We studied whether variants previously associated with congenital long QT syndrome (cLQTS) have a... more We studied whether variants previously associated with congenital long QT syndrome (cLQTS) have an effect on the QTc interval in a Danish population sample. Furthermore, we assessed whether carriers of variants in cLQTS-associated genes are more prone to experience syncope compared with non-carriers and whether carriers have an increased mortality compared with non-carriers. All genetic variants previously associated with cLQTS were surveyed using the Human Gene Mutation Database. We screened a Danish population-based sample with available whole-exome sequencing data (n = 870) and genotype array data (n = 6161) for putative cLQTS genetic variants. In total, 33 of 1358 variants previously reported to associate with cLQTS were identified. Of these, 10 variants were found in 8 or more individuals. Electrocardiogram results showed normal mean QTc intervals in carriers compared with non-carriers. Syncope data analysis between variant and non-variant carriers showed that 4 of 227 (1.8%) a...
A trans-ethnic meta-analysis of type 2 diabetes genome-wide association studies has identified se... more A trans-ethnic meta-analysis of type 2 diabetes genome-wide association studies has identified seven novel susceptibility variants in or near TMEM154, SSR1/RREB1, FAF1, POU5F1/TCF19, LPP, ARL15 and ABCB9/MPHOSPH9. The aim of our study was to investigate associations between these novel risk variants and type 2 diabetes and pre-diabetic traits in a Danish population-based study with measurements of plasma glucose and serum insulin after an oral glucose tolerance test in order to elaborate on the physiological impact of the variants. Case-control analyses were performed in up to 5,777 patients with type 2 diabetes and 7,956 individuals with normal fasting glucose levels. Quantitative trait analyses were performed in up to 5,744 Inter99 participants naïve to glucose-lowering medication. Significant associations between TMEM154-rs6813195 and the beta cell measures insulinogenic index and disposition index and between FAF1-rs17106184 and 2-hour serum insulin levels were selected for furt...
To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to inv... more To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease. Mendelian randomisation meta-analysis of 56 epidemiological studies. 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers. Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption. Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5....
Chemical intolerance (CI) is characterised by negative health effects attributed to a heightened ... more Chemical intolerance (CI) is characterised by negative health effects attributed to a heightened responsiveness to common airborne chemicals. This longitudinal study explored the hypothesised role of negative affect in the development and persistence of CI in a general population. A general population sample aged 19 to 72years was examined in 2006-2008 and again in 2011-2012. Longitudinal data on CI were analysed with the purpose of examining baseline negative affect as a risk factor for having developed CI at 5-year follow-up and for reporting persistent CI. Participants were classified as reporting no signs of CI, having symptoms of CI and as being a likely CI case based on self-reported reactions to 11 common chemical exposures, symptoms related to chemical exposures and daily life adjustments attributed to reactions when exposed to chemicals. A total of 69.4% of the participants who had reported CI at baseline also reported CI at follow-up. In participants with no baseline CI, 1...
Circulation. Cardiovascular genetics, Jan 24, 2015
-There are several well-established lifestyle factors influencing dyslipidemia and currently, 157... more -There are several well-established lifestyle factors influencing dyslipidemia and currently, 157 genetic susceptibility loci have been reported to be associated with serum lipid levels at genome-wide statistical significance. However, the interplay between lifestyle risk factors and these susceptibility loci has not been fully elucidated. We tested if genetic risk scores (GRS) of lipid-associated SNPs associate with fasting serum lipid traits and if the effects are modulated by lifestyle factors or estimates of metabolic health. -The SNPs were genotyped in two Danish cohorts: Inter99 (n=5,961) for discovery analyses and Health2006 (n=2,565) for replication. Based on published effect sizes of SNPs associated with circulating fasting levels of total cholesterol, LDL-cholesterol, HDL-cholesterol or triglyceride, four weighted GRS (wGRS) were constructed. In a cross-sectional design, we investigated if the effect of these wGRSs on lipid levels were modulated by diet, alcohol consumption, physical activity and smoking or the individual metabolic health status as estimated from BMI, waist circumference and insulin resistance assessed using HOMA-IR. All four lipid wGRSs associated strongly with their respective trait (from P=3.3×10(-69) to P=1.1×10(-123)). We found interactions between the triglyceride wGRS and BMI and waist circumference on fasting triglyceride levels in Inter99 and replicated these findings in Health2006 (Pinteraction=9.8×10(-5) and 2.0×10(-5), respectively in combined analysis). -Our findings suggest that individuals who are obese may be more susceptible to the cumulative genetic burden of triglyceride SNPs. Therefore, it is suggested that especially these genetically at-risk individuals may benefit more from targeted interventions aiming at obesity prevention.
European journal of preventive cardiology, Jan 3, 2014
Excessive salt intake causes increased blood pressure which is considered the leading risk for pr... more Excessive salt intake causes increased blood pressure which is considered the leading risk for premature death. One major challenge when evaluating associations between daily salt intake and markers of non-communicable diseases is that a high daily salt intake correlates with obesity, which is also a well described risk factor for poor cardiometabolic outcome. The aim of this study was to evaluate the relationship of estimated daily salt intake with blood pressure and blood lipids and to investigate the effect of taking different measures of obesity into account. We included 3294 men and women aged 18-69 years from a general population based study in Copenhagen, Denmark. Estimated 24-hour sodium excretion was calculated by measurements of creatinine and sodium concentration in spot urine in combination with information of sex, age, height and weight. The relations of estimated 24-hour sodium excretion with blood pressure and blood lipids were evaluated by linear regression models. T...
The aim of this paper was to identify the extent of socioeconomic inequality in participation at ... more The aim of this paper was to identify the extent of socioeconomic inequality in participation at baseline and follow-up visits. The Inter99 study is a randomized intervention with the aim of investigating the effects of an individualized lifestyle consultation on ischaemic heart disease (IHD). The study comprised 61,301 persons of which 13,016 were assigned to the intervention group. The rest formed the control group. All those in the intervention group were invited to participate in health examinations, risk assessments, and lifestyle consultations. Participants at high risk of IHD were invited to follow-up visits after 1, 3, and 5 years. Data on five socioeconomic factors were retrieved from nationwide registers. For each socioeconomic factor we estimated the relative risks and relative index of inequality of participation at the baseline visit and among high-risk participants at follow-up visits. In addition, we conducted analyses of trends in socioeconomic inequality in participation across follow-up visits. Participation rates were 53% at baseline and 61-65% at the three follow-up visits. There was strong socioeconomic inequality in participation at baseline, with increasing probability of participation found with increasing level of socioeconomic position. This was smaller at follow-up visits. Except for education and housing tenure, there was an increase in socioeconomic inequality in participation across follow-up visits. We found strong socioeconomic inequality in participation at baseline and follow-up visits. Effort should be made to increase participation in individualized lifestyle interventions among persons of low socioeconomic position. Otherwise, the consequence may be increased socioeconomic inequality in IHD.
Common diseases like essential hypertension or diabetes mellitus are complex as they are polygeni... more Common diseases like essential hypertension or diabetes mellitus are complex as they are polygenic in nature, such that each genetic variation only has a small influence on the disease. Genes operates in integrated networks providing the blue-print for all biological processes and conditional of the complex genotype determines the state and dynamics of any trait, which may be modified to various extent by non-genetic factors. Thus, diseases are heterogenous ensembles of conditions with a common endpoint. Numerous studies have been performed to define genes of importance for a trait or disease, but only a few genes with small effect have been identified. The major reasons for this modest progress is the unresolved heterogeneity of the regulation of blood pressure and the shortcomings of the prevailing monogenic approach to capture genetic effects in a polygenic condition. Here, a two-step procedure is presented in which physiological heterogeneity is disentangled and genetic effects ...
We studied whether variants previously associated with congenital long QT syndrome (cLQTS) have a... more We studied whether variants previously associated with congenital long QT syndrome (cLQTS) have an effect on the QTc interval in a Danish population sample. Furthermore, we assessed whether carriers of variants in cLQTS-associated genes are more prone to experience syncope compared with non-carriers and whether carriers have an increased mortality compared with non-carriers. All genetic variants previously associated with cLQTS were surveyed using the Human Gene Mutation Database. We screened a Danish population-based sample with available whole-exome sequencing data (n = 870) and genotype array data (n = 6161) for putative cLQTS genetic variants. In total, 33 of 1358 variants previously reported to associate with cLQTS were identified. Of these, 10 variants were found in 8 or more individuals. Electrocardiogram results showed normal mean QTc intervals in carriers compared with non-carriers. Syncope data analysis between variant and non-variant carriers showed that 4 of 227 (1.8%) a...
A trans-ethnic meta-analysis of type 2 diabetes genome-wide association studies has identified se... more A trans-ethnic meta-analysis of type 2 diabetes genome-wide association studies has identified seven novel susceptibility variants in or near TMEM154, SSR1/RREB1, FAF1, POU5F1/TCF19, LPP, ARL15 and ABCB9/MPHOSPH9. The aim of our study was to investigate associations between these novel risk variants and type 2 diabetes and pre-diabetic traits in a Danish population-based study with measurements of plasma glucose and serum insulin after an oral glucose tolerance test in order to elaborate on the physiological impact of the variants. Case-control analyses were performed in up to 5,777 patients with type 2 diabetes and 7,956 individuals with normal fasting glucose levels. Quantitative trait analyses were performed in up to 5,744 Inter99 participants naïve to glucose-lowering medication. Significant associations between TMEM154-rs6813195 and the beta cell measures insulinogenic index and disposition index and between FAF1-rs17106184 and 2-hour serum insulin levels were selected for furt...
To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to inv... more To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease. Mendelian randomisation meta-analysis of 56 epidemiological studies. 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers. Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption. Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5....
Chemical intolerance (CI) is characterised by negative health effects attributed to a heightened ... more Chemical intolerance (CI) is characterised by negative health effects attributed to a heightened responsiveness to common airborne chemicals. This longitudinal study explored the hypothesised role of negative affect in the development and persistence of CI in a general population. A general population sample aged 19 to 72years was examined in 2006-2008 and again in 2011-2012. Longitudinal data on CI were analysed with the purpose of examining baseline negative affect as a risk factor for having developed CI at 5-year follow-up and for reporting persistent CI. Participants were classified as reporting no signs of CI, having symptoms of CI and as being a likely CI case based on self-reported reactions to 11 common chemical exposures, symptoms related to chemical exposures and daily life adjustments attributed to reactions when exposed to chemicals. A total of 69.4% of the participants who had reported CI at baseline also reported CI at follow-up. In participants with no baseline CI, 1...
Circulation. Cardiovascular genetics, Jan 24, 2015
-There are several well-established lifestyle factors influencing dyslipidemia and currently, 157... more -There are several well-established lifestyle factors influencing dyslipidemia and currently, 157 genetic susceptibility loci have been reported to be associated with serum lipid levels at genome-wide statistical significance. However, the interplay between lifestyle risk factors and these susceptibility loci has not been fully elucidated. We tested if genetic risk scores (GRS) of lipid-associated SNPs associate with fasting serum lipid traits and if the effects are modulated by lifestyle factors or estimates of metabolic health. -The SNPs were genotyped in two Danish cohorts: Inter99 (n=5,961) for discovery analyses and Health2006 (n=2,565) for replication. Based on published effect sizes of SNPs associated with circulating fasting levels of total cholesterol, LDL-cholesterol, HDL-cholesterol or triglyceride, four weighted GRS (wGRS) were constructed. In a cross-sectional design, we investigated if the effect of these wGRSs on lipid levels were modulated by diet, alcohol consumption, physical activity and smoking or the individual metabolic health status as estimated from BMI, waist circumference and insulin resistance assessed using HOMA-IR. All four lipid wGRSs associated strongly with their respective trait (from P=3.3×10(-69) to P=1.1×10(-123)). We found interactions between the triglyceride wGRS and BMI and waist circumference on fasting triglyceride levels in Inter99 and replicated these findings in Health2006 (Pinteraction=9.8×10(-5) and 2.0×10(-5), respectively in combined analysis). -Our findings suggest that individuals who are obese may be more susceptible to the cumulative genetic burden of triglyceride SNPs. Therefore, it is suggested that especially these genetically at-risk individuals may benefit more from targeted interventions aiming at obesity prevention.
European journal of preventive cardiology, Jan 3, 2014
Excessive salt intake causes increased blood pressure which is considered the leading risk for pr... more Excessive salt intake causes increased blood pressure which is considered the leading risk for premature death. One major challenge when evaluating associations between daily salt intake and markers of non-communicable diseases is that a high daily salt intake correlates with obesity, which is also a well described risk factor for poor cardiometabolic outcome. The aim of this study was to evaluate the relationship of estimated daily salt intake with blood pressure and blood lipids and to investigate the effect of taking different measures of obesity into account. We included 3294 men and women aged 18-69 years from a general population based study in Copenhagen, Denmark. Estimated 24-hour sodium excretion was calculated by measurements of creatinine and sodium concentration in spot urine in combination with information of sex, age, height and weight. The relations of estimated 24-hour sodium excretion with blood pressure and blood lipids were evaluated by linear regression models. T...
The aim of this paper was to identify the extent of socioeconomic inequality in participation at ... more The aim of this paper was to identify the extent of socioeconomic inequality in participation at baseline and follow-up visits. The Inter99 study is a randomized intervention with the aim of investigating the effects of an individualized lifestyle consultation on ischaemic heart disease (IHD). The study comprised 61,301 persons of which 13,016 were assigned to the intervention group. The rest formed the control group. All those in the intervention group were invited to participate in health examinations, risk assessments, and lifestyle consultations. Participants at high risk of IHD were invited to follow-up visits after 1, 3, and 5 years. Data on five socioeconomic factors were retrieved from nationwide registers. For each socioeconomic factor we estimated the relative risks and relative index of inequality of participation at the baseline visit and among high-risk participants at follow-up visits. In addition, we conducted analyses of trends in socioeconomic inequality in participation across follow-up visits. Participation rates were 53% at baseline and 61-65% at the three follow-up visits. There was strong socioeconomic inequality in participation at baseline, with increasing probability of participation found with increasing level of socioeconomic position. This was smaller at follow-up visits. Except for education and housing tenure, there was an increase in socioeconomic inequality in participation across follow-up visits. We found strong socioeconomic inequality in participation at baseline and follow-up visits. Effort should be made to increase participation in individualized lifestyle interventions among persons of low socioeconomic position. Otherwise, the consequence may be increased socioeconomic inequality in IHD.
Common diseases like essential hypertension or diabetes mellitus are complex as they are polygeni... more Common diseases like essential hypertension or diabetes mellitus are complex as they are polygenic in nature, such that each genetic variation only has a small influence on the disease. Genes operates in integrated networks providing the blue-print for all biological processes and conditional of the complex genotype determines the state and dynamics of any trait, which may be modified to various extent by non-genetic factors. Thus, diseases are heterogenous ensembles of conditions with a common endpoint. Numerous studies have been performed to define genes of importance for a trait or disease, but only a few genes with small effect have been identified. The major reasons for this modest progress is the unresolved heterogeneity of the regulation of blood pressure and the shortcomings of the prevailing monogenic approach to capture genetic effects in a polygenic condition. Here, a two-step procedure is presented in which physiological heterogeneity is disentangled and genetic effects ...
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Papers by Allan Linneberg