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Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes

Gusarova, Viktoria, O’Dushlaine, Colm, Teslovich, Tanya M., Benotti, Peter N., Mirshahi, Tooraj, Gottesman, Omri, Van Hout, Cristopher V., Murray, Michael F., Mahajan, Anubha, Nielsen, Jonas B., Fritsche, Lars, Wulff, Anders Berg, Gudbjartsson, Daniel F., Sjögren, Marketa, Emdin, Connor A., Scott, Robert A., Lee, Wen-Jane, Small, Aeron, Kwee, Lydia C., Dwivedi, Om Prakash, Prasad, Rashmi B., Bruse, Shannon, Lopez, Alexander E., Penn, John, Marcketta, Anthony, Leader, Joseph B., Still, Christopher D., Kirchner, H. Lester, Mirshahi, Uyenlinh L., Wardeh, Amr H., Hartle, Cassandra M., Habegger, Lukas, Fetterolf, Samantha N., Tusie-Luna, Teresa, Morris, Andrew P., Holm, Hilma, Steinthorsdottir, Valgerdur, Sulem, Patrick, Thorsteinsdottir, Unnur, Rotter, Jerome I., Chuang, Lee-Ming, Damrauer, Scott, Birtwell, David, Brummett, Chad M., Khera, Amit V., Natarajan, Pradeep, Orho-Melander, Marju, Flannick, Jason, Lotta, Luca A., Willer, Cristen J., Holmen, Oddgeir L., Ritchie, Marylyn D., Ledbetter, David H., Murphy, Andrew J., Borecki, Ingrid B., Reid, Jeffrey G., Overton, John D., Hansson, Ola, Groop, Leif, Shah, Svati H., Kraus, William E., Rader, Daniel J., Chen, Yii-Der I., Hveem, Kristian, Wareham, Nicholas J., Kathiresan, Sekar, Melander, Olle, Stefansson, Kari, Nordestgaard, Børge G., Tybjærg-Hansen, Anne, Abecasis, Goncalo R., Altshuler, David, Florez, Jose C., Boehnke, Michael, McCarthy, Mark I., Yancopoulos, George D., Carey, David J., Shuldiner, Alan R., Baras, Aris, Dewey, Frederick E., Gromada, Jesper·2018·Nature Communications
DOI 10.1038/s41467-018-04611-zPMC PMC5997992
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Abstract

Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85–0.92, p = 6.3 × 10−10), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49–0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D.

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Fig. 1 ANGPTL4 p.E40K associates with reduced risk of type 2 diabetes. The association between the p.E40K variant and type 2 diabetes was tested in each study using logistic or Firth logistic regression, coding genotypes according to an additive model. “Combined” effects were calculated using inverse variance weighted fixed-effects meta-analysis. For each study, the squares indicate the odds ratio and lines indicate 95% confidence intervals. The square size is proportional to the standard error of the estimate. CI confidence interval, CGPS Copenhagen General Population Studies, DECODE deCODE, DiscovEHR DiscovEHR Discovery Study, DiscovEHR DiscovEHR-30K, DiscovEHR 30K Replication Study, EINT-C EPIC interact–CoreExome, EINT-Q EPIC Interact–Quad660, ENOR EPIC Norfolk, HUNT the Nord-Trøndelag Health study, MDC Malmo Diet and Cancer Study, MGI the Michigan Genomics Initiative, TD2G/GT2D/DG combined analysis of T2D-GENES, GoT2D, and DIAGRAM studies, UKBB United Kingdom Biobank. The study populations are described in full in Supplementary Table 4 and in the Supplementary Note
Fig. 1 ANGPTL4 p.E40K associates with reduced risk of type 2 diabetes. The association between the p.E40K variant and type 2 diabetes was tested in each study using logistic or Firth logistic regression, coding genotypes according to an additive model. “Combined” effects were calculated using inverse variance weighted fixed-effects meta-analysis. For each study, the squares indicate the odds ratio and lines indicate 95% confidence intervals. The square size is proportional to the standard error of the estimate. CI confidence interval, CGPS Copenhagen General Population Studies, DECODE deCODE, DiscovEHR DiscovEHR Discovery Study, DiscovEHR DiscovEHR-30K, DiscovEHR 30K Replication Study, EINT-C EPIC interact–CoreExome, EINT-Q EPIC Interact–Quad660, ENOR EPIC Norfolk, HUNT the Nord-Trøndelag Health study, MDC Malmo Diet and Cancer Study, MGI the Michigan Genomics Initiative, TD2G/GT2D/DG combined analysis of T2D-GENES, GoT2D, and DIAGRAM studies, UKBB United Kingdom Biobank. The study populations are described in full in Supplementary Table 4 and in the Supplementary NoteCC BY · PubMed Central
Fig. 2 Plasma ANGPTL4 levels are reduced in p.G313fs carriers. ANGPTL4 plasma levels were measured in fasted serum from 86 heterozygous p.E40K, 42 heterozygous p.G313fs variant carriers, and 55 controls matched for age, sex, and body mass index. Statistics performed by unpaired t-test with Welch’s correction, comparing each variant carriers group to controls, ****p < 0.0001
Fig. 2 Plasma ANGPTL4 levels are reduced in p.G313fs carriers. ANGPTL4 plasma levels were measured in fasted serum from 86 heterozygous p.E40K, 42 heterozygous p.G313fs variant carriers, and 55 controls matched for age, sex, and body mass index. Statistics performed by unpaired t-test with Welch’s correction, comparing each variant carriers group to controls, ****p < 0.0001CC BY · PubMed Central
Fig. 3 K40 and G313fs abolish ANGPTL4 effect on triglycerides. a Plasma triglycerides levels (4 h fasted) in C57Bl/6 mice before (Baseline) and 7 days after (Day 7) hydrodynamic delivery via tail vein injection of cDNA encoding human E40, K40, and Gly313fs ANGPTL4 variants. Control animals were injected with empty vector. b ANGPTL4 plasma levels were measured in the animals described in (a). All groups had five animals. Values are mean ± SEM. Statistics performed by two-way ANOVA with Bonferroni correction, ****p < 0.0001 vs control
Fig. 3 K40 and G313fs abolish ANGPTL4 effect on triglycerides. a Plasma triglycerides levels (4 h fasted) in C57Bl/6 mice before (Baseline) and 7 days after (Day 7) hydrodynamic delivery via tail vein injection of cDNA encoding human E40, K40, and Gly313fs ANGPTL4 variants. Control animals were injected with empty vector. b ANGPTL4 plasma levels were measured in the animals described in (a). All groups had five animals. Values are mean ± SEM. Statistics performed by two-way ANOVA with Bonferroni correction, ****p < 0.0001 vs controlCC BY · PubMed Central
Fig. 4 Angptl4−/− mice have improved glucose homeostasis. a Serum triglycerides, (b) total cholesterol, and (c) blood glucose levels in Angptl4−/− and littermate control mice on a high-fat diet for 9 weeks. d Oral glucose tolerance test and (e) insulin tolerance test in the animals described in (a–c). All groups had 9–11 animals. Values are mean ± SEM. Statistical analysis by Welch’s t-test (a) and 2-way ANOVA with Sidak’s post-test (d, e), **p < 0.001, ****p < 0.0001. The study was conducted in three different cohorts of mice, with qualitatively similar results in each replicate
Fig. 4 Angptl4−/− mice have improved glucose homeostasis. a Serum triglycerides, (b) total cholesterol, and (c) blood glucose levels in Angptl4−/− and littermate control mice on a high-fat diet for 9 weeks. d Oral glucose tolerance test and (e) insulin tolerance test in the animals described in (a–c). All groups had 9–11 animals. Values are mean ± SEM. Statistical analysis by Welch’s t-test (a) and 2-way ANOVA with Sidak’s post-test (d, e), **p < 0.001, ****p < 0.0001. The study was conducted in three different cohorts of mice, with qualitatively similar results in each replicateCC BY · PubMed Central
Fig. 5 Angptl4−/− mice have reduced liver fat. a Body weight, (b) lean and (c) fat mass in Angptl4−/− and littermate control mice on a high-fat diet. d Liver and (e) epididymal white fat weights were evaluated in mice described in (a–c) at the time of killing. f Hepatic triglyceride levels and (g) neutral lipid staining in the livers described in (d), scale bar = 200 µm. h Respiratory exchange ratio (RER), (i) locomotor activity, (j) food intake, and (k) energy expenditure were measured during dark and light cycles in Angptl4−/− and littermate control mice on a high-fat diet. All values are mean ± SEM. Statistical analysis was conducted by Welch’s t-test; *p < 0.05; **p < 0.01. The study was conducted in two different cohorts of mice, with qualitatively similar results in each replicate
Fig. 5 Angptl4−/− mice have reduced liver fat. a Body weight, (b) lean and (c) fat mass in Angptl4−/− and littermate control mice on a high-fat diet. d Liver and (e) epididymal white fat weights were evaluated in mice described in (a–c) at the time of killing. f Hepatic triglyceride levels and (g) neutral lipid staining in the livers described in (d), scale bar = 200 µm. h Respiratory exchange ratio (RER), (i) locomotor activity, (j) food intake, and (k) energy expenditure were measured during dark and light cycles in Angptl4−/− and littermate control mice on a high-fat diet. All values are mean ± SEM. Statistical analysis was conducted by Welch’s t-test; *p < 0.05; **p < 0.01. The study was conducted in two different cohorts of mice, with qualitatively similar results in each replicateCC BY · PubMed Central

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Research works printed but not linked: 44

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Metadata

Authors
Gusarova, V., O’Dushlaine, C., Teslovich, T. M., Benotti, P. N., Mirshahi, T., Gottesman, O., Van Hout, C. V., Murray, M. F., Mahajan, A., Nielsen, J. B., Fritsche, L., Wulff, A. B., Gudbjartsson, D. F., Sjögren, M., Emdin, C. A., Scott, R. A., Lee, W.-J., Small, A., Kwee, L. C., Dwivedi, O. P., Prasad, R. B., Bruse, S., Lopez, A. E., Penn, J., Marcketta, A., Leader, J. B., Still, C. D., Kirchner, H. L., Mirshahi, U. L., Wardeh, A. H., Hartle, C. M., Habegger, L., Fetterolf, S. N., Tusie-Luna, T., Morris, A. P., Holm, H., Steinthorsdottir, V., Sulem, P., Thorsteinsdottir, U., Rotter, J. I., Chuang, L.-M., Damrauer, S., Birtwell, D., Brummett, C. M., Khera, A. V., Natarajan, P., Orho-Melander, M., Flannick, J., Lotta, L. A., Willer, C. J., Holmen, O. L., Ritchie, M. D., Ledbetter, D. H., Murphy, A. J., Borecki, I. B., Reid, J. G., Overton, J. D., Hansson, O., Groop, L., Shah, S. H., Kraus, W. E., Rader, D. J., Chen, Y.-D. I., Hveem, K., Wareham, N. J., Kathiresan, S., Melander, O., Stefansson, K., Nordestgaard, B. G., Tybjærg-Hansen, A., Abecasis, G. R., Altshuler, D., Florez, J. C., Boehnke, M., McCarthy, M. I., Yancopoulos, G. D., Carey, D. J., Shuldiner, A. R., Baras, A., Dewey, F. E., & Gromada, J.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2018-06-13
Volume
9
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-018-04611-z
PMC
PMC5997992
Cited by
145
References
14
Language
en
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