It is unclear to what extent genetic testing improves the ability to diagnose familial hypercholesterolaemia (FH). We investigated the percentage with FH among individuals referred to Danish lipid ...clinics, and evaluated the impact of genetic testing for a diagnosis of FH.
From September 2020 through November 2021, all patients referred for possible FH to one of the 15 Danish lipid clinics were invited for study participation and >97% (n = 1488) accepted. The Dutch Lipid Clinical Network criteria were used to diagnose clinical FH. The decision of genetic testing for FH was based on local practice.
A total of 1243 individuals were referred, of whom 25.9% were diagnosed with genetic and/or clinical FH. In individuals genetically tested (n = 705), 21.7% had probable or definite clinical FH before testing, a percentage that increased to 36.9% after genetic testing. In individuals with unlikely and possible FH before genetic testing, 24.4% and 19.0%, respectively, had a causative pathogenic variant.
In a Danish nationwide study, genetic testing increased a diagnosis of FH from 22% to 37% in patients referred with hypercholesterolaemia suspected of having FH. Importantly, approximately 20% with unlikely or possible FH, who without genetic testing would not have been considered having FH (and family screening would not have been undertaken), had a pathogenic FH variant. We therefore recommend a more widespread use of genetic testing for evaluation of a possible FH diagnosis and potential cascade screening.
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•Large nationwide study including all 1243 individuals referred to Danish lipid clinics for suspected FH in a 15 month period.•A total of 26% of the referred patients had FH despite only 705/1243 were genetically tested.•Genetic testing increased the diagnoses of FH from 22% to 37% in patients referred with hypercholesterolemia suspected of FH.•Approximately 20% with unlikely or possible FH according to DLCN criteria (before genetic testing) had causative FH mutations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK, ZRSKP
Purpose
The aims of this study were to examine associations between substitutions of poultry and red meat intake with fish (total, lean or fatty) and the risk of peripheral arterial disease (PAD). We ...hypothesised that a higher intake of fish and a concomitant lower intake of poultry or red meat were associated with a lower risk of incident PAD.
Methods
We used data from a Danish cohort where middle-aged participants filled in food frequency and lifestyle questionnaires at baseline. During follow-up, we identified participants with valid diagnoses of PAD and analysed data by multivariable Cox regression analyses. Substitutions of 150 g/week of either poultry, red meat (processed or unprocessed) with 150 g/week of fish (total, lean or fatty) were explored.
Results
We followed the cohort (
n
= 54,597) for a median of 13.6 years and identified 897 cases with PAD. We found modest lower rates of PAD when intake of fish replaced a concomitant lower intake of unprocessed (HR 0.94, 95% CI 0.88–1.01) and processed red meat (HR 0.94, 95% CI 0.87–1.02). Replacing unprocessed (HR 0.89, 95% CI 0.79–1.00) or processed red meat (HR 0.88, 95% CI 0.78–1.01) with fatty fish was associated with lower rates of PAD. No associations were observed when fish intake replaced poultry or when lean fish replaced red meat.
Conclusions
This study suggests that substituting red meat with fish and especially fatty fish may be associated with a lower risk of PAD, although not statistically significant. Replacing poultry with fish was not associated with the risk of PAD.
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DOBA, EMUNI, FIS, FSPLJ, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
IntroductionRheumatoid arthritis (RA) is a chronic autoimmune inflammatory joint disease with multifactorial aetiology. Smoking is a well-established lifestyle risk factor, but diet may also have an ...impact on the risk of RA. Intake of the major marine n-3 polyunsaturated fatty acids in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been hypothesised to lower the risk of RA due to their anti-inflammatory effects, although based on limited knowledge. Therefore, we aim to investigate the associations between dietary intake of EPA and DHA and the risk of incident RA.Methods and analysisA cohort study. The follow-up design will be based on data from the Danish Diet, Cancer and Health cohort, which was established between 1993 and 1997. The participants will be followed through record linkage using nationwide registers including the Danish Civil Registration System, the Danish National Patient Registry and the Danish National Prescription Registry using the unique Civil Personal Registration number. Time-to-event analyses will be conducted with RA as the outcome of interest. The participants will be followed from inclusion until date of RA diagnosis, death, emigration or end of follow-up. HRs with 95% CIs obtained using Cox proportional hazard regression models, with age as underlying time scale and adjustment for established and potential risk factors, will be used as measures of association.Ethics and disseminationThe study has been approved by the Data Protection Committee of Northern Jutland, Denmark (2019-87) and the North Denmark Region Committee on Health Research Ethics (N-20190031). Study results will be disseminated through peer-reviewed journals and presentations at international conferences.
Purpose
We investigated risk of myocardial infarction (MI) associated with the content of linoleic acid (LA) in adipose tissue, a biomarker of long-term dietary intake of LA and a marker of ...endogenous LA exposure.
Methods
Between 1993 and 1997, 57,053 middle-aged subjects were included in the Danish Diet, Cancer and Health cohort. We performed a case–cohort study that included a random sample of the full cohort (
n
= 3167) and all incident MI cases appearing during 16 years of follow-up (
n
= 2819). Information on incident MI cases was obtained by linkage with Danish nationwide registries. Adipose tissue biopsies were taken from the buttocks of the participants, and their fatty acid composition was determined using gas chromatography. HRs (hazard ratios) with 95% confidence intervals (CIs) were used to describe the associations between content of LA in adipose tissue and the risk of MI. HRs were calculated using weighted Cox proportional hazards regression with robust variance.
Results
After adjustment for established risk factors of MI, adipose tissue content of LA was not associated with the risk of MI in men and women combined (quintiles 5 versus 1, HR, 1.03 (95% CI, 0.85–1.25),
P
-trend = 0.970) or in men and women separately (quintiles 5 versus 1, HR, 1.05 (95% CI, 0.83–1.33),
P
-trend = 0.871 and quintiles 5 versus 1, HR, 0.99 (95% CI 0.72–1.37),
P
-trend = 0.928, respectively). Investigating the association between LA and MI with a shorter, 5- or 10-year duration of follow-up provided similar results.
Conclusion
Content of LA in adipose tissue was not associated with the risk of MI.
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DOBA, EMUNI, FIS, FSPLJ, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
We investigated the association between the content of linoleic acid in adipose tissue, a biomarker of long-term intake of linoleic acid, and the risk of ischemic stroke and its subtypes.
The Danish ...cohort study Diet, Cancer and Health included 57 053 patients aged 50 to 65 years at enrollment. All participants had an adipose tissue biopsy performed at enrollment, while information on ischemic stroke during follow-up was obtained from the Danish National Patient Register. Stroke diagnoses were all validated and classified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. Cases and a randomly drawn subcohort of 3500 patients had their fatty acid composition in adipose tissue determined by gas chromatography. Hazard ratios with 95% confidence intervals were calculated using weighted Cox proportional hazard regression. During 13.5 years of follow-up, 1879 ischemic stroke cases were identified, for which 1755 adipose biopsies were available, while adipose biopsies were available for 3203 participants in the subcohort. When comparing the highest and the lowest quartiles of adipose tissue content of linoleic acid there was a negative association with the rate of total ischemic stroke (hazard ratio, 0.78; 95% confidence interval, 0.65-0.93) and large artery atherosclerosis (hazard ratio, 0.61; 95% confidence interval, 0.43-0.88), while there was an indication of a negative association with small-vessel occlusion (hazard ratio, 0.87; 95% confidence interval, 0.69-1.11). There was no clear association with the rate of cardioembolism.
The content of linoleic acid in adipose tissue was inversely associated with the risk of total ischemic stroke and stroke caused by large artery atherosclerosis.
•Very low proportion of monogenic familial hypercholesterolemia in the Faroe Islands.•High proportion polygenic hypercholesterolemia in the Faroe Islands.•High lipoprotein(a) levels associated with ...clinical familial hypercholesterolemia.•Dietary measures healthy in individuals with clinical familial hypercholesterolemia.
The prevalence of clinical familial hypercholesterolemia (FH) is very high in the Faroe Islands, but the possible causes are unknown.
We aimed to describe potential genetic causes of FH in the Faroe Islands and to investigate whether levels of lipoprotein(a) and measures of dietary habits were associated with clinical FH in the Faroe Islands.
In this case-control study, we identified potential clinical FH cases aged 18–75 years registered within a nationwide clinical laboratory database in the Faroe Islands and invited them for diagnostic evaluation according to clinical FH scoring systems. Controls were identified in the background population. Lipoprotein(a) was measured in plasma, while the fatty acid composition was determined in adipose tissue. The habitual diet of the participants was assessed using a food frequency questionnaire. Genetic testing for FH and polygenic variants was performed in a selection of clinical FH cases.
A total of 121 clinical FH cases and 123 age- and sex-matched controls were recruited. We found a very low frequency of monogenic FH (2.5%), but a high level of polygenic FH (63%) in those genetically tested (67%). High levels of plasma lipoprotein(a) were associated with high odds of clinical FH. Clinical FH cases had a lower intake of saturated fatty acids (SFAs) measured by a high fat-score and a lower content of SFAs in adipose tissue compared with controls.
The high prevalence of FH in the Faroe Islands may be due to polygenic causes of hypercholesterolemia and to a lesser extent other genetic factors and elevated plasma lipoprotein(a) levels.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The Danish National Patient Register (DNPR)is widely used for research and administrative purposes. However, its usability is highly dependent of the validity of the registered data. We therefore ...aimed to determine the positive predictive value (PPV) of angina pectoris and acute coronary syndrome (ACS) in the DNPR.
We selected a random sample of 500 patients registered with angina pectoris and a random sample of 500 patients registered with ACS among all hospitalisations at any department in Northern Denmark between 1 January 2007 and 31 December 2007. We reviewed the medical records of the sample patients and recorded whether the angina pectoris and the ACS diagnoses were valid, based on the European Society of Cardiology criteria.
The PPV of definite and probable angina pectoris was 45.9% (95% confidence interval (CI): 41.3-50.6%), whereas the PPV of verified ACS was 86.6% (95% CI: 83.3-89.5%). Stratification by hospital department revealed significantly higher PPVs for diagnoses received in a cardiology unit for both angina pectoris (61.7%; 95% CI: 53.4-69.6%) and ACS (95.5%; 95% CI: 91.3-98.0%). Stratification by gender showed a significantly higher PPV among men registered with angina pectoris (51.2%; 95% CI: 45.3-57.1%).
The angina pectoris and ACS data contained in the DNPR should be used with caution in register studies if validation is not possible. Restricting analyses of ACS data to patients discharged from cardiology wards may be a useful option in register-based studies.
none.
not relevant.
Building a population-specific catalogue of single nucleotide variants (SNVs), indels and structural variants (SVs) with frequencies, termed a national pan-genome, is critical for further advancing ...clinical and public health genetics in large cohorts. Here we report a Danish pan-genome obtained from sequencing 10 trios to high depth (50 × ). We report 536k novel SNVs and 283k novel short indels from mapping approaches and develop a population-wide de novo assembly approach to identify 132k novel indels larger than 10 nucleotides with low false discovery rates. We identify a higher proportion of indels and SVs than previous efforts showing the merits of high coverage and de novo assembly approaches. In addition, we use trio information to identify de novo mutations and use a probabilistic method to provide direct estimates of 1.27e-8 and 1.5e-9 per nucleotide per generation for SNVs and indels, respectively.
Hundreds of thousands of human genomes are now being sequenced to characterize genetic variation and use this information to augment association mapping studies of complex disorders and other ...phenotypic traits. Genetic variation is identified mainly by mapping short reads to the reference genome or by performing local assembly. However, these approaches are biased against discovery of structural variants and variation in the more complex parts of the genome. Hence, large-scale de novo assembly is needed. Here we show that it is possible to construct excellent de novo assemblies from high-coverage sequencing with mate-pair libraries extending up to 20 kilobases. We report de novo assemblies of 150 individuals (50 trios) from the GenomeDenmark project. The quality of these assemblies is similar to those obtained using the more expensive long-read technology. We use the assemblies to identify a rich set of structural variants including many novel insertions and demonstrate how this variant catalogue enables further deciphering of known association mapping signals. We leverage the assemblies to provide 100 completely resolved major histocompatibility complex haplotypes and to resolve major parts of the Y chromosome. Our study provides a regional reference genome that we expect will improve the power of future association mapping studies and hence pave the way for precision medicine initiatives, which now are being launched in many countries including Denmark.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
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