Cardiovascular disease (CVD) is the leading cause of death in the US, and its origins begin in childhood. My research program is devoted to understanding how best to prevent CVD by early detection and management of its major risk factors, most notably elevated levels of blood cholesterol and lipoproteins. These levels are strongly influenced by diet, but there remain large gaps in our understanding of dietary approaches for optimizing CVD risk. When this risk remains high, statins and other lipid lowering drugs can provide an effective adjunct to lifestyle modification. However, there is wide individual variability in the clinical responses to both diet and drug treatments, resulting in part from genetic diversity across the population.  Probing the basis for this variation can provide a path for developing and implementing therapies geared to an individual’s specific needs.    

There are three complementary research activities in my program that address the overall goal of identifying dietary, pharmacologic, and genetic effects on metabolic traits related to the development and management of CVD risk:

1) I am principal investigator of a large NIH P50 grant, now in its fourth year, that integrates multiple lines of investigation to determine genetic influences on clinical efficacy of statin treatment, as well as risk for adverse effects, specifically statin-induced diabetes and myopathy. The grant comprises three research projects as well as a Clinical Core based at Kaiser Permanente of Northern California (KPNC) and an Informatics Core based at the University of Pennsylvania. The largest project, housed at CHORI and led by Dr. Marisa Medina, is using patient-derived induced pluripotent stem cells to interrogate variation in statin effects at the transcriptomic and metabolomic levels. A second project, directed by Dr. Karen Reue at UCLA, is aimed at discovering factors influencing statin effects in a large panel of genetically defined mouse models. The third project, headed by Dr. Neil Risch of UCSF, is using electronic longitudinal health and pharmacy records as well as genetic data from a cohort of nearly 100,000 patients in the KPNC system to identify factors modifying statin clinical responses in a real-world clinical practice setting. Collectively, information derived from these projects can contribute significantly to precision medicine approaches for CVD risk reduction.

2) A continuing activity of my laboratory has been the development and implementation of methodology for analysis of multiple distinct LDL subspecies, which my colleagues and I were the first to identify in human plasma.  This early work led to discovery of a genetically influenced lipoprotein phenotype characterized by increased levels of small, dense LDL particles and associated with higher triglyceride and lower HDL cholesterol. Subsequently termed atherogenic dyslipidemia, this trait constitutes a central feature of the metabolic syndrome and is the characteristic dyslipidemia of type 2 diabetes. Results from a series of our studies pointing to the increased atherogenic potential of small, dense LDL particles are consistent with recent prospective evidence for the association of these particles with CVD risk. Application of this information for clinical research was enabled by development of two high resolution methods for analysis of lipoprotein subspecies that were licensed to large clinical laboratories and that have been widely utilized in clinical practice for evaluating and managing risk for CVD. In the past year, we have applied these methods to the identification of novel lipoprotein subspecies that may be involved in neurodegenerative and retinal disease, as well as CVD.

3) The third major aim of my program has been the determination of dietary macronutrient effects on atherogenic dyslipidemia. Earlier, in a series of randomized controlled dietary trials, we found that high-carbohydrate low-fat diets, at the time widely recommended for CVD prevention, resulted in the induction of the small, dense LDL phenotype in a high proportion of healthy individuals. Correspondingly, we later showed that dietary carbohydrate restriction can reverse this trait and that this effect is independent of saturated fat intake. In addition, we found that individuals with atherogenic dyslipidemia have a reduced capacity to oxidize fat, suggesting a common metabolic impairment that predisposes to both adiposity and dyslipidemia. In recent years, we have published a series of articles and reviews, including a meta-analysis of prospective cohort studies, which have pointed to the absence of an association of dietary saturated fat intake per se with CVD risk, despite the well-documented effect of saturated fat on LDL cholesterol levels.  These findings, which have been confirmed by others, are consistent with our observation that the saturated fat-induced increase in LDL cholesterol is primarily attributable to an effect on larger vs. smaller LDL particles.  Collectively, this work has helped support recent dietary guidelines that place a greater emphasis on limiting refined carbohydrates than fats. Finally, we have just published the results of a large NIH-funded clinical trial demonstrating that, contrary to expectations, red meat and white meat have identical effects on blood cholesterol profiles when saturated fat is held constant These results, which received considerable media attention, are likely to be considered by the 2020 U.S. Dietary Guidelines Advisory Committee. In conjunction with this project, in collaboration with investigators at the Cleveland Clinic, we showed that diets enriched in red meat, but not white meat or non-meat protein, significantly increased levels of a novel CVD biomarker derived from intestinal metabolism by resident microbes.

Recent publications:

Sun, H., Krauss, R.M., Chang, J.T. & Teng, B.B. (2018). PCSK9 deficiency reduces atherosclerosis, apolipoprotein B secretion, and endothelial dysfunction. J. Lipid Res., 59, 207-223. PMC5794417

Hoffman, T.J., Theusch, E., Haldar, T., Ranatunga, D.K., Jorgensen, E., Medina, M.W., Kvale, M.N., Kowk, P.Y., Schaefer, C., Krauss, R.M., Iribarren, C. & Risch, N. (2018). A large electronic-health-record-based genome-wide study of serum lipids. Nat. Genet., 50, 401-413. PMC5942247'

Liang, X., Yee, S.W., Chien, H.C., Chen, E.C., Luo, Q., Zou, L., Piao, M., Mifune, A., Chen, L., Calvert, M.E., King, S., Norheim, F., Abad, J., Krauss, R.M., Giacomini, K.M. (2018). Organic cation transporter 1 (OCT1) modulates multiple cardiometabolic traits through effects on hepatic thiamine content. PLoS Biol., 16, e2002907. PMC5919692
Wei, W.Q., Li, X., Feng, Q., Kubo, M., Kullo, I.J., Peissig, P.L., Karlson, E.W., Jarvik, G.P., Lee, M.T.M., Shang, N., Larson, E.A., Edwards, T., Shaffer, C., Mosley, J.D., Maeda, S., Horikoshi, M., Ritchie, M., Williams, M.S., Larson, E.B., Crosslin, D.R., Bland, S.T., Pacheco, J.A., Rasmussen-Torvik, L.J., Cronkite, D., Hripcsak, G., Cox, N.J., Wilke, R.A., Stein, C.M., Rotter, J.I., Momozawa, Y., Roden, D.M., Krauss, R.M. & Denny, J.C. (2018). LPA variants are associated with residual cardiovascular risk in patients receiving statins. Circulation, 138, 1839-1849. PMC6202211

Delatour, V., Clouet-Foraison, N., Gaie-Levrel, F., Marcovina, S.M., Hoofnagle, A.N., Kuklenyik, Z., Caulfield, M.P., Otvos, J.D., Krauss, R.M., Kulkami, K.R., Contois, J.H., Remaley, A.T., Vesper, H.W., Cobbaert, C.M. & Gillery, P. (2018). Comparability of lipoprotein particle number concentrations across ES-DMA, NMR, LC-MS/MS, immunoephelometry, and VAP: in search of a candidate reference measurememnt procedure for apoB and non-HDL-P standardization. Clin. Chem., 64, 17485-1495. PMID: 30087138

Kim, K., Theusch, E., Kuang, Y.L., Dose, A., Mitchel, K., Cubitt, C., Chen, Y.I., Krauss, R.M. & Medina, M.W. (2018). ZNF542P is a pseudogene associated with LDL response to simvastatin treatment. Sci. Rep., 8, 12443. PMC6102286
Oni-Orisan, A., Hoffman, T.J., Ranatunga, D., Medina, M.W., Jorgenson, E., Schaefer, C., Krauss, R.M., Iribarren, C., Risch, N. (2018). Characterization of statin low-density lipoprotein cholesterol dose-response using electronic health records in a large population-based cohort. Circ. Genom. Precis. Med. 11, e2043. PMC6214660

Vital, M., Howe, A., Bergeron, N., Krauss, R.M., Jansson, J.K., Tiedie, J.M. (2018). Metagenomic insights into the degradation of resistant starch by human gut microbiota. Appl. Environ. Micriobiol. 15, 1562-18. PMC6238065

Ligthart, S., Vaez, A., Võsa, U., Stathopoulou, M.G., de Vries, P.S., Prins, B.P., Van der Most, P.J., Tanaka, T., Naderi, E., Rose, L.M., Wu, Y., Karlsson, R., Barbalic, M., Lin, H., Pool, R., Zhu, G., Macé, A., Sidore, C., Trompet, S., Mangino, M., Sabater-Lleal, M., Kemp, J.P., Abbasi, A., Kacprowski, T., Verweij, N., Smith, A.V., Huang, T., Marzi, C., Feitosa, M.F., Lohman, K.K., Kleber, M.E., Milaneschi, Y., Mueller, C., Huq, M., Vlachopoulou, E., Lyytikäinen, L.P., Oldmeadow, C., Deelen, J., Perola, M., Zhao, J.H., Feenstra, B.; LifeLines Cohort Study, Amini, M.; CHARGE Inflammation Working Group, Lahti, J., Schraut, K.E., Fornage, M., Suktitipat, B., Chen, W.M., Li, X., Nutile, T., Malerba, G., Luan, J., Bak, T., Schork, N., Del Greco, M.F., Thiering, E., Mahajan, A., Marioni, R.E., Mihailov, E., Eriksson, J., Ozel, A.B., Zhang, W., Nethander, M., Cheng, Y.C., Aslibekyan, S., Ang, W., Gandin, I., Yengo, L., Portas, L., Kooperberg, C., Hofer, E., Rajan, K.B., Schurmann, C., den Hollander, W., Ahluwalia, T.S., Zhao, J., Draisma, H.H.M., Ford, I., Timpson, N., Teumer, A., Huang, H., Wahl, S., Liu, Y., Huang, J., Uh, H.W., Geller, F., Joshi, P.K., Yanek, L.R., Trabetti, E., Lehne, B., Vozzi, D., Verbanck, M., Biino, G., Saba, Y., Meulenbelt, I., O'Connell, J.R., Laakso, M., Giulianini, F., Magnusson, P.K.E., Ballantyne, C.M., Hottenga, J.J., Montgomery, G.W., Rivadineira, F., Rueedi, R., Steri, M., Herzig, K.H., Stott, D.J., Menni, C., Frånberg, M., St Pourcain, B., Felix, S.B., Pers, T.H., Bakker, S.J.L., Kraft, P., Peters, A., Vaidya, D., Delgado, G., Smit, J.H., Großmann, V., Sinisalo, J., Seppälä, I., Williams, S.R., Holliday, E.G., Moed, M., Langenberg, C., Räikkönen, K., Ding, J., Campbell, H., Sale, M.M., Chen, Y.I., James, A.L., Ruggiero, D., Soranzo, N., Hartman, C.A., Smith, E.N., Berenson, G.S., Fuchsberger, C., Hernandez, D., Tiesler, C.M.T., Giedraitis, V., Liewald, D., Fischer, K., Mellström, D., Larsson, A., Wang, Y., Scott, W.R., Lorentzon, M., Beilby, J., Ryan, K.A., Pennell, C.E., Vuckovic, D., Balkau, B., Concas, M.P., Schmidt, R., Mendes de Leon, C.F., Bottinger, E.P., Kloppenburg, M., Paternoster, L., Boehnke, M., Musk, A.W., Willemsen, G., Evans, D.M., Madden, P.A.F., Kähönen, M., Kutalik, Z., Zoledziewska, M., Karhunen, V., Kritchevsky, S.B., Sattar, N., Lachance, G., Clarke, R., Harris, T.B., Raitakari, O.T., Attia, J.R., van Heemst, D., Kajantie, E., Sorice, R., Gambaro, G., Scott, R.A., Hicks, A.A., Ferrucci, L., Standl, M., Lindgren, C.M., Starr, J.M., Karlsson, M., Lind, L., Li, J.Z., Chambers, J.C., Mori, T.A., de Geus, E.J.C.N., Heath, A.C., Martin, N.G., Auvinen, J., Buckley, B.M., de Craen, A.J.M., Waldenberger, M., Strauch, K., Meitinger, T., Scott, R.J., McEvoy, M., Beekman, M., Bombieri, C., Ridker, P.M., Mohlke, K.L., Pedersen, N.L., Morrison, A.C., Boomsma, D.I., Whitfield, J.B., Strachan, D.P., Hofman, A., Vollenweider, P., Cucca, F., Jarvelin, M.R., Jukema, J.W., Spector, T.D., Hamsten, A., Zeller, T., Uitterlinden, A.G., Nauck, M., Gudnason, V., Qi, L., Grallert, H., Borecki, I.B., Rotter, J.I., März, W., Wild, P.S., Lokki, M.L., Boyle, M., Salomaa, V., Melbye, M., Eriksson, J.G., Wilson, J.F., Penninx, B.W.J.H., Becker, D.M., Worrall, B.B., Gibson, G., Krauss, R.M., Ciullo, M., Zaza, G., Wareham, N.J., Oldehinkel, A.J., Palmer, L.J., Murray, S.S., Pramstaller, P.P., Bandinelli, S., Heinrich, J., Ingelsson, E., Deary, I.J., Mägi, R., Vandenput, L., van der Harst, P., Desch, K.C., Kooner, J.S., Ohlsson, C., Hayward, C., Lehtimäki, T., Shuldiner, A.R., Arnett, D.K., Beilin, L.J., Robino, A., Froguel, P., Pirastu, M., Jess, T., Koenig, W., Loos, R.J.F., Evans, D.A., Schmidt, H., Smith, G.D., Slagboom, P.E., Eiriksdottir, G., Morris, A.P., Psaty, B.M., Tracy, R.P., Nolte, I.M., Boerwinkle, E., Visvikis-Siest, S., Reiner, A.P., Gross, M., Bis, J.C., Franke, L., Franco, O.H., Benjamin, E.J., Chasman, D.I., Dupuis, J., Snieder, H., Dehghan, A & Alizadeh BZ. (2018). Genome analyses of >2000,000 individuals identify 58 loci for chronic inflammation and highlight pathways that link inflammation and complex disorders. Am. J. Hum. Genet. 103, 691-706. PMCC6218410

Lang, J.M.,Pan, C., Cantor, R.M., Tang, W.H.W., Garcia-Garcia, J.C., Kurtz, I., Hazen, S.L., Bergeron, M., Krauss, R.M. & Lusis, A.J. (2018). Impact of individual traits, saturated fat, and protein source on the gut microbiome. MBio. 9, 1604-18. PMC6299478

Lei, D., Yu, Y., Kuang, Y.L., Liu, J., Krauss, R.. & Ren, G. (2019). Single-molecule 3D imaging of human plasma intermediat-density lipoproteins reveals a polyhedral structure. Biochim. Biophys. Acta. Mol. Cell Biol. Lipids, 1864, 260-270. PMC6409128

Brower, M.A., Hai, Y., Jones, M.R., Gu, X., Chen, Y.I., Rotter, J.I, Krauss, R.M., Legro, R.S., Azziz, R., Goodarzi, M.O. (2019). Bidirectional Mendelian randomization to explore the casual relationships between body mass index and polycystic ovary syndrome. Hum. Reprod., 34, 127-136. PMCC6295958

Wang, Z., Bergeron, N., Levison, B.S., Li, X.S., Chiu, S., Jia, X., Koeth, R.A., Li, L., Wu, Y., Tang, W.H.W., Krauss, R.M & Hazen, S.L. (2019). Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women. Eur. Heart J., 40, 583-594. PMC6374688

Williams, P.T., Bergeron, N., Chiu, S., Krauss, R.M. (2019). A randomized, controlled trial on the effects of almonds on lipoprotein response to a higher carbohydrate, lower fat diet in men and women with abdominal adiposity. Lipids Health Dis., 18, 1025-4. PMC6446393

Butler, A.A., Zhang, J., Price, C.A., Stevens, J.R., Graham, J.L., Stanhope, K.L., King, S., Krauss, R.M., Bremer, A.A & Havel, P.J. (2019). Low plasma adropin concentrations increase risks of weight gain and metabolic dysregulation in response to a high-sugar diet in male nonhuman primates. J. Biol. Chem., 294, 9706-9719. PMC6597842
Butler, A.A., Price, C.A., Graham, J.L., Stanhope, K.L., King, S., Hung, Y.H., Sethupathy, P., Wong, S., Hamilton, J., Krauss, R.M. Bremer, A.A. & Havel, P.J. (2019). Fructose-induced hypertriglyceridemia in rhesus macaques is attenuated with fish oil or ApoC3 RNA interference. J. Lipid Res., 60, 805-818. PMC6446715

Corey, K.E., Wilson, L.A,, Altinbas, A., Yates, K.P., Kleiner, D.E., Chung, R.T., Krauss, R.M., Chalasani, N. & NASH Clinical Research Network. (2019). Relationship between resolution of non-alcoholic steatohepatitis and changes in lipoprotein sub-fractions: a post-hoc analysis of the PIVENS trial. Aliment Pharmacol. Ther, 49, 1205-1213. PMC6461513

Ramms, B., Patel, S., Nora, C., Pessentheiner, A.R., Chang, M.W., Green,, C.R., Golden, G.J., Secrest, P., Krauss, R.M., Metallo, C.M., Benner, C., Alexander, VJ., Witztum, J.L., Tsimikas, S., Esko, J.D. & Gordts, P.L.S.M. (2019). ApoC-III ASO promotes tissue LPL activity in absence of ApoE-Mediated TRL clearance. J. Lipid Res., {Epub ahead of print] PMID: 31092690
Kuang, Y.L., Munoz, A., Nalula, G., Santostefano, K.E., Sanghez, V., Sanchez, G., Terada, N., Mattis, A.N., Iacovino, M., Iribarren, C., Krauss, R.M. & Medina, M.W. (2019). Stem Cell Res., PMC6570500

Lee, S., Parekh, T., King, S.J., Reed, B., Chiu, H.C., Krauss, R.M. & Yassine, H.N. (2019). Low-density lipoprotein particle size subfractions and cerebral amyloidosis. J. Alzheimers Dis., 68, 983-990. PMID: 30883368

Bergeron, N., Chiu, S., Williams, P.T., King, S.M. & Krauss, R.M. (2019). Effects of red meat, white meat, and nonmeat protein sources on atherogenic lipoprotein measures in the context of low compared with high saturated fat intake: a randomized controlled trial. Am. J. Clin. Nutr., {Epub ahead of print] PMC6599736

Bray, G.A., Krauss, R.M., Sacks, F.M. & Qi, L. (2019). Lessons learned from the POUNDS lost study: Genetic, metabolic, and behavioral factors affecting changes in body weight, body composition, and cardiometabolic risk. Curr. Obes. Rep. [Epub ahead of print] PMID: 31214942

Hyde, P.N., Sapper, T.N., Crabtree, C.D., LaFountain, R.A., Bowling, M.L., Buga, A., Fell, B., McSwiney, F.T., Dickerson, R.M., Miller, V.J., Scandling, D., Simonetti, O.P., Phinney, S.D., Kraemer, W.J., King, S.A., Krauss, R.M. & Volek, J.S. (2019). Dietary carbohydrate restriction improves metabolic syndrome independent of weight loss. JCI Insight, 4, 12. PMC6629108

Mach, F., Ray, K.K., Wiklund, O., Corsini, A., Catapano, A.L., Bruckert, E., De Backer, G., Hegele, R.A., Hovingh, G.K., Jacobson, T.A., Krauss, R.M., Laufs, U., Leiter, L.A., Marz, W., Nordestgaard, B.G., Raal, F.J., Roden, M., Santos, R.D., Stein, E.A., Stroes, E.S., Thompson, P.D., Tokgozoglu, L., Vladutiu, G.D., Gencer, B., Stock, J.K., Ginsberg, H.N., Chapman, M.J. & European Atherosclerosis Society Consensus Panel. (2018). Adverse effects of statin therapy: perception vs. the evidence – focus on glucose homeostasis, cognitive, renal and hepatic function, haemorrhagic stroke and cataract. Eur. Heart J., 39, 2526-2539. PMC6047411

Stanhope, K.L., Goran, M.I., Bosy-Westphal, A., King, J.C., Schmidt, L.A., Schwarz, J.M., Stice, E., Sylvetsky, A.C., Turnbaugh, P.J., Bray, G.A., Gardner, C.D., Havel, P.J., Malik, V., Mason, A.E., Ravussin, E., Rosenbaum, M., Welsh, J.A., Allister-Price, C., Sigala, D.M., Greenwood, M.R.C., Astrup, A. & Krauss, R.M. (2018). Pathways and mechanisms linking dietary components to Cardiometabolic disease: thinking beyond calories. Obes. Rev., 19, 1205-1235. PMC3530989

Forohi, N.G., Krauss, R.M., Taubes, G. & Willett, W. (2018). Dietary fat and Cardiometabolic health: evidence, controversies, and consensus for guidance. BMJ, 361, k1239. PMC6053258

Astrup, A., Bertram, H.C., Bonjour, J.P., de Groot, L.C., de Oliveira Otto, M.C., Feeney, E.L., Garg, M.L., Givens, I., Fok, F.J., Krauss, R.M., Lamarche, B., Lecerf, J.M., Legrand, P., McKinley, M., Micha, R., Michalski, M.C., Mozaffarian, D., Soedamah-Muthu, S.S. (2019). BMJ, 366, I4137. PMID: 31270106

Bergeron, N., Siri-Tarino, P.W., Bray, G.A., Krauss, R.M. Nutrition and Cardiometabolic Health (textbook), CRC Press, 2018

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