Biotech Values

[HobGlobulin]

Celera's ApoA Findings; Isis ApoB Inhibitor:

SNP of ApoA correlated with severe CAD:

http://atvb.ahajournals.org/cgi/content/abstract/ATVBAHA.107.141291v1

>> Published online before print June 14, 2007
(Arteriosclerosis, Thrombosis, and Vascular Biology 2007, doi:10.1161/ATVBAHA.107.141291)
PubMed

PubMed Citation
Articles by Luke, M. M.
Articles by Ellis, S. G.
Submitted on February 5, 2007
Accepted on May 23, 2007

A Polymorphism in the Protease-Like Domain of Apolipoprotein(a) Is Associated With Severe Coronary Artery Disease

May M. Luke *; John P. Kane ; Dongming M. Liu ; Charles M. Rowland ; Dov Shiffman ; June Cassano ; Joseph J. Catanese ; Clive R. Pullinger ; Diane U. Leong ; Andre R. Arellano ; Carmen H. Tong ; Irina Movsesyan ; Josephina Naya-Vigne ; Curtis Noordhof ; Nicole T. Feric ; Mary J. Malloy ; Eric J. Topol ; Marlys L. Koschinsky ; James J. Devlin ; and Stephen G. Ellis
From Celera (M.M.L., D.M.L., C.M.R., D.S., J.J.C., D.U.L., A.R.A., C.H.T., J.J.D.), Alameda, Calif; the Cardiovascular Research Institute (J.P.K., C.R.P., I.M., J.N.-V., M.J.M.), UCSF, San Francisco, Calif; The Cleveland Clinic Foundation, Department of Cardiovascular Medicine (J.C., E.J.T., S.G.E.), Cleveland, Ohio; the Department of Biochemistry (C.N., N.T.F., M.L.K.), Queen’s University, Kingston, Ontario, Canada; and The Scripps Research Institute (E.J.T.), La Jolla, Calif.

* To whom correspondence should be addressed. E-mail: [e-mail].


Objectives--The purpose of this study was to identify genetic variants associated with severe coronary artery disease (CAD).

Methods and Results--We used 3 case-control studies of white subjects whose severity of CAD was assessed by angiography. The first 2 studies were used to generate hypotheses that were then tested in the third study. We tested 12 077 putative functional single nucleotide polymorphisms (SNPs) in Study 1 (781 cases, 603 controls) and identified 302 SNPs nominally associated with severe CAD. Testing these 302 SNPs in Study 2 (471 cases, 298 controls), we found 5 (in LPA, CALM1, HAP1, AP3B1, and ABCG2) were nominally associated with severe CAD and had the same risk alleles in both studies. We then tested these 5 SNPs in Study 3 (554 cases, 373 controls). We found 1 SNP that was associated with severe CAD: LPA I4399M (rs3798220). LPA encodes apolipoprotein(a), a component of lipoprotein(a). I4399M is located in the protease-like domain of apolipoprotein(a). Compared with noncarriers, carriers of the 4399M risk allele (2.7% of controls) had an adjusted odds ratio for severe CAD of 3.14 (confidence interval 1.51 to 6.56), and had 5-fold higher median plasma lipoprotein(a) levels (P=0.003).

Conclusions--The LPA I4399M SNP is associated with severe CAD and plasma lipoprotein(a) levels.


Key words: coronary arteriosclerosis • genetics • single nucleotide polymorphism • lipoprotein(a) • risk factors <<



Would this be a concern for an ApoA1 drug?


No one has discussed Isis 301012 recently. It targets ApoB-100 antisensically. There was a mention here of elevated liver enzymes, but these were seen at doses of 300mg/wk and especially 400 mg/wk. Isis has settled on a development dose of 200 mg/wk.

Homozygous Familial Hypercholesterolemia is a rare disease affecting one person in a million, but an effective treatment would eliminate the necessity for desperate measures such as apheresis and liver transplants. The question is will Isis 301012 be acceptable for Heterozygous FH which reportedly affects 1 in 500.

Hob