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Polymorphisms Near EXOC4 and LRGUK on Chromosome 7Q32 Are Associated with Type 2 Diabetes and Fasting Glucose; the NHLBI Family Heart Study Jason M

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Polymorphisms Near EXOC4 and LRGUK on Chromosome 7Q32 Are Associated with Type 2 Diabetes and Fasting Glucose; the NHLBI Family Heart Study Jason M Washington University School of Medicine Digital Commons@Becker Open Access Publications 2008 Polymorphisms near EXOC4 and LRGUK on chromosome 7q32 are associated with Type 2 Diabetes and fasting glucose; The NHLBI Family Heart Study Jason M. Laramie Boston University Jemma B. Wilk Boston University Sally L. Williamson Boston University Michael W. Nagle Boston University Jeanne C. Latourelle Boston University See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Part of the Medicine and Health Sciences Commons Recommended Citation Laramie, Jason M.; Wilk, Jemma B.; Williamson, Sally L.; Nagle, Michael W.; Latourelle, Jeanne C.; Tobin, Jennifer E.; Province, Michael A.; Borecki, Ingrid B.; and Myers, Richard H., ,"Polymorphisms near EXOC4 and LRGUK on chromosome 7q32 are associated with Type 2 Diabetes and fasting glucose; The NHLBI Family Heart Study." BMC Medical Genetics.,. 46. (2008). https://digitalcommons.wustl.edu/open_access_pubs/269 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. Authors Jason M. Laramie, Jemma B. Wilk, Sally L. Williamson, Michael W. Nagle, Jeanne C. Latourelle, Jennifer E. Tobin, Michael A. Province, Ingrid B. Borecki, and Richard H. Myers This open access publication is available at Digital Commons@Becker: https://digitalcommons.wustl.edu/open_access_pubs/269 BMC Medical Genetics BioMed Central Research article Open Access Polymorphisms near EXOC4 and LRGUK on chromosome 7q32 are associated with Type 2 Diabetes and fasting glucose; The NHLBI Family Heart Study Jason M Laramie*†1,2, JemmaBWilk†1,3, Sally L Williamson1, Michael W Nagle1, Jeanne C Latourelle1, Jennifer E Tobin1,4, Michael A Province5, Ingrid B Borecki5 and Richard H Myers1,2,3 Address: 1Department of Neurology, Boston University School of Medicine, Boston, MA, USA, 2Bioinformatics Program, Boston University, Boston, MA, USA, 3The Section of Preventive Medicine and Epidemiology, Department of Medicine, Boston University School of Medicine, Boston, MA, USA, 4Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA, USA and 5Center for Human Genome Sciences, Washington University School of Medicine, St. Louis, MO, USA Email: Jason M Laramie* - [email protected]; Jemma B Wilk - [email protected]; Sally L Williamson - [email protected]; Michael W Nagle - [email protected]; Jeanne C Latourelle - [email protected]; Jennifer E Tobin - [email protected]; Michael A Province - [email protected]; Ingrid B Borecki - [email protected]; Richard H Myers - [email protected] * Corresponding author †Equal contributors Published: 22 May 2008 Received: 17 January 2008 Accepted: 22 May 2008 BMC Medical Genetics 2008, 9:46 doi:10.1186/1471-2350-9-46 This article is available from: http://www.biomedcentral.com/1471-2350/9/46 © 2008 Laramie et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: The chromosome 7q32 region is linked to metabolic syndrome and obesity related traits in the Family Heart Study. As part of a fine mapping study of the region, we evaluated the relationship of polymorphisms to fasting glucose levels and Type 2 diabetes. Methods: Thirty-nine HapMap defined tag SNPs in a 1.08 Mb region and a novel deletion polymorphism were genotyped in 2,603 participants of the NHLBI Family Heart Study (FHS). Regression modeling, adjusting for BMI, age, sex, smoking and the TCF7L2 polymorphism, was used to evaluate the association of these polymorphisms with T2D and fasting glucoses levels. Results: The deletion polymorphism confers a protective effect for T2D, with homozygous deletion carriers having a 53% reduced risk compared to non-deleted carriers. Among non- diabetics, the deletion was significantly associated with lower fasting glucose levels in men (p = 0.038) but not women (p = 0.118). In addition, seven SNPs near the deletion were significantly associated (p < 0.01) to diabetes. Conclusion: Chromosome 7q32 contains both SNPs and a deletion that were associated to T2D. Although the deletion region contains several islands of strongly conserved sequence, it is not known to contain a transcribed gene. The closest nearby gene, EXOC4, is involved in insulin- stimulated glucose transport and may be a candidate for this association. Further work is needed to determine if the deletion represents a functional variant or may be in linkage disequilibrium with a functional mutation influencing EXOC4 or another nearby gene. Page 1 of 9 (page number not for citation purposes) BMC Medical Genetics 2008, 9:46 http://www.biomedcentral.com/1471-2350/9/46 Background plasma glucose (FPG) was also examined among non-dia- Type 2 diabetes (T2D) is characterized by hyperglycemia betics. due to insulin resistance and is accompanied by a failure of β cells to produce sufficient insulin. In the United Methods States, the prevalence of diabetes has risen 40% from Subjects 1990 to 1999 [1]. This increase in T2D has been attributed The National Heart, Lung and Blood Institute (NHLBI) to the recent rise in obesity. The correlation between dia- Family Heart Study (FHS) recruited families from four betes and obesity has been shown in numerous epidemi- existing study centers located in Forsyth County, NC; ological studies [2,3] although the mechanisms Framingham, MA; Minneapolis, MN; and Salt Lake City, underlying this phenomenon are largely unknown. One UT. Approximately one half of the families recruited from current hypothesis proposes that malnutrition in the fetus these study centers were at high risk for coronary heart dis- can lead to the developmental impairment of pancreatic β ease (CHD) while the other half were selected randomly cells, termed a "thrifty phenotype" and that later in life, from their respective study populations. these children are more susceptible to diabetes [4]. The body mass index (BMI) SNP fine mapping study gen- Candidate gene studies in T2D have implicated numerous otyped 2,421 FHS participants including 158 diabetics. gene variants that decrease disease risk, such as PPARG For the deletion study, 416 of these, including two diabet- (P12A) [5], and others that increase disease risk, such as ics, either did not genotype for the deletion or did not KCNJ11(E23K) [6]. One of the strongest T2D-associated have sufficient DNA for the deletion study. Therefore, an loci has been mapped to the transcription factor TCF7L2 additional 182 FHS samples, including 49 diabetics, not [7], (odds ratio ≈1.7) and this association has been repli- originally included in the SNP analysis were typed for the cated in numerous subsequent studies [8-20]. deletion. In total, 2,603 participants, including 207 dia- betics, were studied. In addition to single nucleotide polymorphisms (SNPs), genomic insertion/deletion polymorphisms may also T2D diabetes was defined by self-report of diabetes diag- influence disease risk. One such example is the deletion nosis and limited to those with an age at diagnosis greater polymorphism in the angiotension-converting enzyme than 25. The controls used were participants recruited as (ACE), which has been shown to confer increased risk of part of FHS who did not report a diagnosis of diabetes. An coronary artery disease [21]. Recently the HapMap geno- enzymatic (glucose-oxidase) method (Kodak Ektachem type data was used to search for segregating deletions by 700 Analyzer, Rochester, NY) was used to measure fasting examining physically clustered failed SNP genotype serum glucose as mg/dL. This study was approved by the assays, Mendelian inconsistencies, and departures from institutional review boards (IRB) of the participating insti- Hardy-Weinberg disequilibrium [22]. Five hundred and tutions and appropriate informed consent was obtained. forty-one deletions were identified ranging in size from 1 to 754 kb. One predicted 10.3 kb deletion polymorphism Deletion Detection was located under a widely replicated obesity linkage peak Deletions were detected in the study population using on chromosome 7q22-q36 [23-32] between the EXOC4 real-time polymerase chain reaction (RT-PCR). To accu- and LRGUK genes. Importantly, linkage to metabolic syn- rately type deletion variants, we designed primers to drome has also been reported for the Family Heart Study amplify regions within the proposed chromosomal dele- cohort in the 7q32 region [33]. tion on chromosome 7q32. We performed TaqMan RT- PCR assays, using a VIC-labeled probe for a known dip- The aim of this study was to examine SNPs and a chromo- loid gene PMP22 (NM_153321) as a control reference and somal deletion on chromosome 7q32 in a sample of fam- a VIC-labeled probe (Applied Biosystems, Foster City CA) ilies exhibiting linkage to obesity and metabolic for the experimental region, each run simultaneously. syndrome in the region [27,33]. Due to the presence of a Each DNA sample was run in quadruplicate for each Taq- gene (EXOC4) that is part of the exocyst complex (Exo70), Man assay on the PRISM® 7900 HT Sequence Detection which is involved in insulin-stimulated glucose transport, System. The cycles-to-threshold
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