Apolipoprotein C3 polymorphism is associated with cognitive function in Caribbean Hispanics

Authors: SMITH, CAREN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; TUCKER, KATHERINE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; SCOTT, TAMMY - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; VAN ROMPAY, MARIA - Friedman School At Tufts; Parnell, Laurence; Lai, Chao Qiang; MATTEI, JOSIEMER - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; JUNYENT, MIREIA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; LEE, YU-CHI - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; GARCIA-BAILO, BIBIANA - University Of Toronto; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/14/2009
Publication Date: 5/8/2009
Citation: Smith, C.E., Tucker, K.L., Scott, T.M., Van Rompay, M., Parnell, L.D., Lai, C., Mattei, J., Junyent, M., Lee, Y., Garcia-Bailo, B., Ordovas, J.M. 2009. Apolipoprotein C3 polymorphism is associated with cognitive function in Caribbean Hispanics. PLoS One. 4(5):e5465.

Interpretive Summary: Apolipoprotein C3 (APOC3) represents a link between lipid (fat) metabolism and glucose metabolism. Because APOC3 inhibits a key enzyme in the breakdown of lipids, it is important to lipid metabolism and because insulin regulates APOC3 activity, this apolipoprotein is key to glucose metabolism. The combination of unfavorable lipoprotein profiles and impaired glucose metabolism are linked to cognitive decline, and all three conditions may decrease lifespan. While the relationships between genetic variation at the APOC3 and altered lipid and glucose metabolism are well established, connections to cognitive decline merit investigation. We examined whether APOC3 genetic variants were related to cognitive and metabolic measures, and potential relationships with diabetes in a population of Hispanics of Caribbean origin (n=960, aged 45-74). In-depth statistical analyses indicate that diabetic subjects carrying particular variations of APOC3 showed lower executive function (reduced cognition) and higher blood levels of glucose and total cholesterol, while a second genetic variant was linked to higher levels of triglycerides, total cholesterol and glucose, again, only in diabetics. These genetic variations of APOC3 serve to reinforce previous findings of a major role for insulin-related pathways in complex diseases of aging and may also serve to link to age-related cognitive decline.

Technical Abstract: Background: Apolipoprotein C3(APOC3) modulates triglyceride metabolism through inhibition of lipoprotein lipase, but is itself regulated by insulin, so that APOC3 represents a potential mechanism by which glucose metabolism may affect lipid metabolism. Unfavorable lipoprotein profiles and impaired glucose metabolism are linked to cognitive decline, and all three conditions may decrease lifespan. Associations between apolipoprotein C3(APOC3) gene polymorphisms and impaired lipid and glucose metabolism are well-established, but potential connections between APOC3 polymorphisms, metabolic dysregulation and cognitive decline deserve further attention. Methods: We examined whether APOC3 single nucleotide polymorphisms (SNPs) m482(rs2854117) and 3u386(rs5128) were related to cognitive and metabolic measures, and potential relationships with diabetes. Study subjects were Hispanics of Caribbean origin (n=960, aged 45-74) living in the Boston metropolitan area. Results: Cognitive and metabolic measures differed substantially by type II diabetes status. In multivariate regression models, APOC3 m482 AA subjects with diabetes exhibited lower executive function (P=0.009), Stroop color score (P=0.014) and Stroop incongruent score (P=0.022) compared to AG/GG subjects. APOC3 m482 AA subjects exhibited significantly higher glucose (P=0.029) and total cholesterol (P=0.028) compared to AG/GG subjects. APOC3 3u386 GC/GG subjects with diabetes exhibited significantly higher triglyceride (P=0.004), total cholesterol (P=0.003) and glucose (P=0.015) compared to CC subjects. Conclusions: In summary, we identified significant associations between APOC3 polymorphisms, metabolic dysregulation and impaired cognition in subjects with diabetes. These associations reinforce previous findings of a major role for insulin-related pathways in complex diseases of aging which reduce longevity, but may also represent a novel finding for APOC3 and age-related cognitive decline.