavage with HhaI. J Lipid Res 199031545-548
• Paik YK. Nucleotide sequence and structure of the
  human apolipoprotein E gene. Proc Natl Acad Sci
  USA 1985823445-3449
• Lenzen HJ, Assmann G, Buchwalsky R, Schulte H.
  Association of apolipoprotein E polymorphism,
  low-density lipoprotein cholesterol, and coronary
  artery disease. Clin Chem 198632778-781
• Kyoko Kogawa, Yoshiki Nishizawa, Masayuki Hosoi,
  Takahiko Kawagishi, Kiyoshi Maekawa, Tetsuo
  Shoji, Yasuhisa Okuno, and Hirotoshi Morii.
  Effect of polymorphism of apolipoprotein E and
  angiotensin-converting enzyme genes on arterial
  wall thickness. Diabetes 199746682-687

35
????????E????2???????????????

• ?????,???125?2???????50?????????
• ????,????E4/4?E3/4???????????????(72),???????????
  ??(E3/3 37,E2/3?E2/2 32)
• ????????????(44.8)???????(14.0)

36
????????E????2???????????????(?)

• ??????,???????E3/4???????????(?10.0?20.8),?E3/3?
  ??????????(?76.0?62.4)
• ?1997?,Kogawa??????????????????????E??????????????
  ?????????????????

37
????B(ApoB)

• ????B???????2p23,??29?????28????,????43000????
• ???????????B????????????????????????

38
??????B(ApoB)?????

• Yang XJ, Xiang GD, Ding XH. ?????????
  199511206-209
• Chen SH, Yang CY,Chen PF. The complete cDNA and
  amino acie sequence of human apolipoprotein
  B-100. J Bio Chem, 1986, 26112918-12921

39
????????B??????2???????????????

• ?41???????51????????????60?????????????????B??????
  ?(EcoRI?XbaI)
• ?2??????(????????)?,EcoRI?XbaI?????(?????,???-)??
  ??????
• ?2???????EcoRI??????????????,XbaI?????????????????

40
????B??????2???????????????
41
??

• ???,???????????????????(NIDDM)????????????????????
  ?????
• ???????????????????????????????????????
• ????????????????????????????

42
??(?)

• ????????????????(CETP),????E( apoE),???(a)(Lp(a)),
  ???B(apo B (EcoRI and XbaI))???????(Hind???)??????
  ????????,?????????????????????????????

43
??(?)

• ????????,?????????????????????????????????,???????
  ???????????

44
?????????????????????????????BMI???