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Author Kelly, M.A.; Rees, S.D.; Hydrie, M.Z.I.; Shera, A.S.; Bellary, S.; O'Hare, J.P.; Kumar, S.; Taheri, S.; Basit, A.; Barnett, A.H. url  doi
  Title Circadian gene variants and susceptibility to type 2 diabetes: a pilot study Type Journal Article
  Year 2012 Publication PloS one Abbreviated Journal PLoS One  
  Volume 7 Issue 4 Pages e32670  
  Keywords Circadian Rhythm Signaling Peptides and Proteins/*genetics; Diabetes Mellitus, Type 2/*genetics; Female; Gene Frequency; Genetic Association Studies; *Genetic Predisposition to Disease; Genotyping Techniques; Humans; Male; Pilot Projects; *Polymorphism, Single Nucleotide; Risk Factors  
  Abstract BACKGROUND: Disruption of endogenous circadian rhythms has been shown to increase the risk of developing type 2 diabetes, suggesting that circadian genes might play a role in determining disease susceptibility. We present the results of a pilot study investigating the association between type 2 diabetes and selected single nucleotide polymorphisms (SNPs) in/near nine circadian genes. The variants were chosen based on their previously reported association with prostate cancer, a disease that has been suggested to have a genetic link with type 2 diabetes through a number of shared inherited risk determinants. METHODOLOGY/PRINCIPAL FINDINGS: The pilot study was performed using two genetically homogeneous Punjabi cohorts, one resident in the United Kingdom and one indigenous to Pakistan. Subjects with (N = 1732) and without (N = 1780) type 2 diabetes were genotyped for thirteen circadian variants using a competitive allele-specific polymerase chain reaction method. Associations between the SNPs and type 2 diabetes were investigated using logistic regression. The results were also combined with in silico data from other South Asian datasets (SAT2D consortium) and white European cohorts (DIAGRAM+) using meta-analysis. The rs7602358G allele near PER2 was negatively associated with type 2 diabetes in our Punjabi cohorts (combined odds ratio [OR] = 0.75 [0.66-0.86], p = 3.18 x 10(-5)), while the BMAL1 rs11022775T allele was associated with an increased risk of the disease (combined OR = 1.22 [1.07-1.39], p = 0.003). Neither of these associations was replicated in the SAT2D or DIAGRAM+ datasets, however. Meta-analysis of all the cohorts identified disease associations with two variants, rs2292912 in CRY2 and rs12315175 near CRY1, although statistical significance was nominal (combined OR = 1.05 [1.01-1.08], p = 0.008 and OR = 0.95 [0.91-0.99], p = 0.015 respectively). CONCLUSIONS/SIGNIFICANCE: None of the selected circadian gene variants was associated with type 2 diabetes with study-wide significance after meta-analysis. The nominal association observed with the CRY2 SNP, however, complements previous findings and confirms a role for this locus in disease susceptibility.  
  Address College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom. m.a.kelly@bham.ac.uk  
  Corporate Author SAT2D Consortium Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1932-6203 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:22485135; PMC3317653 Approved no  
  Call Number HUNT @ maria.stuifbergen @ Serial 1536  
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Author Kvaloy, K.; Holmen, J.; Hveem, K.; Holmen, T.L. url  doi
  Title Genetic Effects on Longitudinal Changes from Healthy to Adverse Weight and Metabolic Status – The HUNT Study Type Journal Article
  Year 2015 Publication PLoS One Abbreviated Journal PloS one  
  Volume 10 Issue 10 Pages e0139632  
  Keywords HUNT2; HUNT3; Adolescent; Adult; Apolipoproteins A/genetics; Blood Glucose/analysis; Blood Pressure; Body Mass Index; Cholesterol, HDL/blood; Cross-Sectional Studies; Female; Humans; Longitudinal Studies; Male; Metabolic Syndrome X/blood/*etiology/genetics; Middle Aged; Overweight/blood/*complications/*genetics; *Polymorphism, Single Nucleotide; Proteins/genetics; Receptors, Dopamine D2/genetics; Triglycerides/blood; Weight Gain; Young Adult  
  Abstract INTRODUCTION: The complexity of obesity and onset and susceptibility of cardio-metabolic disorders are still poorly understood and is addressed here through studies of genetic influence on weight gain and increased metabolic risk longitudinally. SUBJECTS/METHODS: Twenty seven previously identified obesity, eating disorder or metabolic risk susceptibility SNPs were tested for association with weight or metabolically related traits longitudinally in 3999 adults participating both in the HUNT2 (1995-97) and HUNT3 (2006-08) surveys. Regression analyses were performed with changes from normal weight to overweight/obesity or from metabolically healthy to adverse developments with regards to blood pressure, glucose, HDL cholesterol, triglycerides or metabolic syndrome as outcomes. Additionally, a sub-sample of 1380 adolescents was included for testing association of nine SNPs with longitudinal weight gain into young adulthood. RESULTS: The most substantial effect on BMI-based weight gain from normal to overweight/obesity in adults was observed for the DRD2 variant (rs6277)(OR: 0.79, 95% CI: 0.69-0.90, P = 3.9x10-4, adj. P = 0.015). DRD2 was not associated with BMI on a cross-sectional level. In the adolescent sample, FTO (rs1121980) was associated with change to overweight at adulthood in the combined male-female sample (OR: 1.27, 95% CI: 1.09-1.49, P = 3.0x10-3, adj. P = 0.019) and in females (OR: 1.53, 95% CI: 1.23-1.91, P = 1.8x10-4, adj. P = 0.003). When testing for association to longitudinal adverse developments with regard to blood pressure, blood lipids and glucose, only rs964184 (ZNF259/APOA5) was significantly associated to unfavourable triglyceride changes (OR: 1.66, 95% CI: 1.36-2.03, P = 5.7x10-7, adj. P = 0.001). Pleiotropic effects on metabolic traits, however, were observed for several genetic loci cross-sectionally, ZNF259/APOA5, LPL and GRB14 being the most important. CONCLUSIONS: DRD2 exhibits effects on weight gain from normal weight to overweight/obesity in adults, while, FTO is associated to weight gain from adolescence to young adulthood. Unhealthy longitudinal triglyceride development is strongly affected by ZNF259/APOA. Our main finding, linking the DRD2 variant directly to the longitudinal weight gain observed, has not previously been identified. It suggests a genetic pre-disposition involving the dopaminergic signalling pathways known to play a role in food reward and satiety linked mechanisms.  
  Address  
  Corporate Author Thesis  
  Publisher Place of Publication HUNT Research Center, Department of Public Health and General Practice, Faculty of Medicine, Norwegi Editor  
  Language Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN ISBN Medium  
  Area Expedition Conference  
  Notes Kvaloy, KirstiHolmen, JosteinHveem, KristianHolmen, Turid Lingaaseng2015/10/09 06:00PLoS One. 2015 Oct 7;10(10):e0139632. doi: 10.1371/journal.pone.0139632. eCollection 2015. Approved no  
  Call Number HUNT @ maria.stuifbergen @ Kvaloy2015 Serial 1833  
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Author Kvehaugen, A.S.; Melien, O.; Holmen, O.L.; Laivuori, H.; Dechend, R.; Staff, A.C. url  doi
  Title Hypertension after preeclampsia and relation to the C1114G polymorphism (rs4606) in RGS2: data from the Norwegian HUNT2 study Type Journal Article
  Year 2014 Publication BMC Medical Genetics Abbreviated Journal BMC Med Genet  
  Volume 15 Issue Pages 28  
  Keywords Adult; Case-Control Studies; Exercise; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Hypertension/epidemiology/*genetics; Norway; *Polymorphism, Single Nucleotide; Pre-Eclampsia/epidemiology/*genetics; Pregnancy; Prevalence; RGS Proteins/*genetics; Risk Factors; HUNT2  
  Abstract BACKGROUND: Preeclampsia is associated with an increased risk of hypertension later in life. The regulator of G protein signaling 2 negatively regulates several vasoconstrictors. We recently demonstrated an association between preeclampsia and the CG or GG genotype of the C1114G polymorphism (rs4606) of the regulator of G protein signaling 2 gene. Here, we examined the polymorphism with respect to the development of hypertension after pregnancy. METHODS: We genotyped 934 women on average 15.1 years after preeclampsia and 2011 age matched women with previous normotensive pregnancy. All women in this study were retrospectively recruited from the Nord-Trondelag Health Study (HUNT2). Information from HUNT2 was linked to the Medical Birth Registry of Norway to identify women with a history of preeclampsia and women without a history of preeclampsia. RESULTS: No significant association was found between hypertension (blood pressure >/=140/90 mmHg and/or taking antihypertensive drugs) and the polymorphism in crude analysis (OR (95% CI): CG genotype: 1.07 (0.90-1.27); GG genotype: 1.23 (0.90-1.67)). However, in a minimally adjusted model (age and BMI adjusted), a significant association between the GG genotype and hypertension was found (OR (95% CI): 1.49 (1.05-2.11)). This association remained significant also after adjustment for a history of preeclampsia (OR (95% CI): 1.46 (1.02-2.09)), but not in a model adjusted for multiple other variables (OR (95% CI): 1.26 (0.82-1.94)). In multivariate, but not in crude, analysis, the GG genotype of rs4606 (OR (95% CI): 1.93 (1.05-3.53)) was significantly and independently associated with severe hypertension later in life, defined as systolic blood pressure >/=160 mmHg (stage 2 hypertension) and/or taking antihypertensive drugs. A significant association was also found for the merged CG and GG genotypes (OR (95% CI): 1.43 (1.02-2.00)). Moreover, an interaction with physical activity was found. A history of preeclampsia was a significant and independent predictor of either definition of hypertension, both in crude and adjusted analyses. CONCLUSION: Women carrying the rs4606 CG or GG genotype are at elevated risk for developing hypertension after delivery. Physical activity may interact with the association. Preeclampsia remains an independent risk factor for subsequent hypertension after adjusting for this polymorphism and classical CVD risk factors.  
  Address From the Department of Obstetrics and Department of Gynecology, Oslo University Hospital, Ulleval, Oslo, Norway and Faculty of Medicine, University of Oslo, Oslo, Norway. UXNNAF@ous-hf.no  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1471-2350 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:24593135; PMC3973870 Approved no  
  Call Number HUNT @ maria.stuifbergen @ Serial 1624  
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Author Kvehaugen, A.S.; Melien, O.; Holmen, O.L.; Laivuori, H.; Oian, P.; Andersgaard, A.B.; Dechend, R.; Staff, A.C. url  doi
  Title Single nucleotide polymorphisms in G protein signaling pathway genes in preeclampsia Type Journal Article
  Year 2013 Publication Hypertension Abbreviated Journal Hypertension  
  Volume 61 Issue 3 Pages 655-661  
  Keywords Adult; Atherosclerosis/epidemiology/genetics; Biological Specimen Banks/statistics & numerical data; European Continental Ancestry Group/genetics/statistics & numerical data; Female; Gene Frequency; Genetic Predisposition to Disease/epidemiology; Heterotrimeric GTP-Binding Proteins/*genetics; Humans; Norway/epidemiology; Polymorphism, Genetic; *Polymorphism, Single Nucleotide; Pre-Eclampsia/epidemiology/*genetics; Pregnancy; Prevalence; RGS Proteins/*genetics; Receptor, Angiotensin, Type 1/genetics; Signal Transduction/*genetics; Young Adult  
  Abstract Preeclampsia is a pregnancy specific disorder and a risk factor for later cardiovascular disease. The cause and detailed pathophysiology remains unknown. G protein signaling is involved in a variety of physiological processes, including blood pressure regulation. We assessed whether distributions of 3 single nucleotide polymorphisms in genes coding for components of G protein signaling pathways that have been associated with hypertension differ between women with preeclampsia and normotensive pregnant women; the G protein beta3 subunit gene (GNB3) C825T polymorphism (rs5443), the angiotensin II type 1 receptor gene (AGTR1) 3'UTR A1166C polymorphism (rs5186), and the regulator of G protein signaling 2 gene (RGS2) 3'UTR C1114G polymorphism (rs4606). Two separate Norwegian study populations were used; a large population based study and a smaller, but clinically well-described pregnancy biobank. A descriptive study of 43 women with eclampsia was additionally included. In the population-based study, an increased odds of preeclampsia (odds ratio, 1.21; [95% confidence interval, 1.05-1.40]; P=0.009) and recurrent preeclampsia (odds ratio, 1.43; [95% confidence interval, 1.06-1.92];, P=0.017) was found in women carrying the rs4606 CG or GG genotype. In early-onset preeclamptic patients with decidual spiral artery biopsies available (n=24), the rs4606 CG or GG genotype was more frequent in those with acute atherosis (resembling early stage of atherosclerosis) compared with those without: odds ratio, 15.0; (95% confidence interval, 2.02-111.2); P=0.004. No association was found between preeclampsia and the rs5443 or the rs5186. The genotype distribution in eclamptic women was not different from preeclamptic women. In conclusion, RGS2 rs4606 may affect the risk and progression of preeclampsia.  
  Address Department of Obstetrics, Oslo University Hospital, Oslo, Norway  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0194-911X ISBN Medium  
  Area Expedition Conference  
  Notes PMID:23339167 Approved no  
  Call Number HUNT @ maria.stuifbergen @ Serial 1432  
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Author Lange, L.A.; Hu, Y.; Zhang, H.; Xue, C.; Schmidt, E.M.; Tang, Z.-Z.; Bizon, C.; Lange, E.M.; Smith, J.D.; Turner, E.H.; Jun, G.; Kang, H.M.; Peloso, G.; Auer, P.; Li, K.-P.; Flannick, J.; Zhang, J.; Fuchsberger, C.; Gaulton, K.; Lindgren, C.; Locke, A.; Manning, A.; Sim, X.; Rivas, M.A.; Holmen, O.L.; Gottesman, O.; Lu, Y.; Ruderfer, D.; Stahl, E.A.; Duan, Q.; Li, Y.; Durda, P.; Jiao, S.; Isaacs, A.; Hofman, A.; Bis, J.C.; Correa, A.; Griswold, M.E.; Jakobsdottir, J.; Smith, A.V.; Schreiner, P.J.; Feitosa, M.F.; Zhang, Q.; Huffman, J.E.; Crosby, J.; Wassel, C.L.; Do, R.; Franceschini, N.; Martin, L.W.; Robinson, J.G.; Assimes, T.L.; Crosslin, D.R.; Rosenthal, E.A.; Tsai, M.; Rieder, M.J.; Farlow, D.N.; Folsom, A.R.; Lumley, T.; Fox, E.R.; Carlson, C.S.; Peters, U.; Jackson, R.D.; van Duijn, C.M.; Uitterlinden, A.G.; Levy, D.; Rotter, J.I.; Taylor, H.A.; Gudnason, V.J.; Siscovick, D.S.; Fornage, M.; Borecki, I.B.; Hayward, C.; Rudan, I.; Chen, Y.E.; Bottinger, E.P.; Loos, R.J.F.; Saetrom, P.; Hveem, K.; Boehnke, M.; Groop, L.; McCarthy, M.; Meitinger, T.; Ballantyne, C.M.; Gabriel, S.B.; O'Donnell, C.J.; Post, W.S.; North, K.E.; Reiner, A.P.; Boerwinkle, E.; Psaty, B.M.; Altshuler, D.; Kathiresan, S.; Lin, D.-Y.; Jarvik, G.P.; Cupples, L.A.; Kooperberg, C.; Wilson, J.G.; Nickerson, D.A.; Abecasis, G.R.; Rich, S.S.; Tracy, R.P.; Willer, C.J. url  doi
  Title Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol Type Journal Article
  Year 2014 Publication American Journal of Human Genetics Abbreviated Journal Am J Hum Genet  
  Volume 94 Issue 2 Pages 233-245  
  Keywords Adult; Aged; Apolipoproteins E/blood/genetics; Cholesterol, LDL/*genetics; Cohort Studies; Dyslipidemias/blood/genetics; *Exome; Female; Follow-Up Studies; *Gene Frequency; Genetic Code; *Genome-Wide Association Study; Genotype; Humans; Lipase/genetics; Male; Middle Aged; Phenotype; *Polymorphism, Single Nucleotide; Proprotein Convertases/genetics; Receptors, LDL/genetics; Sequence Analysis, DNA; Serine Endopeptidases/genetics; HUNT3  
  Abstract Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.  
  Address Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: cristen@umich.edu  
  Corporate Author NHLBI Grand Opportunity Exome Sequencing Project Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0002-9297 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:24507775; PMC3928660 Approved no  
  Call Number HUNT @ maria.stuifbergen @ Serial 1625  
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Author Skarpengland, T.; Laugsand, L.E.; Janszky, I.; Luna, L.; Halvorsen, B.; Platou, C.G.; Wang, W.; Vatten, L.J.; Damas, J.K.; Aukrust, P.; Bjoras, M.; Asvold, B.O. url  doi
  Title Genetic variants in the DNA repair gene NEIL3 and the risk of myocardial infarction in a nested case-control study. The HUNT Study Type Journal Article
  Year 2015 Publication DNA Repair (Amst) Abbreviated Journal DNA repair  
  Volume 28 Issue Pages 21-27  
  Keywords HUNT3; Atherosclerosis; DNA glycosylase; Myocardial infarction; NEIL3; SNP; Aged; Aged, 80 and over; Case-Control Studies; DNA Glycosylases/genetics; DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics; DNA-Binding Proteins/genetics; Female; Humans; Male; Middle Aged; Myocardial Infarction/*genetics; N-Glycosyl Hydrolases/*genetics; *Polymorphism, Single Nucleotide  
  Abstract BACKGROUND: Enhanced generation of reactive oxygen species and increased oxidative-induced DNA damage have been identified as possible contributors to atherosclerosis. The base excision repair (BER) pathway is the principal mechanism by which mammalian cells repair oxidative DNA damage. BER deficiency can potentially accelerate atherogenesis. METHODS: We evaluated the association of Single Nucleotide Polymorphisms (SNPs) in genes encoding four different BER proteins (NEIL3, OGG1, APEX1 and XRCC1) with the incidence of myocardial infarction in a nested case-control study among participants of the second survey of the HUNT Study. The study population included 1624 cases and 4087 age- and sex-matched controls. RESULTS: For the NEIL3 SNP rs12645561, the TT genotype was associated with increased risk of MI (OR 1.47, 95% CI 1.02-2.12, p uncorrected for multiple comparisons=0.04) both in the genotypic test (compared to the CC genotype) and in the recessive genetic model (compared to the CC and CT genotypes combined). For the other two NEIL3 SNPs (rs10013040 and rs1395479) and for the SNPs of OGG1 (rs1052133), APEX1 (rs1878703) and XRCC1 (rs25489) we observed no association with risk of myocardial infarction. CONCLUSION: We found that the NEIL3 rs12645561 SNP TT genotype was associated with increased risk of myocardial infarction. If confirmed in other studies, this association may suggest a possible role of attenuated DNA repair, and NEIL3 in particular, in atherogenesis.  
  Address  
  Corporate Author Thesis  
  Publisher Place of Publication Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; Institute Editor  
  Language Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN ISBN Medium  
  Area Expedition Conference  
  Notes Skarpengland, TonjeLaugsand, Lars ErikJanszky, ImreLuna, LuisaHalvorsen, BentePlatou, Carl G PWang, WeiVatten, Lars JDamas, Jan KristianAukrust, PalBjoras, MagnarAsvold, Bjorn OENG2015/02/24 06:00DNA Repair (Amst). 2015 Feb 2;28C:21-27. doi: 10.1016/j.dnarep.2015.01.013. Approved no  
  Call Number HUNT @ maria.stuifbergen @ Skarpengland2015 Serial 1860  
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