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Vol. 75, No. 1, 2013
Issue release date: May 2013
Free Access
Hum Hered 2013;75:34-43
(DOI:10.1159/000346195)

Genetic Variation at NCAN Locus Is Associated with Inflammation and Fibrosis in Non-Alcoholic Fatty Liver Disease in Morbid Obesity

Gorden A.a, c · Yang R.b, c · Yerges-Armstrong L.M.b, c · Ryan K.A.b, c · Speliotes E.d · Borecki I.B.e · Harris T.B.f · Chu X.g · Wood G.C.g · Still C.D.g · Shuldiner A.R.b,c,h · Gerhard G.S.g · the GOLD Consortium1
Divisions of aGastroenterology and bEndocrinology, Diabetes and Nutrition, and cProgram in Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Md., dUniversity of Michigan School of Medicine, Ann Arbor, Mich., eDivision of Statistical Genomics, Washington University School of Medicine, St. Louis, Mo., fLaboratory of Epidemiology, Demography and Biometry, National Institute on Aging, National Institutes of Health, Bethesda, Md., gGeisinger Clinic Obesity Institute, Danville, Pa., and hGeriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, Md., USA
email Corresponding Author

Abstract

Objective: Obesity-associated non-alcoholic fatty liver disease (NAFLD) may cause liver dysfunction and failure. In a previously reported genome-wide association meta-analysis, single nucleotide polymorphisms (SNPs) near PNPLA3, NCAN, GCKR, LYPLAL1 and PPP1R3B were associated with NAFLD and with distinctive serum lipid profiles. The present study examined the relevance of these variants to NAFLD in extreme obesity. Methods: In 1,092 bariatric surgery patients, the candidate SNPs were genotyped and association analyses with liver histology and serum lipids were performed. Results: We replicated the association of hepatosteatosis with PNPLA3 rs738409[G] and with NCAN rs2228603[T]. We also replicated the association of rs2228603[T] with hepatic inflammation and fibrosis. rs2228603[T] was associated with lower serum low-density lipoprotein, total cholesterol and triglycerides. After stratification by the presence or absence of NAFLD, these associations were present predominantly in the subgroup with NAFLD. Conclusion:NCAN rs2228603[T] is a risk factor for liver inflammation and fibrosis, suggesting that this locus is responsible for progression from steatosis to steatohepatitis. In this bariatric cohort, rs2228603[T] was associated with low serum lipids only in patients with NAFLD. This supports a NAFLD model in which the liver may sequester triglycerides as a result of either increased triglyceride uptake and/or decreased lipolysis.


 goto top of outline Key Words


  • Obesity
  • Dyslipidemia
  • Steatohepatitis
  • Cirrhosis
  • Steatosis


 goto top of outline Abstract

Objective: Obesity-associated non-alcoholic fatty liver disease (NAFLD) may cause liver dysfunction and failure. In a previously reported genome-wide association meta-analysis, single nucleotide polymorphisms (SNPs) near PNPLA3, NCAN, GCKR, LYPLAL1 and PPP1R3B were associated with NAFLD and with distinctive serum lipid profiles. The present study examined the relevance of these variants to NAFLD in extreme obesity. Methods: In 1,092 bariatric surgery patients, the candidate SNPs were genotyped and association analyses with liver histology and serum lipids were performed. Results: We replicated the association of hepatosteatosis with PNPLA3 rs738409[G] and with NCAN rs2228603[T]. We also replicated the association of rs2228603[T] with hepatic inflammation and fibrosis. rs2228603[T] was associated with lower serum low-density lipoprotein, total cholesterol and triglycerides. After stratification by the presence or absence of NAFLD, these associations were present predominantly in the subgroup with NAFLD. Conclusion:NCAN rs2228603[T] is a risk factor for liver inflammation and fibrosis, suggesting that this locus is responsible for progression from steatosis to steatohepatitis. In this bariatric cohort, rs2228603[T] was associated with low serum lipids only in patients with NAFLD. This supports a NAFLD model in which the liver may sequester triglycerides as a result of either increased triglyceride uptake and/or decreased lipolysis.

Copyright © 2013 S. Karger AG, Basel


 goto top of outline References
  1. Eckel RH, Alberti KG, Grundy SM, Zimmet PZ: The metabolic syndrome. Lancet 2010;375:181-183.
  2. Argo CK, Caldwell SH: Epidemiology and natural history of non-alcoholic steatohepatitis. Clin Liver Dis 2009;13:511-513.
  3. Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH: Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. J Hepatol 2009;51:371-379.
  4. Bellentani S, Saccoccio G, Masutti F, Crocè LS, Brandi G, Sasso F, Cristanini G, Tiribelli C: Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med 2000;132:112-117.
  5. Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, Grundy SM, Hobbs HH: Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004;40:1387-1395.
  6. Rinella ME, Alonso E, Rao S, Whitington P, Fryer J, Abecassis M, Superina R, Flamm SL, Blei AT: Body mass index as a predictor of hepatic steatosis in living liver donors. Liver Transpl 2001;7:409-414.
  7. Stranges S, Dorn JM, Muti P, Freudenheim JL, Farinaro E, Russell M, Nochajski TH, Trevisan M: Body fat distribution, relative weight, and liver enzyme levels: a population-based study. Hepatology 2004;39:754-763.
  8. Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, Boerwinkle E, Cohen JC, Hobbs HH: Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008;40:1461-1465.
  9. Romeo S, Sentinelli F, Dash S, Yeo GS, Savage DB, Leonetti F, Capoccia D, Incani M, Maglio C, Iacovino M, OʼRahilly S, Baroni MG: Morbid obesity exposes the association between PNPLA3 I148M (rs738409) and indices of hepatic injury in individuals of European descent. Int J Obes (Lond) 2010;34:190-194.
  10. Speliotes EK, Butler JL, Palmer CD, Voight BF, GIANT Consortium, MIGen Consortium, NASH CRN, Hirschhorn JN: PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease. Hepatology 2010;52:904-912.
  11. Speliotes EK, Yerges-Armstrong LM, Wu J, Hernaez R, Kim LJ, Palmer CD, et al: Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet 2011;7:e1001324.
  12. Wood GC, Chu X, Manney C, Strodel W, Petrick A, Gabrielsen J, Seiler J, Carey D, Argyropoulos G, Benotti P, Still CD, Gerhard GS: An electronic health record-enabled obesity database. BMC Med Inform Decis Mak 2012;12:45.
  13. Gerhard GS, Chokshi R, Still CD, Benotti P, Wood GC, Freedman-Weiss M, Rider C, Petrick AT: The influence of iron status and genetic polymorphisms in the HFE gene on the risk for postoperative complications after bariatric surgery: a prospective cohort study in 1,064 patients. Patient Saf Surg 2011;5:1.
  14. Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR: Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol 1999;94:2467-2474.
  15. Still CD, Wood GC, Chu X, Erdman R, Manney CH, Benotti PN, Petrick AT, Strodel WE, Mirshahi UL, Mirshahi T, Carey DJ, Gerhard GS: High allelic burden of four obesity SNPs is associated with poorer weight loss outcomes following gastric bypass surgery. Obesity (Silver Spring). 2011;19:1676-1683.
  16. Christou N, Efthimiou E: Five-year outcomes of laparoscopic adjustable gastric banding and laparoscopic roux-en-Y gastric bypass in a comprehensive bariatric surgery program in Canada. Can J Surg 2009;52:E249-E258.

    External Resources

  17. Jakobsen GS, Hofso D, Roislien J, Sandbu R, Hjelmesaeth J: Morbidly obese patients - who undergoes bariatric surgery? Obes Surg 2010;20:1142-1148.
  18. LABS Writing Group for the LABS Consortium; Belle SH, Chapman W, Courcoulas AP, Flum DR, Gagner M, et al: Relationship of body mass index with demographic and clinical characteristics in the longitudinal assessment of bariatric surgery (LABS). Surg Obes Relat Dis 2008;4:474-480.
  19. Chatrath H, Vuppalanchi R, Chalasani N: Dyslipidemia in patients with nonalcoholic fatty liver disease. Semin Liver Dis 2012;32:22-29.
  20. Sookoian S, Castano GO, Burgueno AL, Gianotti TF, Rosselli MS, Pirola CJ: A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity. J Lipid Res 2009;50:2111-2116.
  21. Sookoian S, Pirola CJ: Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology 2011;53:1883-1894.
  22. Valenti L, Al-Serri A, Daly AK, Galmozzi E, Rametta R, Dongiovanni P, et al: Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 2010;51:1209-1217.
  23. Krarup NT, Grarup N, Banasik K, Friedrichsen M, Færch K, Sandholt CH, Jørgensen T, Poulsen P, Witte DR, Vaag A, Sørensen T, Pedersen O, Hansen T: The PNPLA3 rs738409 G-allele associates with reduced fasting serum triglyceride and serum cholesterol in Danes with impaired glucose regulation. PLoS One 2012;7:e40376.
  24. Palmer CN, Maglio C, Pirazzi C, Burza MA, Adiels M, Burch L, et al: Paradoxical lower serum triglyceride levels and higher type 2 diabetes mellitus susceptibility in obese individuals with the PNPLA3 148M variant. PLoS One 2012;7:e39362.
  25. Bi M, Kao WH, Boerwinkle E, Hoogeveen RC, Rasmussen-Torvik LJ, Astor BC, North KE, Coresh J, Köttgen A: Association of rs780094 in GCKR with metabolic traits and incident diabetes and cardiovascular disease: the ARIC study. PLoS One 2010;5:e11690.
  26. Onuma H, Tabara Y, Kawamoto R, Shimizu I, Kawamura R, Takata Y, Nishida W, Ohashi J, Miki T, Kohara K, Makino H, Osawa H: The GCKR rs780094 polymorphism is associated with susceptibility of type 2 diabetes, reduced fasting plasma glucose levels, increased triglycerides levels and lower HOMA-IR in Japanese population. J Hum Genet 2010;55:600-604.
  27. Pollin TI, Jablonski KA, McAteer JB, Saxena R, Kathiresan S, Kahn SE, Goldberg RB, Altshuler D, Florez JC, Diabetes Prevention Program Research Group: Triglyceride response to an intensive lifestyle intervention is enhanced in carriers of the GCKR Pro446Leu polymorphism. J Clin Endocrinol Metab 2011;96:E1142-E1147.
  28. Kathiresan S, Melander O, Guiducci C, Surti A, Burtt NP, Rieder MJ, et al: Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet 2008;40:189-197.
  29. Willer CJ, Sanna S, Jackson AU, Scuteri A, Bonnycastle LL, Clarke R, et al: Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 2008;40:161-169.
  30. Zhou L, Ding H, Zhang X, He M, Huang S, Xu Y, Shi Y, Cui G, Cheng L, Wang QK, Hu FB, Wang D, Wu T: Genetic variants at newly identified lipid loci are associated with coronary heart disease in a Chinese Han population. PLoS One 2011;6:e27481.
  31. Rauch U, Feng K, Zhou XH: Neurocan: a brain chondroitin sulfate proteoglycan. Cell Mol Life Sci 2001;58:1842-1856.
  32. Retzler C, Gohring W, Rauch U: Analysis of neurocan structures interacting with the neural cell adhesion molecule N-CAM. J Biol Chem 1996;271:27304-27310.
  33. Friedlander DR, Milev P, Karthikeyan L, Margolis RK, Margolis RU, Grumet M: The neuronal chondroitin sulfate proteoglycan neurocan binds to the neural cell adhesion molecules ng-CAM/L1/NILE and N-CAM, and inhibits neuronal adhesion and neurite outgrowth. J Cell Biol 1994;125:669-680.
  34. Grumet M, Milev P, Sakurai T, Karthikeyan L, Bourdon M, Margolis RK, Margolis RU: Interactions with tenascin and differential effects on cell adhesion of neurocan and phosphacan, two major chondroitin sulfate proteoglycans of nervous tissue. J Biol Chem 1994;269:12142-12146.
  35. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR: A method and server for predicting damaging missense mutations. Nat Methods 2010;7:248-249.
  36. Lam TK, Gutierrez-Juarez R, Pocai A, Bhanot S, Tso P, Schwartz GJ, Rossetti L: Brain glucose metabolism controls the hepatic secretion of triglyceride-rich lipoproteins. Nat Med 2007;13:171-180.
  37. Nogueiras R, Wiedmer P, Perez-Tilve D, Veyrat-Durebex C, Keogh JM, Sutton GM, et al: The central melanocortin system directly controls peripheral lipid metabolism. J Clin Invest 2007;117:3475-3488.
  38. van den Hoek AM, Voshol PJ, Karnekamp BN, Buijs RM, Romijn JA, Havekes LM, Pijl H: Intracerebroventricular neuropeptide Y infusion precludes inhibition of glucose and VLDL production by insulin. Diabetes 2004;53:2529-2534.
  39. Powley TL: Vagal circuitry mediating cephalic-phase responses to food. Appetite 2000;34:184-188.
  40. Bruinstroop E, Pei L, Ackermans MT, Foppen E, Borgers AJ, Kwakkel J, Alkemade A, Fliers E, Kalsbeek A: Hypothalamic neuropeptide Y (NPY) controls hepatic VLDL-triglyceride secretion in rats via the sympathetic nervous system. Diabetes 2012;61:1043-1050.
  41. Robertson MD, Mason AO, Frayn KN: Timing of vagal stimulation affects postprandial lipid metabolism in humans. Am J Clin Nutr 2002;76:71-77.
  42. Cohn JS, Wagner DA, Cohn SD, Millar JS, Schaefer EJ: Measurement of very low density and low density lipoprotein apolipoprotein (apo) B-100 and high density lipoprotein apo A-I production in human subjects using deuterated leucine. Effect of fasting and feeding. J Clin Invest 1990;85:804-811.
  43. Stafford JM, Yu F, Printz R, Hasty AH, Swift LL, Niswender KD: Central nervous system neuropeptide Y signaling modulates VLDL triglyceride secretion. Diabetes 2008;57:1482-1490.

 goto top of outline Author Contacts

Glenn S. Gerhard, MD
Department of Biochemistry and Molecular Biology, Institute for Personalized Medicine
Pennsylvania State University College of Medicine
Hershey, PA 17033 (USA)
E-mail ggerhard@hmc.psu.edu


 goto top of outline Article Information

Received: August 21, 2012
Accepted after revision: November 27, 2012
Published online: April 10, 2013
Number of Print Pages : 10
Number of Figures : 5, Number of Tables : 3, Number of References : 43
Additional supplementary material is available online - Number of Parts : 1


 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 75, No. 1, Year 2013 (Cover Date: May 2013)

Journal Editor: Clerget-Darpoux F. (Paris)
ISSN: 0001-5652 (Print), eISSN: 1423-0062 (Online)

For additional information: http://www.karger.com/HHE


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Objective: Obesity-associated non-alcoholic fatty liver disease (NAFLD) may cause liver dysfunction and failure. In a previously reported genome-wide association meta-analysis, single nucleotide polymorphisms (SNPs) near PNPLA3, NCAN, GCKR, LYPLAL1 and PPP1R3B were associated with NAFLD and with distinctive serum lipid profiles. The present study examined the relevance of these variants to NAFLD in extreme obesity. Methods: In 1,092 bariatric surgery patients, the candidate SNPs were genotyped and association analyses with liver histology and serum lipids were performed. Results: We replicated the association of hepatosteatosis with PNPLA3 rs738409[G] and with NCAN rs2228603[T]. We also replicated the association of rs2228603[T] with hepatic inflammation and fibrosis. rs2228603[T] was associated with lower serum low-density lipoprotein, total cholesterol and triglycerides. After stratification by the presence or absence of NAFLD, these associations were present predominantly in the subgroup with NAFLD. Conclusion:NCAN rs2228603[T] is a risk factor for liver inflammation and fibrosis, suggesting that this locus is responsible for progression from steatosis to steatohepatitis. In this bariatric cohort, rs2228603[T] was associated with low serum lipids only in patients with NAFLD. This supports a NAFLD model in which the liver may sequester triglycerides as a result of either increased triglyceride uptake and/or decreased lipolysis.



 goto top of outline Author Contacts

Glenn S. Gerhard, MD
Department of Biochemistry and Molecular Biology, Institute for Personalized Medicine
Pennsylvania State University College of Medicine
Hershey, PA 17033 (USA)
E-mail ggerhard@hmc.psu.edu


 goto top of outline Article Information

Received: August 21, 2012
Accepted after revision: November 27, 2012
Published online: April 10, 2013
Number of Print Pages : 10
Number of Figures : 5, Number of Tables : 3, Number of References : 43
Additional supplementary material is available online - Number of Parts : 1


 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 75, No. 1, Year 2013 (Cover Date: May 2013)

Journal Editor: Clerget-Darpoux F. (Paris)
ISSN: 0001-5652 (Print), eISSN: 1423-0062 (Online)

For additional information: http://www.karger.com/HHE


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Eckel RH, Alberti KG, Grundy SM, Zimmet PZ: The metabolic syndrome. Lancet 2010;375:181-183.
  2. Argo CK, Caldwell SH: Epidemiology and natural history of non-alcoholic steatohepatitis. Clin Liver Dis 2009;13:511-513.
  3. Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH: Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. J Hepatol 2009;51:371-379.
  4. Bellentani S, Saccoccio G, Masutti F, Crocè LS, Brandi G, Sasso F, Cristanini G, Tiribelli C: Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med 2000;132:112-117.
  5. Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, Grundy SM, Hobbs HH: Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004;40:1387-1395.
  6. Rinella ME, Alonso E, Rao S, Whitington P, Fryer J, Abecassis M, Superina R, Flamm SL, Blei AT: Body mass index as a predictor of hepatic steatosis in living liver donors. Liver Transpl 2001;7:409-414.
  7. Stranges S, Dorn JM, Muti P, Freudenheim JL, Farinaro E, Russell M, Nochajski TH, Trevisan M: Body fat distribution, relative weight, and liver enzyme levels: a population-based study. Hepatology 2004;39:754-763.
  8. Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, Boerwinkle E, Cohen JC, Hobbs HH: Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008;40:1461-1465.
  9. Romeo S, Sentinelli F, Dash S, Yeo GS, Savage DB, Leonetti F, Capoccia D, Incani M, Maglio C, Iacovino M, OʼRahilly S, Baroni MG: Morbid obesity exposes the association between PNPLA3 I148M (rs738409) and indices of hepatic injury in individuals of European descent. Int J Obes (Lond) 2010;34:190-194.
  10. Speliotes EK, Butler JL, Palmer CD, Voight BF, GIANT Consortium, MIGen Consortium, NASH CRN, Hirschhorn JN: PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease. Hepatology 2010;52:904-912.
  11. Speliotes EK, Yerges-Armstrong LM, Wu J, Hernaez R, Kim LJ, Palmer CD, et al: Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet 2011;7:e1001324.
  12. Wood GC, Chu X, Manney C, Strodel W, Petrick A, Gabrielsen J, Seiler J, Carey D, Argyropoulos G, Benotti P, Still CD, Gerhard GS: An electronic health record-enabled obesity database. BMC Med Inform Decis Mak 2012;12:45.
  13. Gerhard GS, Chokshi R, Still CD, Benotti P, Wood GC, Freedman-Weiss M, Rider C, Petrick AT: The influence of iron status and genetic polymorphisms in the HFE gene on the risk for postoperative complications after bariatric surgery: a prospective cohort study in 1,064 patients. Patient Saf Surg 2011;5:1.
  14. Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR: Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol 1999;94:2467-2474.
  15. Still CD, Wood GC, Chu X, Erdman R, Manney CH, Benotti PN, Petrick AT, Strodel WE, Mirshahi UL, Mirshahi T, Carey DJ, Gerhard GS: High allelic burden of four obesity SNPs is associated with poorer weight loss outcomes following gastric bypass surgery. Obesity (Silver Spring). 2011;19:1676-1683.
  16. Christou N, Efthimiou E: Five-year outcomes of laparoscopic adjustable gastric banding and laparoscopic roux-en-Y gastric bypass in a comprehensive bariatric surgery program in Canada. Can J Surg 2009;52:E249-E258.

    External Resources

  17. Jakobsen GS, Hofso D, Roislien J, Sandbu R, Hjelmesaeth J: Morbidly obese patients - who undergoes bariatric surgery? Obes Surg 2010;20:1142-1148.
  18. LABS Writing Group for the LABS Consortium; Belle SH, Chapman W, Courcoulas AP, Flum DR, Gagner M, et al: Relationship of body mass index with demographic and clinical characteristics in the longitudinal assessment of bariatric surgery (LABS). Surg Obes Relat Dis 2008;4:474-480.
  19. Chatrath H, Vuppalanchi R, Chalasani N: Dyslipidemia in patients with nonalcoholic fatty liver disease. Semin Liver Dis 2012;32:22-29.
  20. Sookoian S, Castano GO, Burgueno AL, Gianotti TF, Rosselli MS, Pirola CJ: A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity. J Lipid Res 2009;50:2111-2116.
  21. Sookoian S, Pirola CJ: Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology 2011;53:1883-1894.
  22. Valenti L, Al-Serri A, Daly AK, Galmozzi E, Rametta R, Dongiovanni P, et al: Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 2010;51:1209-1217.
  23. Krarup NT, Grarup N, Banasik K, Friedrichsen M, Færch K, Sandholt CH, Jørgensen T, Poulsen P, Witte DR, Vaag A, Sørensen T, Pedersen O, Hansen T: The PNPLA3 rs738409 G-allele associates with reduced fasting serum triglyceride and serum cholesterol in Danes with impaired glucose regulation. PLoS One 2012;7:e40376.
  24. Palmer CN, Maglio C, Pirazzi C, Burza MA, Adiels M, Burch L, et al: Paradoxical lower serum triglyceride levels and higher type 2 diabetes mellitus susceptibility in obese individuals with the PNPLA3 148M variant. PLoS One 2012;7:e39362.
  25. Bi M, Kao WH, Boerwinkle E, Hoogeveen RC, Rasmussen-Torvik LJ, Astor BC, North KE, Coresh J, Köttgen A: Association of rs780094 in GCKR with metabolic traits and incident diabetes and cardiovascular disease: the ARIC study. PLoS One 2010;5:e11690.
  26. Onuma H, Tabara Y, Kawamoto R, Shimizu I, Kawamura R, Takata Y, Nishida W, Ohashi J, Miki T, Kohara K, Makino H, Osawa H: The GCKR rs780094 polymorphism is associated with susceptibility of type 2 diabetes, reduced fasting plasma glucose levels, increased triglycerides levels and lower HOMA-IR in Japanese population. J Hum Genet 2010;55:600-604.
  27. Pollin TI, Jablonski KA, McAteer JB, Saxena R, Kathiresan S, Kahn SE, Goldberg RB, Altshuler D, Florez JC, Diabetes Prevention Program Research Group: Triglyceride response to an intensive lifestyle intervention is enhanced in carriers of the GCKR Pro446Leu polymorphism. J Clin Endocrinol Metab 2011;96:E1142-E1147.
  28. Kathiresan S, Melander O, Guiducci C, Surti A, Burtt NP, Rieder MJ, et al: Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet 2008;40:189-197.
  29. Willer CJ, Sanna S, Jackson AU, Scuteri A, Bonnycastle LL, Clarke R, et al: Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 2008;40:161-169.
  30. Zhou L, Ding H, Zhang X, He M, Huang S, Xu Y, Shi Y, Cui G, Cheng L, Wang QK, Hu FB, Wang D, Wu T: Genetic variants at newly identified lipid loci are associated with coronary heart disease in a Chinese Han population. PLoS One 2011;6:e27481.
  31. Rauch U, Feng K, Zhou XH: Neurocan: a brain chondroitin sulfate proteoglycan. Cell Mol Life Sci 2001;58:1842-1856.
  32. Retzler C, Gohring W, Rauch U: Analysis of neurocan structures interacting with the neural cell adhesion molecule N-CAM. J Biol Chem 1996;271:27304-27310.
  33. Friedlander DR, Milev P, Karthikeyan L, Margolis RK, Margolis RU, Grumet M: The neuronal chondroitin sulfate proteoglycan neurocan binds to the neural cell adhesion molecules ng-CAM/L1/NILE and N-CAM, and inhibits neuronal adhesion and neurite outgrowth. J Cell Biol 1994;125:669-680.
  34. Grumet M, Milev P, Sakurai T, Karthikeyan L, Bourdon M, Margolis RK, Margolis RU: Interactions with tenascin and differential effects on cell adhesion of neurocan and phosphacan, two major chondroitin sulfate proteoglycans of nervous tissue. J Biol Chem 1994;269:12142-12146.
  35. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR: A method and server for predicting damaging missense mutations. Nat Methods 2010;7:248-249.
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