Genetic Architecture of Ischaemic Strokes after COVID-19 Shows Similarities with Large Vessel Strokes.

We aimed to analyse whether patients with ischaemic stroke (IS) occurring within eight days after the onset of COVID-19 (IS-COV) are associated with a specific aetiology of IS. We used SUPERGNOVA to identify genome regions that correlate between the IS-COV cohort (73 IS-COV cases vs. 701 population controls) and different aetiological subtypes. Polygenic risk scores (PRSs) for each subtype were generated and tested in the IS-COV cohort using PRSice-2 and PLINK to find genetic associations. Both analyses used the IS-COV cohort and GWAS from MEGASTROKE (67,162 stroke patients vs. 454,450 population controls), GIGASTROKE (110,182 vs. 1,503,898), and the NINDS Stroke Genetics Network (16,851 vs. 32,473). Three genomic regions were associated (p-value < 0.05) with large artery atherosclerosis (LAA) and cardioembolic stroke (CES). We found four loci targeting the genes PITX2 (rs10033464, IS-COV beta = 0.04, p-value = 2.3 × 10-2, se = 0.02), previously associated with CES, HS6ST1 (rs4662630, IS-COV beta = -0.04, p-value = 1.3 × 10-3, se = 0.01), TMEM132E (rs12941838 IS-COV beta = 0.05, p-value = 3.6 × 10-4, se = 0.01), and RFFL (rs797989 IS-COV beta = 0.03, p-value = 1.0 × 10-2, se = 0.01). A statistically significant PRS was observed for LAA. Our results suggest that IS-COV cases are genetically similar to LAA and CES subtypes. Larger cohorts are needed to assess if the genetic factors in IS-COV cases are shared with the general population or specific to viral infection.

Recontacting biobank participants to collect lifestyle, behavioural and cognitive information via online questionnaires: lessons from a pilot study within FinnGen.

OBJECTIVES: To recontact biobank participants and collect cognitive, behavioural and lifestyle information via a secure online platform. DESIGN: Biobank-based recontacting pilot study. SETTING: Three Finnish biobanks (Helsinki, Auria, Tampere) recruiting participants from February 2021 to July 2021. PARTICIPANTS: All eligible invitees were enrolled in FinnGen by their biobanks (Helsinki, Auria, Tampere), had available genetic data and were >18 years old. Individuals with severe neuropsychiatric disease or cognitive or physical disabilities were excluded. Lastly, 5995 participants were selected based on their polygenic score for cognitive abilities and invited to the study. Among invitees, 1115 had successfully participated and completed the study questionnaire(s). OUTCOME MEASURES: The primary outcome was the participation rate among study invitees. Secondary outcomes included questionnaire completion rate, quality of data collected and comparison of participation rate boosting strategies. RESULTS: The overall participation rate was 18.6% among all invitees and 23.1% among individuals aged 18-69. A second reminder letter yielded an additional 9.7% participation rate in those who did not respond to the first invitation. Recontacting participants via an online healthcare portal yielded lower participation than recontacting via physical letter. The completion rate of the questionnaire and cognitive tests was high (92% and 85%, respectively), and measurements were overall reliable among participants. For example, the correlation (r) between self-reported body mass index and that collected by the biobanks was 0.92. CONCLUSION: In summary, this pilot suggests that recontacting FinnGen participants with the goal to collect a wide range of cognitive, behavioural and lifestyle information without additional engagement results in a low participation rate, but with reliable data. We suggest that such information be collected at enrolment, if possible, rather than via post hoc recontacting.

The human genetic epidemiology of COVID-19.

Human genetics can inform the biology and epidemiology of coronavirus disease 2019 (COVID-19) by pinpointing causal mechanisms that explain why some individuals become more severely affected by the disease upon infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. Large-scale genetic association studies, encompassing both rare and common genetic variants, have used different study designs and multiple disease phenotype definitions to identify several genomic regions associated with COVID-19. Along with a multitude of follow-up studies, these findings have increased our understanding of disease aetiology and provided routes for management of COVID-19. Important emergent opportunities include the clinical translatability of genetic risk prediction, the repurposing of existing drugs, exploration of variable host effects of different viral strains, study of inter-individual variability in vaccination response and understanding the long-term consequences of SARS-CoV-2 infection. Beyond the current pandemic, these transferrable opportunities are likely to affect the study of many infectious diseases.

Reduced reproductive success is associated with selective constraint on human genes.

Genome-wide sequencing of human populations has revealed substantial variation among genes in the intensity of purifying selection acting on damaging genetic variants1. Although genes under the strongest selective constraint are highly enriched for associations with Mendelian disorders, most of these genes are not associated with disease and therefore the nature of the selection acting on them is not known2. Here we show that genetic variants that damage these genes are associated with markedly reduced reproductive success, primarily owing to increased childlessness, with a stronger effect in males than in females. We present evidence that increased childlessness is probably mediated by genetically associated cognitive and behavioural traits, which may mean that male carriers are less likely to find reproductive partners. This reduction in reproductive success may account for 20% of purifying selection against heterozygous variants that ablate protein-coding genes. Although this genetic association may only account for a very minor fraction of the overall likelihood of being childless (less than 1%), especially when compared to more influential sociodemographic factors, it may influence how genes evolve over time.

Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality.

BackgroundThere is considerable variability in COVID-19 outcomes among younger adults, and some of this variation may be due to genetic predisposition.MethodsWe combined individual level data from 13,888 COVID-19 patients (n = 7185 hospitalized) from 17 cohorts in 9 countries to assess the association of the major common COVID-19 genetic risk factor (chromosome 3 locus tagged by rs10490770) with mortality, COVID-19-related complications, and laboratory values. We next performed metaanalyses using FinnGen and the Columbia University COVID-19 Biobank.ResultsWe found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (HR, 1.4; 95% CI, 1.2-1.7). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (OR, 2.1; 95% CI, 1.6-2.6), venous thromboembolism (OR, 1.7; 95% CI, 1.2-2.4), and hepatic injury (OR, 1.5; 95% CI, 1.2-2.0). Risk allele carriers age 60 years and younger had higher odds of death or severe respiratory failure (OR, 2.7; 95% CI, 1.8-3.9) compared with those of more than 60 years (OR, 1.5; 95% CI, 1.2-1.8; interaction, P = 0.038). Among individuals 60 years and younger who died or experienced severe respiratory failure, 32.3% were risk-variant carriers compared with 13.9% of those not experiencing these outcomes. This risk variant improved the prediction of death or severe respiratory failure similarly to, or better than, most established clinical risk factors.ConclusionsThe major common COVID-19 genetic risk factor is associated with increased risks of morbidity and mortality, which are more pronounced among individuals 60 years or younger. The effect was similar in magnitude and more common than most established clinical risk factors, suggesting potential implications for future clinical risk management.

Trait Expression and Environmental Responses of Pea (Pisum sativum L.) Genetic Resources Targeting Cultivation in the Arctic.

In the Arctic part of the Nordic region, cultivated crops need to specifically adapt to adverse and extreme climate conditions, such as low temperatures, long days, and a short growing season. Under the projected climate change scenarios, higher temperatures and an earlier spring thaw will gradually allow the cultivation of plants that could not be previously cultivated there. For millennia, Pea (Pisum sativum L.) has been a major cultivated protein plant in Nordic countries but is currently limited to the southern parts of the region. However, response and adaptation to the Arctic day length/light spectrum and temperatures are essential for the productivity of the pea germplasm and need to be better understood. This study investigated these factors and identified suitable pea genetic resources for future cultivation and breeding in the Arctic region. Fifty gene bank accessions of peas with a Nordic landrace or cultivar origin were evaluated in 2-year field trials at four Nordic locations in Denmark, Finland, Sweden, and Norway (55° to 69° N). The contrasting environmental conditions of the trial sites revealed differences in expression of phenological, morphological, crop productivity, and quality traits in the accessions. The data showed that light conditions related to a very long photoperiod partly compensated for the lack of accumulated temperature in the far north. A critical factor for cultivation in the Arctic is the use of cultivars with rapid flowering and maturation times combined with early sowing. At the most extreme site (69°N), no accession reached full maturation. Nonetheless several accessions, predominantly landraces of a northern origin, reached a green harvest state. All the cultivars reached full maturation at the sub-Arctic latitude in northern Sweden (63°N) when plants were established early in the season. Seed yield correlated positively with seed number and aboveground biomass, but negatively with flowering time. A high yield potential and protein concentration of dry seed were found in many garden types of pea, confirming their breeding potential for yield. Overall, the results indicated that pea genetic resources are available for breeding or immediate cultivation, thus aiding in the northward expansion of pea cultivation. Predicted climate changes would support this expansion.

Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality.

BACKGROUND: There is considerable variability in COVID-19 outcomes amongst younger adults-and some of this variation may be due to genetic predisposition. We characterized the clinical implications of the major genetic risk factor for COVID-19 severity, and its age-dependent effect, using individual-level data in a large international multi-centre consortium. METHOD: The major common COVID-19 genetic risk factor is a chromosome 3 locus, tagged by the marker rs10490770. We combined individual level data for 13,424 COVID-19 positive patients (N=6,689 hospitalized) from 17 cohorts in nine countries to assess the association of this genetic marker with mortality, COVID-19-related complications and laboratory values. We next examined if the magnitude of these associations varied by age and were independent from known clinical COVID-19 risk factors. FINDINGS: We found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (hazard ratio [HR] 1·4, 95% confidence interval [CI] 1·2-1·6) and COVID-19 related mortality (HR 1·5, 95%CI 1·3-1·8). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (odds ratio [OR] 2·0, 95%CI 1·6-2·6), venous thromboembolism (OR 1·7, 95%CI 1·2-2·4), and hepatic injury (OR 1·6, 95%CI 1·2-2·0). Risk allele carriers ≤ 60 years had higher odds of death or severe respiratory failure (OR 2·6, 95%CI 1·8-3·9) compared to those > 60 years OR 1·5 (95%CI 1·3-1·9, interaction p-value=0·04). Amongst individuals ≤ 60 years who died or experienced severe respiratory COVID-19 outcome, we found that 31·8% (95%CI 27·6-36·2) were risk variant carriers, compared to 13·9% (95%CI 12·6-15·2%) of those not experiencing these outcomes. Prediction of death or severe respiratory failure among those ≤ 60 years improved when including the risk allele (AUC 0·82 vs 0·84, p=0·016) and the prediction ability of rs10490770 risk allele was similar to, or better than, most established clinical risk factors. INTERPRETATION: The major common COVID-19 risk locus on chromosome 3 is associated with increased risks of morbidity and mortality-and these are more pronounced amongst individuals ≤ 60 years. The effect on COVID-19 severity was similar to, or larger than most established risk factors, suggesting potential implications for clinical risk management. FUNDING: Funding was obtained by each of the participating cohorts individually.

The contribution of X-linked coding variation to severe developmental disorders.

Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders.

Cognitive impairment and health-related quality of life following traumatic brain injury.

BACKGROUND: Cognitive impairment is a common and disabling consequence of traumatic brain injury (TBI) but its impact on health-related quality of life is not well understood. OBJECTIVE: To investigate the relationship between cognitive impairment and health-related quality of life (HRQoL) after TBI. METHODS: Retrospective, cross-sectional study of a specialist TBI outpatient clinic patient sample. OUTCOME MEASURES: Addenbrooke's Cognitive Examination Tool - Revised (ACE-R), and SF-36 quality of life, Beck Depression Inventory II (BDI-II), Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) questionnaires. RESULTS: 240 adults were assessed: n = 172 (71.7%) moderate-severe, 41 (23.8%) mild, 27 (11.3%) symptomatic TBI, 174 (72.5%) male, median age (range): 44 (22-91) years. TBI patients reported poorer scores on all domains of SF-36 compared to age-matched UK normative data. Cognitively impaired patients reported poorer HRQoL on the physical, social role and emotional role functioning, and mental health domains. Cognitive impairment predicted poorer HRQoL on the social and emotional role functioning domains, independently of depressive symptoms, sleep disturbance, daytime sleepiness and TBI severity. Mediation analysis revealed that the effect of depressive symptoms on the emotional role functioning domain of HRQoL was partially mediated by cognitive dysfunction. CONCLUSION: Cognitive impairment is associated with worse health-related quality of life after TBI and partially mediates the effect of depressive symptoms on emotional role functioning.

Quantifying the contribution of recessive coding variation to developmental disorders.

We estimated the genome-wide contribution of recessive coding variation in 6040 families from the Deciphering Developmental Disorders study. The proportion of cases attributable to recessive coding variants was 3.6% in patients of European ancestry, compared with 50% explained by de novo coding mutations. It was higher (31%) in patients with Pakistani ancestry, owing to elevated autozygosity. Half of this recessive burden is attributable to known genes. We identified two genes not previously associated with recessive developmental disorders, KDM5B and EIF3F, and functionally validated them with mouse and cellular models. Our results suggest that recessive coding variants account for a small fraction of currently undiagnosed nonconsanguineous individuals, and that the role of noncoding variants, incomplete penetrance, and polygenic mechanisms need further exploration.

Common genetic variants contribute to risk of rare severe neurodevelopmental disorders.

There are thousands of rare human disorders that are caused by single deleterious, protein-coding genetic variants1. However, patients with the same genetic defect can have different clinical presentations2-4, and some individuals who carry known disease-causing variants can appear unaffected5. Here, to understand what explains these differences, we study a cohort of 6,987 children assessed by clinical geneticists to have severe neurodevelopmental disorders such as global developmental delay and autism, often in combination with abnormalities of other organ systems. Although the genetic causes of these neurodevelopmental disorders are expected to be almost entirely monogenic, we show that 7.7% of variance in risk is attributable to inherited common genetic variation. We replicated this genome-wide common variant burden by showing, in an independent sample of 728 trios (comprising a child plus both parents) from the same cohort, that this burden is over-transmitted from parents to children with neurodevelopmental disorders. Our common-variant signal is significantly positively correlated with genetic predisposition to lower educational attainment, decreased intelligence and risk of schizophrenia. We found that common-variant risk was not significantly different between individuals with and without a known protein-coding diagnostic variant, which suggests that common-variant risk affects patients both with and without a monogenic diagnosis. In addition, previously published common-variant scores for autism, height, birth weight and intracranial volume were all correlated with these traits within our cohort, which suggests that phenotypic expression in individuals with monogenic disorders is affected by the same variants as in the general population. Our results demonstrate that common genetic variation affects both overall risk and clinical presentation in neurodevelopmental disorders that are typically considered to be monogenic.

Gendered use of experts in the media: Analysis of the gender gap in Finnish news journalism.

Several studies conducted in Western democracies have indicated that men continue to be overrepresented and women underrepresented as experts in the media. This article explores the situation in Finland, a progressive and 'female-friendly' Nordic country with highly educated women who are widely present in the job market. The analysis is based on three sets of research data featuring a wide set of media data, a survey and interviews. This study reveals that public expertise continues to be male dominated in Finland: less than 30% of the experts interviewed in the news media are women. While the distribution of work and power in the labour market may explain some of the observed gender gap, journalistic practices and a masculine tradition of public expertise are likely to play a role as well.

Prevalence and correlates of vitamin D deficiency in adults after traumatic brain injury.

OBJECTIVES: Traumatic brain injury (TBI) is a major cause of long-term disability with variable recovery. Preclinical studies suggest that vitamin D status influences the recovery after TBI. However, there is no published clinical data on links between vitamin D status and TBI outcomes. The aim was to determine the (i) prevalence of vitamin D deficiency/insufficiency, and associations of vitamin D status with (ii) demographic factors and TBI severity, and with (iii) cognitive function, symptoms and quality of life, in adults after TBI. DESIGN: Retrospective audit of patients seen between July 2009 and March 2015. Serum vitamin D (25-hydroxy-cholecalciferol) was categorized as deficient (<40 nmol/l), insufficient (40-70 nmol/l) or replete (>70 nmol/l). PATIENTS: A total of 353 adults seen in tertiary hospital clinic (75·4% lighter skinned, 74·8% male, age median 35·1 year, range 26·6-48·3 year), 0·3-56·5 months after TBI (74·5% moderate-severe). MEASUREMENTS: Serum vitamin D concentrations; Addenbrooke's Cognitive Examination (ACE-R), Beck Depression Inventory-II (BDI-II), SF-36 Quality of Life, Pittsburgh Sleep Quality Index. RESULTS: In total, 46·5% of patients after TBI had vitamin D deficiency and 80·2% insufficiency/deficiency. Patients with vitamin D deficiency had lower ACE-R scores than those of vitamin D replete (mean effect size ± SEM 4·5 ± 2·1, P = 0·034), and higher BDI-II scores than those of vitamin D insufficient (4·5 ± 1·6, P = 0·003), correcting for age, gender, time since TBI and TBI severity. There was no association between vitamin D status and markers of TBI severity, sleep or quality of life. CONCLUSION: Vitamin D deficiency is common in patients after TBI and associated with impaired cognitive function and more severe depressive symptoms.

Two founder mutations in the alpha-tropomyosin and the cardiac myosin-binding protein C genes are common causes of hypertrophic cardiomyopathy in the Finnish population.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is predominantly caused by a large number of various mutations in the genes encoding sarcomeric proteins. However, two prevalent founder mutations for HCM in the alpha-tropomyosin (TPM1-D175N) and myosin-binding protein C (MYBPC3-Q1061X) genes have previously been identified in eastern Finland. OBJECTIVE: To assess the prevalence of these founder mutations in a large population of patients with HCM from all over Finland. Patients and methods. We screened for two founder mutations (TPM1-D175N and MYBPC3-Q1061X) in 306 unrelated Finnish patients with HCM from the regions covering a population of ∼4,000,000. RESULTS: The TPM1-D175N mutation was found in 20 patients (6.5%) and the MYBPC3-Q1061X in 35 patients (11.4%). Altogether, the two mutations accounted for 17.9% of the HCM cases. In addition, 61 and 59 relatives of the probands were found to be carriers of TPM1-D175N and MYBPC3-Q1061X, respectively. The mutations showed regional clustering. TPM1-D175N was prevalent in central and western Finland, and MYBPC3-Q1061X in central and eastern Finland. CONCLUSION: The TPM1-D175N and MYBPC3-Q1061X mutations account for a substantial part of all HCM cases in the Finnish population, indicating that routine genetic screening of these mutations is warranted in Finnish patients with HCM.

Exercise electrocardiography detection of coronary artery disease by ST-segment depression/heart rate hysteresis in women: the Finnish Cardiovascular Study.

INTRODUCTION: The performance of exercise electrocardiography (ECG) for the detection of coronary artery disease (CAD) in women has been limited. The recently developed computerized variable, ST-segment depression/heart rate (ST/HR) hysteresis, has been proved to detect CAD in men more accurately than traditional methods. However, the diagnostic performance of ST/HR hysteresis has not been evaluated in women. MATERIALS AND METHODS: The study population comprised 161 female patients from the Finnish Cardiovascular Study (FINCAVAS). All patients were referred for a routine bicycle exercise test. The maximum values of ST/HR hysteresis, ST/HR index, ST-segment depression at peak exercise (STpeak), at the end of one (ST1rec) and three (ST3rec) minutes of post-exercise were determined. Significant CAD was present in 48, while 65 women showed no angiographic CAD. Also a group of 48 women with low likelihood of CAD (LLC) was formed. Diagnostic performance of variables was assessed by receiver operating characteristic (ROC) analysis. Furthermore, sensitivity values at 80% specificity and specificities at 80% sensitivity were determined. RESULTS: In a comparison between CAD and LLC groups, the ROC areas for ST/HR hysteresis, ST/HR index, STpeak, ST1rec and ST3rec were 0.89, 0.74, 0.65, 0.84 and 0.73, and sensitivities at 80% specificity were 88%, 67%, 52%, 75% and 60%, respectively. Comparing CAD and no-CAD groups, the ROC areas were 0.73, 0.67, 0.56, 0.63 and 0.60, and specificities at 80% sensitivity were 60%, 38%, 27%, 33% and 30%. CONCLUSIONS: ST/HR hysteresis is a more competent method in CAD detection in women than ST-segment depression or ST/HR index.

Heart rate variability derived from exercise ECG in the detection of coronary artery disease.

The diagnostic performance of heart rate variability (HRV) analysis from exercise ECG in the detection of coronary artery disease (CAD) is unknown. Bicycle exercise ECG recordings from The Finnish Cardiovascular Study (FINCAVAS) of angiography-proofed CAD patients (n = 112) and a patient group with a low likelihood of CAD (n = 114) were analyzed. HRV parameters (SDNN, RMSSD, Poincaré SD1 and SD2) were calculated from 1 min segments before exercise, during exercise and after exercise. All the parameters were in addition calculated from heart rate (HR)-corrected RR-interval segments. The ST-segment depressions in each stage were also determined. The diagnostic performance of the parameters was evaluated with the area under the receiver operating characteristic (ROC) curve method. The uncorrected HRV parameters showed the best diagnostic performance in the recovery segments but the correlation with HR was also high (SDNN: 0.758/-0.64, RMSSD: 0.747/-0.60; area under the ROC/correlation coefficient). The HR correction decreased the correlation and the diagnostic performance in recovery segments (SDNN: 0.515/-0.12, RMSSD: 0.609/0.20). The diagnostic performance of ST-level at its best was higher than any of HRV parameters (ST-level: 0.795/0.36). According to the results, the HR correction decreased the diagnostic performance of the recovery phase. The HRV parameters calculated from 1 min segments of exercise test ECG were not as capable as traditional ST-segment analysis. In conclusion, the HRV analysis from exercise or recovery phase seems to be inadequate in the detection of CAD.

The p22phox C242T gene polymorphism is associated with a reduced risk of angiographically verified coronary artery disease in a high-risk Finnish Caucasian population. The Finnish Cardiovascular Study.

BACKGROUND: Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is a major source of the superoxide anion, which may play an important role in the development of atherosclerosis and coronary artery disease (CAD). The p22phox, a component of the NADPH oxidase, is essential for the activation of this enzyme, and intensive expression of the p22phox has been reported in human atherosclerotic arteries. However, studies on the association of the C242T polymorphism in the p22phox gene with CAD have produced conflicting results, and the relation of this polymorphism with CAD is not well known in a population with acquired risk factors enhancing the NADPH-dependent superoxide production. METHODS: As part of the Finnish Cardiovascular Study, a case-control study was conducted with 402 high-risk Finnish Caucasian patients undergoing coronary angiography. Genotyping was performed using the 5' nuclease TaqMan assay. RESULTS: The prevalence of the T allele (TT + TC genotypes) was significantly lower among angiographically verified CAD patients (n = 250) than among control subjects (n = 152, P = .013). In contrast to subjects with the CC genotype, the T allele was found protective against CAD (odds ratio = 0.531, 95% CI 0.331-0.852, P = .009), and the results remained significant after adjustment for other significant coronary risk factors. CONCLUSIONS: The T allele in the C242Tpolymorphism of the p22phox gene had a protective effect against the development of CAD despite the exposure of study subjects to risk factors related to excessive NADPH-dependent superoxide production.

The Finnish Cardiovascular Study (FINCAVAS): characterising patients with high risk of cardiovascular morbidity and mortality.

BACKGROUND: The purpose of the Finnish Cardiovascular Study (FINCAVAS) is to construct a risk profile--using genetic, haemodynamic and electrocardiographic (ECG) markers--of individuals at high risk of cardiovascular diseases, events and deaths. METHODS AND DESIGN: All patients scheduled for an exercise stress test at Tampere University Hospital and willing to participate have been and will be recruited between October 2001 and December 2007. The final number of participants is estimated to reach 5,000. Technically successful data on exercise tests using a bicycle ergometer have been collected of 2,212 patients (1,400 men and 812 women) by the end of 2004. In addition to repeated measurement of heart rate and blood pressure, digital high-resolution ECG at 500 Hz is recorded continuously during the entire exercise test, including the resting and recovery phases. About 20% of the patients are examined with coronary angiography. Genetic variations known or suspected to alter cardiovascular function or pathophysiology are analysed to elucidate the effects and interactions of these candidate genes, exercise and commonly used cardiovascular medications. DISCUSSION: FINCAVAS compiles an extensive set of data on patient history, genetic variation, cardiovascular parameters, ECG markers as well as follow-up data on clinical events, hospitalisations and deaths. The data enables the development of new diagnostic and prognostic tools as well as assessments of the importance of existing markers.

Vascular endothelial growth factor-D expression in human atherosclerotic lesions.

OBJECTIVE: Vascular endothelial growth factor-D (VEGF-D) is a recently characterized member of the VEGF family, but its expression in atherosclerotic lesions remains unknown. We studied the expression of VEGF-D and its receptors (VEGFR-2 and VEGFR-3) in normal and atherosclerotic human arteries, and compared that to the expression pattern of VEGF-A. METHODS: Human arterial samples (n=39) obtained from amputation operations and fast autopsies were classified according to the stage of atherosclerosis and studied by immunohistochemistry. The results were confirmed by in situ hybridization and RT-PCR. RESULTS: We found that while VEGF-A expression increased during atherogenesis, VEGF-D expression remained relatively stable only decreasing in complicated lesions. In normal arteries and in early lesions VEGF-D was mainly expressed in smooth muscle cells, whereas in complicated atherosclerotic lesions the expression was most prominent in macrophages and also colocalized with plaque neovascularization. By comparing the staining profiles of different antibodies, we found that proteolytic processing of VEGF-D was efficient in the vessel wall. VEGFR-2, but not VEGFR-3, was expressed in the vessel wall at every stage of atherosclerosis. CONCLUSIONS: Our results suggest that in large arteries VEGF-D is mainly expressed in smooth muscle cells and that it may have a role in the maintenance of vascular homeostasis. However, in complicated lesions it was also expressed in macrophages and may contribute to plaque neovascularization. The constitutive expression of VEGFR-2 in arteries suggests that it may be one of the principal mediators of the VEGF-D effects in large arteries.