Photo: KG Pressfoto

Contact

Address

Department of Clinical Sciences Malmö
Diabetes and Cardiovascular Diseases, Genetic Epidemiology
CRC, Entr 72, building 91, level 12, University Hospital Malmö
SE-205 02  Malmö, Sweden

Phone

+46 40 391210

Fax

+46 40 391222

E-mail

Marju.Orho-Melander@remove-this-part.med.lu.se

Head: Marju Orho-Melander

Professor of genetic epidemiology

Background to current projects

Genome-wide association studies (GWAS) have identified more than 200 common disease-predisposing loci for cardiovascular and metabolic traits. I have led (1) or participated (2-4) in several of the discovery and confirmation efforts for lipid and lipoprotein traits and recently within the GLGC (Global Lipid Genetics consortium) we identified 95 distinct loci reproducibly associated with lipoprotein concentrations (4). These loci explain 25-30% of heritability of lipid/lipoprotein traits and individuals in the highest quartile of a risk score of these variants are at 12-, 6-, and 5-times higher risk of having too high LDL-cholesterol- and trigluceride levels and too low HDL levels compare dto individuals in the lowest risk score quintile (4).

GWA studies with large meta-analyses and extensive replication efforts have pinpointed at least 40 loci for obesity, 50 for T2D and 30 for CVD. Very little is, however, known about how the genetic risk for T2D, obesity or CVD is modified by dietary or other environmental factors. As one of the first studies showing that genetic susceptibility for obestiy can be dependent on dietary factors my group has recently demonstrated that a genetic variant in the strongest common obesity gene FTO (Fat and Obesity associated) interacts with dietary fat- and carbohydrate content i.e. the risk of obesity by FTO was only seen among individuals consuming high fat or low carbohydrate diet (5) and we have recently replicated this finding in the large Malmö Diet and Cancer Study (MDCS) with >28,000 participants (6).

Another great challenge of the post-genomic era is to translate GWAS findings into mechanistic insights with predicitive and therapeutic implications. In the DGI scan, we identified the glucokinase regulatory protein (GCKR) region as a novel locus for plasma triglyceride level. Thereafter, we have in large-scale association and fine mapping studies provided comprehensive evidence that a common Pro446A1a variant in GCKR is associated with opposite effects on fasting plasma triglyceride and glucose levels thus uncoupling the usual positive correlation observed between these traits (7). Finally, our functional studies in vitro demonstrated that P446L-GKRP has diminished fructose-1-phosphate regulation at physiological concentrations resulting in increased GCK activity (8). In addition to GCKR, we have been involoved in fine-mapping and functional characterisation of sortilin (SORT1) locus (9). These findings represent two of the very first examples where follow-up studies of GWAS association already have pinpointed the causal variants and functional studies have given the explanation for the molecular mechansims.

Free fatty acids (FFAs) serve as physiologically important energy substrates and their release from the adipose tissue by lipolysis is regulated according to the energy demands of the body. Although FFA-levels are to 50-60% defined by genetic factors, such genetic factors have remained unknown. FFAs are known to bo increased in most obese patients as well as in type 2 diabetes, hepatic steatosis and cardiovascular disease. We therefore have performed a genome wide analysis of FFA-levels during fasting and after an oral glucose tolerance test (OGTT).

Main Objectives of my Research Group

  1. To dissect interactions between identified T2D/obesity/CVD/lipid/lipoprotein associated loci and dietary factors (macronutrient and fiber intakes, food groups):
    a. We investigate how such interactions modify the genetic risk of T2D, obesity or CVD;
    b. We investigate how genetic risk can affect the effect of diet on the risk of T2D, obesity or CVD;
    c. We study how dietary factors affect the lipoprotein sub-fraction profile and investigate gene x diet interactions modifying lipoprotin profiles and risk of CVD;
  2. To identify genetic regulators of free ratty acid (FFA) levels during OGTT:
    a. We perform fine mapping of the loci we already have replicated with p<5x10 -8 to be associated with 2-hour FFA levels;
    b. We perform functional in vivo and in vitro characterization of the causal variants identified in a.

References

1. Kathiresan S, Melander O, Guiducci C, Surti A, Burtt NP, Cooper GM, Roos C, Voight BF, Havilunna AS, Hedner T, Berglund G, Vartianen E, Jousilahti P, Hedblad B, Newton-Cheh C, Salomaa V, Peltonen L, Groop L, Altshuler DM, Orho-Melander M: Six new loci associated wigh blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triclycerides in humans, Nat Genet 40:189-97, 2008

2. Diabetes Genetics Initiative Consortium: Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316, 1331-6 (2007) (Orho-Melander M is a coauthor of DGI Consortium)

3. Kathiresan S, Willer C, Peloso G, Demissie S, Musunuru K, Schadt E, Kaplan L, Bonnycastle L, Jackson A, Crawford G, Surti A, Guiducci C, Burtt N, Yang O, Lunetta K, Dupuis J, deBakker PI, O´Donnell CJ, Groop L, Altshuler D, Melander O, Salomaa V, Peltonen L, Orho-Melander M, Ordovas J, Boehnke M, Abecasis G, Mohlke K, L. Adrienne Cupples: Common DNA Sequence Variants at Thirty Genetic Loci Contribute to Polygenic Dyslipidemia, Nature Genet 41:56-65, 2009

4. Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, Pirruccello JP, Ripatti S, Chasman DI, Willer CJ, Johansen CT, Fouchier SW, Isaacs A, Peloso GM, Barbalic M, Ricketts SL, Bis JC, Aulchenko YS, Thorleifsson G, Feitosa MF, Chambers J, Orho-Melander M et al.: Biological, Clinical and Population Relevance of 95 Loci mapped for Serum Lipid Concentrations. Nature 466:707-713, 2010

5. Sonestedt Em, Roos C, Gullberg B, Ericson U, Wirfält E and Orho-Melander M: Fat and carbohydrate intake modify the association between genetic variation in FTO and obesity. Am J Clin Nutr 90:1418-, 2009

6. Sonestedt E, Gullberg G, Ericson U, Wirfält E, Hedblad B, Orho-Melander M: Association between fat intake, physical activity and mortality depending on genetic variation in FTO. Int J Obe 35;1041-9,2011

 

7. Orho-Melander M, Melander O, Guiducci C, Perez-Martinez P, Corella C, Roos C, Rieder MJ, Abecasis G, Tai ES, Arnett DK, Lyssenko V, Lindholm E, Saxena R, de Bakker P, Burtt N, Voight B, Hirschorn JN, Tucker KL, Hedner T, Tuomi T, Isomaa B, Eriksson K-F, Taskinen M-R, Hughes TE, Parnell LD, Lai C-Q, Peltonen L, Vartiainen L, Jousilahti P, Havulinna AS, Salomaa V, Groop L, Altshuler D, Ordovas JM & kathiresan S. A common missense variant in the glucokinase regulatory protein (GCKR) gene is associated wigh increased plasma triglyceride but lower fasting glucose levels. Diabetes, 57:3112-21, 2008.

8. Beer NL, Tribble ND, McCulloch LJ, Roos C, Johnson PR, Orho-Melander M, Gloyn AL: The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. Hum Mol Genet, 18:4081-8, 2009

9. Musunuru K, Strong A, Frank-Kamenetsky M, Wong J, Cantley W, Li H, Ejebe KG, Schadt EE, Orho-Melander M, Melander O, Cowan CA, Koteliansky V, Fitzgerald K, Krauss RM, Kathiresan S, Rader DJ: From DNA Sequence variant to liporotein phenotype at a novel cholesterol and myocardial infarction locus. Nature 466:714-719, 2010

10 selected recent publiactions

1. Sonestedt E, Wirfält E, Wallström P, Gullberg B, Drake I, Hlebowicz J, Nordin Fredriksson G, Hedblad B, Nilsson J, Krauss RM, Orho-Melander M: High disaccaride intake associates with atherogenic lipoprotein profile. Br J Nutr. Oct 20:1-8, 2011

2. Voight BR, Peloso GM, Schunkert H, Samani NJ, Orho-Melander M, Frikke-Schmidt R, Barbalic M, Jensen MK, Hindy G, Thompson JF, Li M, Thorleifsson G, Newton-Cheh C, Musunuru K, Stefansson K, Thorsteinsdottir U, Hólm H, Thorgeirsson G, Anand S, Engert JC, Morgan T, Spertus J, Stoll M, Berger K, Martinelli N, Girelli D, McKeown PP, Patterson CC, Epstein SE, Bakker J, Demissie S, Willer C, Ordovas JM, Abecasis GR, Boehnke M, Mohlke D, Daly MJ, Guiducci C, Burtt NP, Surti A, Gonzalez E, Purcelli S, Gabriel S, Erdmann J, Willenborg C, König IR, Ziegler A, Hall AS, Marrugat J, Overvad K, Rimm E, Boerwinkle E, Tybjaerg Hansen A, Cupples LA, Reilly MP, Melander O, Mannucci PM, Ardissino D, Siscovick D, Elosua R, O´Donnell CJ, Salomaa V, Rader DJ, Peltonen L, Schwartz SM, Altshuler D, Kathiresan S for the Myocardial Infarction Genetics Consortium: A Mendelian randomization study for plasma high-density lipoprotein cholesterol and risk for myocardial infarction. Lancet in press 2011

3. Sonestedt E, Gullberg G, Ericson U, Wirfält E, Hedblad B, Orho-Melander M: Association between fat intake, physical activity and mortality depending on genetic variation in FTO. Int J Obe 35;1041-9,2010

4. Ripatti S, Tikkanen E, Orho-Melander M, Havulinna AS, Silander K, Sharma A, Guiducci C, Gonzalez E, Perola M, Jula A, Sinisalo J, Lokki M, Nieminen MS, Melander O, Salomaa V, peltonen L, Kathiresan S: A multilocus genetic risk score and risk for incident coronary heart disease. Lancet 376 (9750): 1393-400, 2010

5. Musunuru K, Strong A, Frank-Kamenetsky M, Wong J, Cantley W, Li H, Ejebe KG, Schadt EE, Orho-Melander M, Melander O, Cowan CA, Koteliansky V, Fitzgerald K, Krauss RM, Kathiresan S, Rader DJ: From DNA sequence variant to lipoprotein phenotype at a novel cholesterol and myocardial infarction locus. Nature 466:714-719, 2010

6.  

6. Sonestedt E, Roos C, Gullberg B, Ericson U, Wirfält E and Orho-Melander M: Fat and carbohydrate intake modify the association between genetic variation in FTO and obesity. Am J Clin Nutr 90:1418-1425,2009

7. Musunuru K*, Orho-Melander M*, Caulfield MP, Li S, Salameh WA, Reitz RE, Berglund G, Hedblad B, Engström G, Williamsn PT, Kathiresan S, Melander O, Krauss RM: Ion mobility analysis of lipoprotein subfractions identifies three independent axes of cardiovascular risk. Arteriosc Thromb Vasc Biol, 29:1975.80,2009

8. Orho-Melander M, Melander O, Guiducci C, Perez-Martinez P, Corelia C, Roos C, Rieder MJ, Abecasis G, Tai ES, Arnett DK, Lyssenko V, Lindholm E, Saxena R, de Bakker P, Burtt N, Voight B, Hirschorn JN, Tucker KL, Hedner T, Tuomi T, Isomaa B, Eriksson K-F, Taskinen M-R, Hughes TE, Parnell LD, Lai C-Q, peltonen L, Vartiainen L, Jousilahti P, Havulinna AS, Salomaa V, Groop L, Altshuler D, Ordovas JM & Kathiresan S. A common missense variant in the glucokinase regulatory protein (GCKR) gene is associated with increased plasma triglyceride but lower fasting glucose levels. Diabetes, 57:3112-21,2008

9. Kathiresan S, Melander O, Roos C, Guiducci C, Burtt N, Anevski D, Hirschhorn J, Berglund G, Hedblad B, Groop L, Altshuler D, Newton Cheh C, Orho-Melander M: Polymorphisms associated with cholesterol and risk of cardiovascular events. N Engl J Med 358:1240-9,2008

10. Kathiresan S, Melander O, Guiducci C, Surti A, Burtt NP, Rieder MJ, Cooper GM, Roos C, Voight BF, Havilunna AS, Hedner T, Berglund G, Vartianen E, Jousilahti P, Hedblad B, Newton-Chec C, Salomaa V, Peltonen L, Groop L, Altshuler DM, Orho-Melander M: Six new loci associated in humans, Nat Genet 40:189-97,2008

Last updated: January 18, 2012
Website contact: LUDC webteam

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