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Holmen, O. L., Zhang, H., Fan, Y., Hovelson, D. H., Schmidt, E. M., Zhou, W., et al. (2014). Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk. Nat Genet, 46(4), 345–351.
Abstract: Blood lipid levels are heritable, treatable risk factors for cardiovascular disease. We systematically assessed genome-wide coding variation to identify new genes influencing lipid traits, fine map known lipid loci and evaluate whether low-frequency variants with large effects exist for these traits. Using an exome array, we genotyped 80,137 coding variants in 5,643 Norwegians. We followed up 18 variants in 4,666 Norwegians and identified ten loci with coding variants associated with a lipid trait (P < 5 x 10(-8)). One variant in TM6SF2 (encoding p.Glu167Lys), residing in a known genome-wide association study locus for lipid traits, influences total cholesterol levels and is associated with myocardial infarction. Transient TM6SF2 overexpression or knockdown of Tm6sf2 in mice alters serum lipid profiles, consistent with the association observed in humans, identifying TM6SF2 as a functional gene within a locus previously known as NCAN-CILP2-PBX4 or 19p13. This study demonstrates that systematic assessment of coding variation can quickly point to a candidate causal gene.
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Lindberg, M., Midthjell, K., & Bjerve, K. S. (2013). Long-term tracking of plasma phospholipid fatty acid concentrations and their correlation with the dietary intake of marine foods in newly diagnosed diabetic patients: results from a follow-up of the HUNT Study, Norway. Br J Nutr, 109(6), 1123–1134.
Abstract: Analysis of long-chain n-3 and n-6 fatty acid (FA) concentrations is used to evaluate their potential health effects in epidemiological studies, and, recently, also to counsel patients with a suboptimal intake of n-3 FA. Data on the method's ability to track and detect differences within and between individuals in appropriate populations are, however, lacking. The present study provides such data for twenty-nine plasma phospholipid (PL) FA concentrations and indices measured in 214 newly diagnosed type 2 diabetic patients at baseline and after 3 years. 20 : 3n-6 and the 20 : 4n-6:20 : 3n-6 ratio showed the highest tracking coefficients (Spearman's r 0.68), while DHA, EPA and PLN3-index (EPA+DHA) coefficients were 0.60, 0.47 and 0.55, respectively. Fish consumption measured simultaneously with EPA, DHA, sum n-3 and PLN3 index showed Spearman's correlation coefficients of 0.47, 0.44, 0.48 and 0.49, respectively, decreasing to 0.20, 0.19, 0.22 and 0.21 when measured 3 years apart. The within-subject CV of EPA, DHA and PLN3 index were 39.9, 14.3 and 18.0 %, respectively. The corresponding between-subject CV were 33.6, 16.5 and 18.7 %, while the reference change values were 112, 41 and 52 %. In conclusion, PL n-3 FA concentrations showed a significant long-term tracking and were positively correlated with marine food intake. Analytical precision, biological variability, reference change value and the index of individuality of EPA, DHA and PLN3 index are similar to commonly used clinical biomarkers, supporting their validity as dietary markers in clinical and epidemiological work.
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Liu, D. J., Peloso, G. M., Yu, H., Butterworth, A. S., Wang, X., Mahajan, A., et al. (2017). Exome-wide association study of plasma lipids in >300,000 individuals. Nat Genet, 49(12), 1758–1766.
Abstract: We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.
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Sandvei, M. S., Lindekleiv, H., Romundstad, P. R., Muller, T. B., Vatten, L. J., Ingebrigtsen, T., et al. (2012). Risk factors for aneurysmal subarachnoid hemorrhage – BMI and serum lipids: 11-year follow-up of the HUNT and the Tromso Study in Norway. Acta Neurol Scand, 125(6), 382–388.
Abstract: OBJECTIVES: Life-style factors have been associated with the risk for aneurysmal subarachnoid hemorrhage (aSAH), but it is not clear whether body mass index (BMI) and serum lipids are associated with risk. We prospectively assessed these associations in two large population studies. METHODS: A total of 65,526 participants in the Nord-Trondelag Health Study (1995-1997) and 26,882 participants in the Tromso Study (1994-1995) were included. Studies included measurements of body weight and height, serum lipids, and self-administered questionnaires. Participants who experienced aSAH were identified, and hazard ratios (HRs) were estimated using Cox regression analysis. RESULTS: During 11 years of follow-up, aSAH was diagnosed in 122 participants. Overweight (BMI 25-29.9) was negatively associated with the risk of aSAH (HR 0.7, 95% CI 0.4-1.0). There was no over all association of total serum cholesterol, HDL cholesterol, or triglycerides with the risk of aSAH, but in participants younger than 50 years, HDL cholesterol was inversely associated with the risk (HR per standard deviation increase 0.6, 95% CI 0.4-0.9). CONCLUSIONS: Overweight may be associated with reduced risk of aSAH, but there was no over all association of total serum cholesterol, HDL cholesterol, or triglycerides with the risk of aSAH in this prospective study.
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