The fat mass and obesity-associated (FTO) gene variant rs9939609 predicts long-term incidence of cardiovascular disease and related death independent of the traditional risk factors.

OBJECTIVE AND METHODS: The impact of the rs9939609 FTO variant on cardiovascular events was investigated in the 19-year follow-up of subjects recruited to the OPERA study. RESULTS: A total of 212 cardiovascular disease (CVD) and 152 coronary heart disease (CHD) events or deaths occurred during follow-up. The logistic regression analysis revealed that among the AA genotype the incidence of CHD (OR 1.905; 95% CI 1.250-2.903, p = 0.001) and CVD (OR 1.849; 1.265-2.702, p = 0.003) events or death was significantly higher when adjusted for age, sex, and study group. After further adjustment with BMI, smoking status, systolic blood pressure, and low-density lipoprotein cholesterol, the higher incidence of CHD and CVD events or death among subjects with the AA genotype remained significant (OR 1.895; p = 0.002 and p = 0.004, respectively). In Cox regression analysis, the AA genotype displayed a higher rate of CVD and CHD death when the model was adjusted for sex, age, and study group (p = 0.006 and p = 0.046). FTO rs9939609 AA genotype improved the C-index of the final predictive model from 0.709 to 0.715. In reclassification analyses, the integrated discrimination index was significant 0.011 (p = 0.010). CONCLUSION: The AA genotype of FTO rs9939609 seems to be associated with a higher risk of CVD, and this phenomenon seems to be independent of the traditional risk factors for atherosclerosis.

Fat mass- and obesity-associated gene Fto affects the dietary response in mouse white adipose tissue.

Common variants of human fat mass- and obesity-associated gene Fto have been linked with higher body mass index, but the biological explanation for the link has remained obscure. Recent findings suggest that these variants affect the homeobox protein IRX3. Here we report that FTO has a role in white adipose tissue which modifies its response to high-fat feeding. Wild type and Fto-deficient mice were exposed to standard or high-fat diet for 16 weeks after which metabolism, behavior and white adipose tissue morphology were analyzed together with adipokine levels and relative expression of genes regulating white adipose tissue adipogenesis and Irx3. Our results indicate that Fto deficiency increases the expression of genes related to adipogenesis preventing adipocytes from becoming hypertrophic after high-fat diet. In addition, we report a novel finding of increased Irx3 expression in Fto-deficient mice after high-fat feeding indicating a complex link between FTO, IRX3 and fat metabolism.

Elevated messenger RNA expression and plasma protein levels of osteopontin and matrix metalloproteinase types 2 and 9 in patients with ascending aortic aneurysms.

OBJECTIVE: Ascending aortic aneurysms result from a degenerative process in the aortic wall, characterized by the loss of smooth muscle cells and elastic fibers. We hypothesized that there would be changes in plasma protein and aortic tissue messenger RNA levels of osteopontin, matrix metalloproteinase type 2, matrix metalloproteinase type 9, and tissue inhibitor of matrix metalloproteinases type 1 in ascending aortic aneurysm samples. METHODS: Plasma, aortic tissue, and aortic mRNA samples were collected from patients with an ascending aortic aneurysm or an abdominal aortic aneurysm and from control individuals. Plasma protein levels of osteopontin, matrix metalloproteinase (MMP) types 2 and 9, and tissue inhibitor of matrix metalloproteinases type 1 were determined by quantitative sandwich enzyme-linked immunosorbent assay. Aortic mRNA levels of these same proteins were analyzed with the quantitative real-time polymerase chain reaction (RT-PCR) method and protein levels from the aortic tissues were assayed by immunostaining. Quantitative RT-PCR results were estimated by the normalized expression method (ΔΔCt). RESULTS: Plasma protein levels were significantly elevated for osteopontin, MMP-2, and MMP-9 in the samples of ascending and abdominal aortic aneurysm group compared with controls. Plasma protein levels of MMP-9 were higher in the nonoperated compared with the operated ascending aortic aneurysm group. Aortic osteopontin, MMP-2, and MMP-9 mRNA levels were increased for ascending aortic aneurysm samples. CONCLUSIONS: This study reveals an important role of osteopontin, MMP-2 and MMP-9 in the development of ascending and abdominal aortic aneurysm.

Long telomeres in blood leukocytes are associated with a high risk of ascending aortic aneurysm.

Ascending aortic aneurysm is a connective tissue disorder. Even though multiple novel gene mutations have been identified, risk profiling and diagnosis before rupture still represent a challenge. There are studies demonstrating shorter telomere lengths in the blood leukocytes of abdominal aortic aneurysm patients. The aim of this study was to measure whether relative telomere lengths are changed in the blood leukocytes of ascending aortic aneurysm patients. We also studied the expression of telomerase in aortic tissue samples of ascending aortic aneurysms. Relative lengths of leukocyte telomeres were determined from blood samples of patients with ascending aortic aneurysms and compared with healthy controls. Telomerase expression, both at the level of mRNA and protein, was quantified from the aortic tissue samples. Mean relative telomere length was significantly longer in ascending aortic aneurysm blood samples compared with controls (T/S ratio 0.87 vs. 0.61, p<0.001). Expressions of telomerase mRNA and protein were elevated in the aortic aneurysm samples (p<0.05 and p<0.01). Our study reveals a significant difference in the mean length of blood leukocyte telomeres in ascending aortic aneurysm and controls. Furthermore, expression of telomerase, the main compensating factor for telomere loss, is elevated at both the mRNA and protein level in the samples of aneurysmal aorta. Further studies will be needed to confirm if this change in telomere length can serve as a tool for assessing the risk of ascending aortic aneurysm.

Plasma levels of antibodies against oxidized LDL are inherited but not associated with HDL-cholesterol level in families with early coronary heart disease.

OBJECTIVE: Oxidized low-density lipoproteins (oxLDL) and antibodies against them (anti-oxLDLs) are thought to play a central role in atherosclerosis. One proposed antiatherosclerotic mechanism for HDL is to prevent oxidation of LDL. This study examined whether plasma HDL-cholesterol (HDL-C) is related to plasma anti-oxLDL levels. METHODS: We collected families based on probands with low HDL-C and premature coronary heart disease (CHD). Antibody levels were determined in samples from 405 subjects. Immunoglobulin G, M and A levels against two in vitro models of oxLDL, malondialdehyde-acetaldehyde-modified LDL (MAA-LDL) and copper oxidized LDL (CuOx-LDL), were measured by ELISA. We carried out heritability estimation of antibody traits and bivariate analyses between HDL-C, LDL-C and antibody traits. RESULTS: All the antibody levels were significantly inherited (p < 0.001), heritability estimates ranging from 0.28 to 0.65. HDL-C exhibited no environmental or genetic cross-correlations with antibody levels. Significant environmental correlations were detected between LDL-C and both IgG levels (ρ(E) = 0.40, p = 0.046 and ρ(E) = 0.39, p < 0.001). There were no differences in antibody levels between subjects with normal and low HDL-C, or between CHD-affected and non-affected subjects. CONCLUSION: In this study, low HDL-C level displayed no significant associations with the anti-oxLDL levels measured. The heritability of the anti-oxLDL levels was a novel and interesting finding.

Effects of phosphatidylethanol on mouse adipocyte differentiation and expression of stearoyl-CoA desaturase 1.

BACKGROUND: Phosphatidylethanol (PEth) is an aberrant phospholipid formed in vivo only in the presence of ethanol. In circulation PEth is associated with lipoproteins and is transferred from one lipoprotein to another. Lipoprotein-associated PEth affects endothelial and smooth muscle cells of blood vessels, but its effects on other cell types have not been explored. Adipocytes have a central role in metabolic syndrome and obesity. In this study we tested whether lipoprotein-associated PEth affects stearoyl-CoA desaturase 1 (SCD1) which plays a major role in lipid-mediated signaling in the differentiation of adipocytes. METHODS: Mouse 3T3-L1 preadipocytes were differentiated to adipocytes in the presence of high-density lipoproteins (HDL) isolated from the plasma of healthy volunteers or PEth-containing HDL modified in vitro. After incubation, fat accumulation, SCD1 mRNA expression, SCD1 protein content, and fatty acid composition of adipocytes were determined. RESULTS: Phosphatidylethanol-containing HDL particles inhibited adipocyte differentiation and decreased the 18:1/18:0 ratio of cellular fatty acids by 28% compared with native HDL particles. Moreover, PEth-containing HDL reduced the SCD1 protein content by 39%. CONCLUSIONS: Lipoprotein-associated PEth may mediate the effects of ethanol on SCD1 and differentiation of preadipocytes to adipocytes.