Common Missense Variant in the Glucokinase Regulatory Protein Gene Is Associated With Increased Plasma Triglyceride and C-Reactive
Protein but Lower Fasting Glucose Concentrations
Marju Orho-Melander ...1 ,
Olle Melander 1 ,
Candace Guiducci 2 ,
Pablo Perez-Martinez 3 4 5 ,
Dolores Corella 5 ,
Charlotta Roos 1 ,
Ryan Tewhey 2 ,
Mark J. Rieder 6 ,
Jennifer Hall 7 ,
Goncalo Abecasis 8 ,
E. Shyong Tai 9 ,
Cullan Welch 7 ,
Donna K. Arnett 10 ,
Valeriya Lyssenko 1 ,
Eero Lindholm 1 ,
Richa Saxena 2 ,
Paul I.W. de Bakker 2 ,
Noel Burtt 2 ,
Benjamin F. Voight 2 ,
Joel N. Hirschhorn 2 ,
Katherine L. Tucker 11 ,
Thomas Hedner 12 ,
Tiinamaija Tuomi 13 14 ,
Bo Isomaa 14 ,
Karl-Fredrik Eriksson 1 ,
Marja-Riitta Taskinen 13 ,
Björn Wahlstrand 12 ,
Thomas E. Hughes 15 ,
Laurence D. Parnell 4 ,
Chao-Qiang Lai 4 ,
Göran Berglund 16 ,
Leena Peltonen 17 ,
Erkki Vartiainen 18 ,
Pekka Jousilahti 18 ,
Aki S. Havulinna 18 ,
Veikko Salomaa 18 ,
Peter Nilsson 1 ,
Leif Groop 1 13 ,
David Altshuler 2 19 20 ,
Jose M. Ordovas 4 and
Sekar Kathiresan 2 21
1 Department of Clinical Sciences, University Hospital Malmö, Clinical Research Center, Lund University, Malmö, Sweden
2 Program in Medical and Population Genetics, Broad Institute of the Massachusetts Institute of Technology and Harvard University,
Cambridge, Massachusetts
3 Lipids and Atherosclerosis Research Unit, Reina Sofia University Hospital, University of Cordoba, Cordoba, Spain
4 Nutrition and Genomics Laboratory, Jean Mayer-U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts
University, Boston, Massachusetts
5 Genetic and Molecular Epidemiology Unit and CIBER Fisiopatología de la Obesidad y Nutrición, School of Medicine University
of Valencia, Valencia, Spain
6 Department of Genome Sciences, University of Washington, Seattle, Washington
7 Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis, Minnesota
8 Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan
9 Department of Endocrinology, Singapore General Hospital, Singapore
10 Dietary Assessment and Epidemiology Research Program, Jean Mayer-U.S. Department of Agriculture Human Nutrition Research Center
on Aging, Tufts University, Boston, Massachusetts
11 Department of Epidemiology, University of Alabama, Birmingham, Alabama
12 Department of Clinical Pharmacology, Sahlgrenska Academy, Göteborg, Sweden
13 Department of Medicine, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
14 Folkhälsan Research Center, Helsinki, Finland
15 Novartis Institutes for BioMedical Research, Cambridge, Massachusetts
16 Department of Clinical Sciences, Medicine, Lund University, Malmö, Sweden
17 Department of Molecular Medicine, National Public Health Institute, Biomedicum, Helsinki, Finland
18 Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland
19 Center for Human Genetic Research and Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts
20 Department of Genetics, Harvard Medical School, Boston, Massachusetts
21 Cardiovascular Disease Prevention Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard
Medical School, Boston, Massachusetts
Corresponding author: Marju Orho-Melander, marju.orho-melander{at}med.lu.se
Abstract
OBJECTIVE— Using the genome-wide association approach, we recently identified the glucokinase regulatory protein gene ( GCKR , rs780094) region as a novel quantitative trait locus for plasma triglyceride concentration in Europeans. Here, we sought
to study the association of GCKR variants with metabolic phenotypes, including measures of glucose homeostasis, to evaluate the GCKR locus in samples of non-European ancestry and to fine- map across the associated genomic interval.
RESEARCH DESIGN AND METHODS— We performed association studies in 12 independent cohorts comprising >45,000 individuals representing several ancestral groups
(whites from Northern and Southern Europe, whites from the U.S., African Americans from the U.S., Hispanics of Caribbean origin,
and Chinese, Malays, and Asian Indians from Singapore). We conducted genetic fine-mapping across the ∼417-kb region of linkage
disequilibrium spanning GCKR and 16 other genes on chromosome 2p23 by imputing untyped HapMap single nucleotide polymorphisms (SNPs) and genotyping 104
SNPs across the associated genomic interval.
RESULTS— We provide comprehensive evidence that GCKR rs780094 is associated with opposite effects on fasting plasma triglyceride ( P meta = 3 × 10 −56 ) and glucose ( P meta = 1 × 10 −13 ) concentrations. In addition, we confirmed recent reports that the same SNP is associated with C-reactive protein (CRP) level
( P = 5 × 10 −5 ). Both fine-mapping approaches revealed a common missense GCKR variant (rs1260326, Pro446Leu, 34% frequency, r 2 = 0.93 with rs780094) as the strongest association signal in the region.
CONCLUSIONS— These findings point to a molecular mechanism in humans by which higher triglycerides and CRP can be coupled with lower plasma
glucose concentrations and position GCKR in central pathways regulating both hepatic triglyceride and glucose metabolism.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 4 August 2008.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted July 29, 2008.
Received April 17, 2008.
DIABETES
Diurnal type (chronotype) differentiates individuals on an axis between the extremes of evening type to morning type. These diurnal-type preferences are thought to be relatively stable, but follow-up ...studies are sparse. The study aims were (1) to compare cross-sectional studies of diurnal type preferences between two decades and (2) to analyze the consistency of diurnal-type preferences using a longitudinal dataset. We analyzed a total of 18 087 adult males from four datasets with information on diurnal type and age. Of these, 2144 were available for survival analysis and 567 for analysis of longitudinal diurnal consistency. Diurnal type was assessed by asking the individual to what extent they would rate themselves a morning or an evening person, categorized into four groups. Statistical tests for stability of diurnal type were based on transition matrices and p values obtained using likelihood ratios. Cox regression was used to calculate the relative risk of all-cause mortality in each of the four diurnal type groups. After direct age standardization, 9.5% (95% CI: 9.0-10.1%) of participants in the four datasets were evening types. The cross-sectional data yielded that morning types were less common in the 2000s than two decades earlier. The longitudinal dataset revealed a significant shift from evening type to another type from 1985 to 2008 (p = 0.002). The relative risk of all-cause mortality was 1.3-fold (95% CI: 1.0-1.6; p = 0.05) higher for evening types compared to morning types. At the population level, eveningness appears to have become more prevalent over recent decades. However, on the individual level, the more morningness the chronotype, the more persistent it remains with aging.
The extremely high cardiovascular mortality in an eastern province North Karelia in Finland caused great concern among the local population. Action to reduce the problem was demanded in a petition to ...the Finnish government signed by local representatives of the population. In response, the North Karelia project was launched in 1972 to carry out a comprehensive community based prevention program. After the first five years, prevention activities were also started nationally. The main aim was to reduce the extremely high serum cholesterol, blood pressure and smoking levels with lifestyle changes and improved drug treatment, especially for hypertension. Major declines were seen in serum cholesterol, blood pressure and smoking levels. Coronary mortality reduced in middle age population by 84% from 1972 to 2014. About 2/3 of the mortality decline was explained by risk factor changes and 1/3 by improvement of new treatments developed since 1980s. Population-based prevention through changes in lifestyle and environment is the most cost effective and sustainable way of controlling cardiovascular and other major non-communicable diseases. In the current global situation it is a powerful lesson.
In rural and remote Australia, cardiovascular mortality and morbidity rates are higher than metropolitan rates.This study analysed cardiovascular and other chronic disease risk factors and related ...health behaviours by occupational status, to determine whether agricultural workers have higher cardiovascular disease (CVD) risk than other rural workers.
Cross-sectional surveys in three rural regions of South Eastern Australia (2004-2006). A stratified random sample of 1001 men and women aged 25-74 from electoral rolls were categorised by occupation into agricultural workers (men = 214, women = 79), technicians (men = 123), managers (men = 148, women = 272) and 'home duties' (women = 165). Data were collected from self-administered questionnaire, physical measurements and laboratory tests. Cardiovascular disease (CVD) and coronary heart disease (CHD) risk were assessed by Framingham 5 years risk calculation.
Amongst men, agricultural workers had higher occupational physical activity levels, healthier more traditional diet, lower alcohol consumption, lower fasting plasma glucose, the lowest proportion of daily smokers and lower age-adjusted 5 year CVD and CHD risk scores.Amongst women, managers were younger with higher HDL cholesterol, lower systolic blood pressure, less hypertension, lower waist circumference, less self-reported diabetes and better 5 year CVD and CHD risk scores.Agricultural workers did not have higher cardiovascular disease risk than other occupational groups.
Previous studies have suggested that farmers have higher risks of cardiovascular disease but this is because the risk has been compared with non-rural populations. In this study, the comparison has been made with other rural occupations. Cardiovascular risk reduction programs are justified for all. Programs tailored only for agricultural workers are unwarranted.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Randomised controlled trials demonstrate a 60% reduction in type 2 diabetes incidence through lifestyle modification programmes. The aim of this study is to determine whether such programmes are ...feasible in primary health care.
An intervention study including 237 individuals 40-75 years of age with moderate or high risk of developing type 2 diabetes. A structured group programme with six 90 minute sessions delivered during an eight month period by trained nurses in Australian primary health care in 2004-2006. Main outcome measures taken at baseline, three, and 12 months included weight, height, waist circumference, fasting plasma glucose and lipids, plasma glucose two hours after oral glucose challenge, blood pressure, measures of psychological distress and general health outcomes. To test differences between baseline and follow-up, paired t-tests and Wilcoxon rank sum tests were performed.
At twelve months participants' mean weight reduced by 2.52 kg (95% confidence interval 1.85 to 3.19) and waist circumference by 4.17 cm (3.48 to 4.87). Mean fasting glucose reduced by 0.14 mmol/l (0.07 to 0.20), plasma glucose two hours after oral glucose challenge by 0.58 mmol/l (0.36 to 0.79), total cholesterol by 0.29 mmol/l (0.18 to 0.40), low density lipoprotein cholesterol by 0.25 mmol/l (0.16 to 0.34), triglycerides by 0.15 mmol/l (0.05 to 0.24) and diastolic blood pressure by 2.14 mmHg (0.94 to 3.33). Significant improvements were also found in most psychological measures.
This study provides evidence that a type 2 diabetes prevention programme using lifestyle intervention is feasible in primary health care settings, with reductions in risk factors approaching those observed in clinical trials.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Only three Japanese prospective studies have suggested an inverse association between coffee drinking and liver cancer risk. No prospective studies on the association between serum ...gamma‐glutamyltransferase (GGT) and liver cancer risk have been reported. We aimed to determine the single and joint associations of coffee consumption and serum GGT with the risk of primary liver cancer. Study cohorts included 60,323 Finnish participants who were 25‐74 years of age and free of any cancer at baseline. During a median follow‐up period of 19.3 years (interquartile range: 9.3‐29.2 years), 128 participants were diagnosed with an incident liver cancer. The multivariable‐adjusted (age, sex, alcohol consumption, education, smoking, diabetes and chronic liver disease at baseline and during follow‐up, and body mass index) hazards ratios of liver cancer in participants who drank 0‐1, 2‐3, 4‐5, 6‐7, and ≥8 cups of coffee daily were 1.00, 0.66, 0.44, 0.38, and 0.32 (P for trend = 0.003), respectively. Further adjustment for serum GGT in subgroup analysis affected the results only slightly. The multivariable‐adjusted and coffee‐adjusted hazard ratio of liver cancer for the highest versus the lowest quartile of serum GGT was 3.13 (95% confidence interval = 1.22‐8.07). The multivariable‐adjusted inverse association between coffee consumption and liver cancer risk persisted when stratified by baseline factors: age more/less than 50 years, current smoker/never smoked/ever smoked, alcohol drinker/never drinker, obese/nonobese, and the highest/lowest three quartiles of serum GGT. A combination of very low coffee consumption and high level of serum GGT was associated with nearly nine‐fold increased risk. Conclusion: Coffee drinking has an inverse and graded association with the risk of liver cancer. High serum GGT is associated with an increased risk of liver cancer. (HEPATOLOGY 2008.)
To assess the trends in prevalence and in control of hypertension in various parts of Finland during 1982-2007.
Three independent cross-sectional population surveys were conducted in 1982, 2002 and ...2007 with age-stratified samples of men and women aged 25-64 years from the national population register. The total number of participants with complete blood pressure (BP) measurements was 16 775.
Overall, during 1982-2007, the prevalence of hypertension (systolic BP > or = 140 mmHg and/or diastolic BP > or = 90 mmHg and/or current use of antihypertensive drug treatment) fell significantly in both sexes. In men, it fell from 63.3 to 52.1%; in women, from 48.1 to 33.6% (P < 0.001 for both sexes). However, during the past 5-year period, a decline was observed only in women in south-western Finland (P = 0.003). Furthermore, previously observed significant increases in the proportions of treated and controlled hypertensive individuals did not continue among men during 2002-2007. Despite the evident progress in all aspects of hypertension care since 1982, still in 2007, only 68% of all hypertensive individuals were aware of their condition, 52% of those who were aware were treated with antihypertensive drugs and 37% of the drug-treated patients had normal BP.
Steady progress has been made in the prevention and treatment of hypertension in Finland. However, further improvements are clearly needed.
Cardiovascular disease (CVD) incidence, complications and burden differ markedly between women and men. Although there is variation in the distribution of lifestyle factors between the genders, they ...do not fully explain the differences in CVD incidence and suggest the existence of gender-specific genetic risk factors. We aimed to estimate whether the genetic risk profiles of coronary heart disease (CHD), ischemic stroke and the composite end-point of CVD differ between the genders.
We studied in two Finnish population cohorts, using the case-cohort design the association between common variation in 46 candidate genes and CHD, ischemic stroke, CVD, and CVD-related quantitative risk factors. We analyzed men and women jointly and also conducted genotype-gender interaction analysis. Several allelic variants conferred disease risk for men and women jointly, including rs1801020 in coagulation factor XII (HR = 1.31 (1.08-1.60) for CVD, uncorrected p = 0.006 multiplicative model). Variant rs11673407 in the fucosyltransferase 3 gene was strongly associated with waist/hip ratio (uncorrected p = 0.00005) in joint analysis. In interaction analysis we found statistical evidence of variant-gender interaction conferring risk of CHD and CVD: rs3742264 in the carboxypeptidase B2 gene, p(interaction) = 0.009 for CHD, and rs2774279 in the upstream stimulatory factor 1 gene, p(interaction) = 0.007 for CHD and CVD, showed strong association in women but not in men, while rs2069840 in interleukin 6 gene, p(interaction) = 0.004 for CVD, showed strong association in men but not in women (uncorrected p-values). Also, two variants in the selenoprotein S gene conferred risk for ischemic stroke in women, p(interaction) = 0.003 and 0.007. Importantly, we identified a larger number of gender-specific effects for women than for men.
A false discovery rate analysis suggests that we may expect half of the reported findings for combined gender analysis to be true positives, while at least third of the reported genotype-gender interaction results are true positives. The asymmetry in positive findings between the genders could imply that genetic risk loci for CVD are more readily detectable in women, while for men they are more confounded by environmental/lifestyle risk factors. The possible differences in genetic risk profiles between the genders should be addressed in more detail in genetic studies of CVD, and more focus on female CVD risk is also warranted in genome-wide association studies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Introduction. To examine whether midregional pro-adrenomedullin (MR-proADM) plasma concentrations predict incident cardiovascular outcomes in the general population. Natriuretic peptides ...(N-terminal pro-brain natriuretic peptide (NT-proBNP), B-type natriuretic peptide (BNP), and midregional pro-atrial natriuretic peptide (MR-proANP)) were analyzed for comparison.
Material and methods. MR-proADM plasma concentrations and those of the natriuretic peptides were determined in 8444 individuals of the FINRISK 1997 cohort. Patients were followed for 14 years (median). Cox regression analyses, discrimination, and reclassification analyses adjusting for Framingham risk factors were performed to evaluate the additional benefit from MR-proADM.
Results. MR-proADM concentrations significantly predicted all-cause death (hazard ratio highest quintile versus lowest 1.18, 95% confidence interval 1.08-1.28), stroke (1.20, 1.05-1.38), major adverse cardiac events (MACE) (1.27, 1.17-1.37), and heart failure (1.67, 1.49-1.87). MR-proADM remained associated with MACE, death, and heart failure even after additional adjustment for NT-proBNP and C-reactive protein. Adding MR-proADM to the Framingham risk factors significantly improved discrimination (P < 0.001 for C-statistics and integrated discrimination improvement) and risk reclassification for heart failure (net reclassification improvement 12.12%, P < 0.001).
Conclusions. In a healthy general population sample of the FINRISK 1997 cohort MR-proADM significantly predicted all-cause death, MACE, and especially heart failure even beyond NT- proBNP. It also improved risk reclassification for heart failure.
Fish contains high concentrations of omega-3 polyunsaturated fatty acids. Several studies have reported depletions of omega-3 fats among depressed patients, and a cross-national comparison has ...revealed a significant inverse correlation between annual prevalence of major depression and fish consumption. In a sample of 3,204 Finnish adults, depressive symptoms were estimated with the Beck Depression Inventory. A frequency question was used to measure fish consumption. Multiple logistic regression analysis was conducted to assess the association between depression and fish consumption. After the analysis adjusted for potential confounders, the likelihood of having depressive symptoms was significantly higher among infrequent fish consumers than among frequent consumers.
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