Clusterin variants extend links between Alzheimer disease and blood lipids

A recent report in the American Journal of Clinical Nutrition shows that genetic variation in the gene encoding clusterin (CLU or APOJ) showed strong and significant association with plasma fatty acids in an Alaskan Eskimo population. This is relevant to liver function, heart disease and Alzheimer disease (AD). In fact, other characteristics of CLU serve to strengthen the links between AD and blood lipids in a manner similar to APOE (apolipoprotein E).

There are in excess of 100 scientific publications describing different aspects of CLU gene and protein function. Those are not easily summarized here but can be accessed here. Briefly, the protein has no known function and seems to be involved in several basic biological events such as cell death, tumor progression, and neurodegenerative disorders (provided by RefSeq).

I have collected some interesting data on CLU:

Two separate GWAS have shown an association with Alzheimer disease. These are papers by Harold, et al. (2009) and Lambert, et al. (2009) in populations in Europe or of European ancestry. Otowa, et al (2009) showed also by GWAS an association to panic disorder in a Japanese population.

According to SymAtlas, this gene is very highly expressed in human liver.

Our preliminary analysis indicates that CLU is under positive selection in the human lineage (based on amino acid substitution rates). This could indicate responsiveness to some character of the environment. Diet perhaps?

Proteomic analysis of aortas of Apoe -/- mice showed a large increase in Clu protein expression (Wu, Tan, et al. (2007) J. Proteome Res. 6:4728).

Lastly and perhaps most interestingly, CLU is differentially expressed in human individuals with low vs high response to caloric restriction in terms of weight loss (Bouchard Vohl 2010 Am J Clin Nutr 91:309).

Lipoprotein-associated phospholipase A2 and heart disease-risk

Researchers at UC Davis have discovered that a substance found in blood, which is linked with inflammation, serves as a predictor of coronary artery disease in African-Americans. These results have been published recently in J. Clinical Endocrinology and Metabolism.

The compound in question is lipoprotein-associated phospholipase A2 (Lp-PLA2). This is also known as PLA2G7. While this blood factor is also associated with risk of heart disease in Whites, that association is not always accurate.

A colleague of mine offers that this result is interesting. Publication in JCEM rather than a cardiology journal may be related to the relatively small samples - "336 Caucasians and 224 African-Americans who were about to undergo diagnostic coronary arteriography."

With respect to the differences, obesity prevalence is 51% greater in African Americans than Whites, which could be relevant to inflammation. Alternatively, coronary disease in African Americans may be more advanced than in Whites at the point at which arteriography is performed.

I agree - especially in terms of disparities in health care among groups of ethnic minority in the USA.

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Reference

Enkhmaa B, Anuurad E, Zhang W, Pearson TA, Berglund L. (2010) Association of Lp-PLA(2) activity with allele-specific Lp(a) levels in a bi-ethnic population. Atherosclerosis. in press.