Journal of Diabetes and Obesity

A genome-wide association study (GWAS) and subsequent replication studies in diverse ethnic groups indicate that common Niemann-Pick C1 gene (NPC1) polymorphisms are associated with morbid-adult obesity or diabetes independent of body weight. The objectives for this prospective cross-sectional study were to determine allele frequencies for NPC1 polymorphisms (644A>G, 1926C>G, 2572A>G, and 3797G>A) and association with metabolic disease phenotypes in an ethnically diverse New Mexican obstetric population. Allele frequencies for 1926C>G, 2572A>G, and 3797G>A were significantly different between race/ ethnic groups (non-Hispanic white, Hispanic, and Native American). The results also indicated a significant pairwise linkage-disequilibrium between each of the four NPC1 polymorphisms in race/ethnic groups. Moreover, the derived and major allele for 1926C>G was associated (OR 2.11, 95% CI 1.10-3.96, P = 0.022) with increased risk for maternal prepregnancy overweight (BMI 25.0-29.9kg/m2) while the ancestral and major allele for 2572A>G was associated (OR 4.68, 95% CI 1.23-17.8, P = 0.024) with increased risk for gestational diabetes in non-Hispanic whites, but not Hispanics or Native Americans. In summary, this is the first transferability study to investigate common NPC1 polymorphisms in a multiethnic population and demonstrate a differential association with increased risk for maternal prepregnancy overweight and gestational diabetes. *Corresponding Author: William S. Garver, Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA; Tel: 1-505-272-4790; Fax: 1-505-2726587; E-Mail: wgarver@unm.edu

[1]  Yvonne W. Cheng,et al.  Racial disparities in pregnancy outcomes in obese women , 2014, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[2]  David Jelínek,et al.  The C57BL/6J Niemann-Pick C1 mouse model with decreased gene dosage has impaired glucose tolerance independent of body weight. , 2013, Gene.

[3]  Yingchang Lu,et al.  Obesity genomics: assessing the transferability of susceptibility loci across diverse populations , 2013, Genome Medicine.

[4]  D. Meyre,et al.  Analysis of the contribution of FTO, NPC1, ENPP1, NEGR1, GNPDA2 and MC4R genes to obesity in Mexican children , 2013, BMC Medical Genetics.

[5]  M. Clerici,et al.  Mammalian NPC1 genes may undergo positive selection and human polymorphisms associate with type 2 diabetes , 2012, BMC Medicine.

[6]  L. Grummer-Strawn,et al.  Prepregnancy Obesity Trends Among Low-Income Women, United States, 1999–2008 , 2012, Maternal and Child Health Journal.

[7]  R. Heidenreich,et al.  The Niemann‐Pick C1 gene interacts with a high‐fat diet and modifying genes to promote weight gain , 2011, American journal of medical genetics. Part A.

[8]  R. Reynolds,et al.  The consequences of obesity and excess weight gain in pregnancy , 2011, Proceedings of the Nutrition Society.

[9]  K. Rooney,et al.  Maternal over-nutrition and offspring obesity predisposition: targets for preventative interventions , 2011, International Journal of Obesity.

[10]  R. Erickson,et al.  Decreased Npc1 Gene Dosage in Mice Is Associated With Weight Gain , 2010, Obesity.

[11]  G. Francis,et al.  The National Niemann-Pick Type C1 Disease Database: correlation of lipid profiles, mutations, and biochemical phenotypes , 2010, Journal of Lipid Research.

[12]  K. Flegal,et al.  Prevalence and trends in obesity among US adults, 1999-2008. , 2010, JAMA.

[13]  Barbara Heude,et al.  Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations , 2009, Nature Genetics.

[14]  Pardis C Sabeti,et al.  Genome-wide detection and characterization of positive selection in human populations , 2007, Nature.

[15]  G. Francis,et al.  The National Niemann–Pick C1 disease database: Report of clinical features and health problems , 2007, American journal of medical genetics. Part A.

[16]  R. Gordon,et al.  NPC1 late endosomes contain elevated levels of non-esterified ('free') fatty acids and an abnormally glycosylated form of the NPC2 protein. , 2005, The Biochemical journal.

[17]  C. Iturriaga,et al.  Identification of 25 new mutations in 40 unrelated Spanish Niemann‐Pick type C patients: genotype‐phenotype correlations , 2005, Clinical genetics.

[18]  J. Repa,et al.  Niemann-Pick C1 expression is not regulated by the amount of cholesterol flowing through cells in the mouse Published, JLR Papers in Press, June 1, 2005. DOI 10.1194/jlr.M500130-JLR200 , 2005, Journal of Lipid Research.

[19]  Yiannis A. Ioannou,et al.  Topological Analysis of Niemann-Pick C1 Protein Reveals That the Membrane Orientation of the Putative Sterol-sensing Domain Is Identical to Those of 3-Hydroxy-3-methylglutaryl-CoA Reductase and Sterol Regulatory Element Binding Protein Cleavage-activating Protein* , 2000, The Journal of Biological Chemistry.

[20]  R. Erickson,et al.  Localization of the murine Niemann-Pick C1 protein to two distinct intracellular compartments. , 2000, Journal of lipid research.

[21]  G. Millat,et al.  Niemann-Pick C1 disease: the I1061T substitution is a frequent mutant allele in patients of Western European descent and correlates with a classic juvenile phenotype. , 1999, American journal of human genetics.

[22]  J. Dietschy,et al.  Cholesterol balance and metabolism in mice with loss of function of Niemann-Pick C protein. , 1999, The American journal of physiology.

[23]  P. Froguel,et al.  From obesity genetics to the future of personalized obesity therapy , 2014, Nature Reviews Endocrinology.

[24]  B. Balkau,et al.  Contribution of 24 obesity-associated genetic variants to insulin resistance, pancreatic beta-cell function and type 2 diabetes risk in the French population , 2013, International Journal of Obesity.

[25]  ACOG Committee Opinion No. 470: Challenges for overweight and obese urban women. , 2010, Obstetrics and gynecology.

[26]  M. Beydoun,et al.  The obesity epidemic in the United States--gender, age, socioeconomic, racial/ethnic, and geographic characteristics: a systematic review and meta-regression analysis. , 2007, Epidemiologic reviews.

[27]  R. Gordon,et al.  NPC 1 late endosomes contain elevated levels of non-esterified ( ‘ free ’ ) fatty acids and an abnormally glycosylated form of the NPC 2 protein , 2005 .