Browsing by Subject "coronary artery disease"

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  • Preussner, Annina (Helsingin yliopisto, 2021)
    The Y chromosome has an essential role in the genetic sex determination in humans and other mammals. It contains a male-specific region (MSY) which escapes recombination and is inherited exclusively through the male line. The genetic variations inherited together on the MSY can be used in classifying Y chromosomes into haplogroups. Y-chromosomal haplogroups are highly informative of genetic ancestry, thus Y chromosomes have been widely used in tracing human population history. However, given the peculiar biology and analytical challenges specific to the Y chromosome, the chromosome is routinely excluded from genetic association studies. Consequently, potential impacts of Y-chromosomal variation on complex disease remain largely uncharacterized. Lately the access to large-scale biobank data has enabled to extend the Y-chromosomal genetic association studies. A recent UK Biobank study suggested links between Y-chromosomal haplogroup I1 and coronary artery disease (CAD) in the British population, but this result has not been validated in other datasets. Since Finland harbours a notable frequency of Y-chromosomal haplogroup I1, the relationship between haplogroup I1 and CAD can further be inferred in the Finnish population using data from the FinnGen project. The first aim of this thesis was to determine the prevalence of Y-chromosomal haplogroups in Finland and characterize their geographical distributions using genotyping array data from the FinnGen project. The second aim was to assess the role between Finnish Y-chromosomal haplogroups and coronary artery disease (CAD) by logistic regression. This thesis characterized the Y-chromosomal haplogroups in Finland for 24 160 males and evaluated the association between Y-chromosomal haplogroups and CAD in Finland. The dataset used in this study was extensive, providing an opportunity to study the Y-chromosomal variation geographically in Finland and its role in complex disease more accurately compared to previous studies. The geographical distribution of the Y-chromosomal haplogroups was characterized on 20 birth regions, and between eastern and western areas of Finland. Consistent with previous studies, the results demonstrated that two major Finnish Y-chromosomal haplogroup lineages, N1c1 and I1, displayed differing distributions within regions, especially between eastern and western Finland. Results from logistic regression analysis between CAD and Y-chromosomal haplogroups suggested no significant association between haplogroup I1 and CAD. Instead, the major Finnish Y-chromosomal haplogroup N1c1 displayed a decreased risk for CAD in the association analysis when compared against other haplogroups. Moreover, this thesis also demonstrated that the association results were not straightforwardly comparable between populations. For instance, haplogroup I1 displayed a decreased risk for CAD in the FinnGen dataset when compared against haplogroup R1b, whereas the same association was reported as risk increasing for CAD in the UK Biobank. Overall, this thesis demonstrates the possibility to study the genetics of Y chromosome using data from the FinnGen project, and highlights the value of including this part of the genome in the future complex disease studies.
  • Shiri, Rahman; Heliovaara, Markku; Moilanen, Leena; Viikari, Jorma; Liira, Helena Johanna; Viikari-Juntura, Eira (2011)
  • Ramo, Joel T.; Ripatti, Pietari; Tabassum, Rubina; Soderlund, Sanni; Matikainen, Niina; Gerl, Mathias J.; Klose, Christian; Surma, Michal A.; Stitziel, Nathan O.; Havulinna, Aki S.; Pirinen, Matti; Salomaa, Veikko; Freimer, Nelson B.; Jauhiainen, Matti; Palotie, Aarno; Taskinen, Marja-Riitta; Simons, Kai; Ripatti, Samuli (2019)
    Background-We asked whether, after excluding familial hypercholesterolemia, individuals with high low-density lipoprotein cholesterol (LDL-C) or triacylglyceride levels and a family history of the same hyperlipidemia have greater coronary artery disease risk or different lipidomic profiles compared with population-based hyperlipidemias. Methods and Results-We determined incident coronary artery disease risk for 755 members of 66 hyperlipidemic families (>2 first-degree relatives with similar hyperlipidemia) and 19 644 Finnish FINRISK population study participants. We quantified 151 circulating lipid species from 550 members of 73 hyperlipidemic families and 897 FINRISK participants using mass spectrometric shotgun lipidomics. Familial hypercholesterolemia was excluded using functional LDL receptor testing and genotyping. Hyperlipidemias (LDL-C or triacylglycerides >90th population percentile) associated with increased coronary artery disease risk in meta-analysis of the hyperlipidemic families and the population cohort (high LDL-C: hazard ratio, 1.74 [95% CI, 1.48-2.04]; high triacylglycerides: hazard ratio, 1.38 [95% CI 1.09-1.74]). Risk estimates were similar in the family and population cohorts also after adjusting for lipid-lowering medication. In lipidomic profiling, high LDL-C associated with 108 lipid species, and high triacylglycerides associated with 131 lipid species in either cohort (at 5% false discovery rate; P-value range 0.038-2.3x 10(-56)). Lipidomic profiles were highly similar for hyperlipidemic individuals in the families and the population (LDL-C: r=0.80; triacylglycerides: r=0.96; no lipid species deviated between the cohorts). Conclusions-Hyperlipidemias with family history conferred similar coronary artery disease risk as population-based hyperlipidemias. We identified distinct lipidomic profiles associated with high LDL-C and triacylglycerides. Lipidomic profiles were similar between hyperlipidemias with family history and population-ascertained hyperlipidemias, providing evidence of similar and overlapping underlying mechanisms.
  • Mustonen, Erja; Horhammer, Iiris; Absetz, Pilvikki; Patja, Kristiina; Lammintakanen, Johanna; Talja, Martti; Kuronen, Risto; Linna, Miika (2020)
    Objective To evaluate the long-term effect of telephone health coaching on health care and long-term care (LTC) costs in type 2 diabetes (T2D) and coronary artery disease (CAD) patients. Data Sources/Study Setting Randomized controlled trial (RCT) data were linked to Finnish national health and social care registries and electronic health records (EHR). Post-trial eight-year economic evaluation was conducted. Study Design A total of 1,535 patients (>= 45 years) were randomized to the intervention (n = 1034) and control groups (n = 501). The intervention group received monthly telephone health coaching for 12 months. Usual health care and LTC were provided for both groups. Principal Findings Intention-to-treat analysis showed no significant change in total health and long-term care costs (intervention effect euro1248 [3 percent relative reduction], CI -6347 to 2217) in the intervention compared to the control group. There were also no significant changes among subgroups of patients with T2D or CAD. Conclusions Health coaching had a nonsignificant effect on health care and long-term care costs in the 8-year follow-up among patients with T2D or CAD. More research is needed to study, which patient groups, at which state of the disease trajectory of T2D and cardiovascular disease, would best benefit from health coaching.
  • Jia, Qiong; Han, Yi; Huang, Pin; Woodward, Nicholas C.; Gukasyan, Janet; Kettunen, Johannes; Ala-Korpela, Mika; Anufrieva, Olga; Wang, Qin; Perola, Markus; Raitakari, Olli; Lehtimaki, Terho; Viikari, Jorma; Jarvelin, Marjo-Riitta; Boehnke, Michael; Laakso, Markku; Mohlke, Karen L.; Fiehn, Oliver; Wang, Zeneng; Tang, W. H. Wilson; Hazen, Stanley L.; Hartiala, Jaana A.; Allayee, Hooman (2019)
    Background-Recent studies have revealed sexually dimorphic associations between the carbamoyl-phosphate synthase 1 locus, intermediates of the metabolic pathway leading from choline to urea, and risk of coronary artery disease (CAD) in women. Based on evidence from the literature, the atheroprotective association with carbamoyl-phosphate synthase 1 could be mediated by the strong genetic effect of this locus on increased circulating glycine levels. Methods and Results-We sought to identify additional genetic determinants of circulating glycine levels by carrying out a metaanalysis of genome-wide association study data in up to 30 118 subjects of European ancestry. Mendelian randomization and other analytical approaches were used to determine whether glycine-associated variants were associated with CAD and traditional risk factors. Twelve loci were significantly associated with circulating glycine levels, 7 of which were not previously known to be involved in glycine metabolism (ACADM, PHGDH, COX1 8-ADAMTS3, PSPH, TRIB 1 , PTPRD, and ABO). Glycine-raising alleles at several loci individually exhibited directionally consistent associations with decreased risk of CAD. However, these effects could not be attributed directly to glycine because of associations with other CAD-related traits. By comparison, genetic models that only included the 2 variants directly involved in glycine degradation and for which there were no other pleiotropic associations were not associated with risk of CAD or blood pressure, lipid levels, and obesity-related traits. Conclusions-These results provide additional insight into the genetic architecture of glycine metabolism, but do not yield conclusive evidence for a causal relationship between circulating levels of this amino acid and risk of CAD in humans.
  • SUMMIT Steering Comm; CARDIOGRAMplusC4D Steering Comm; van Zuydam, Natalie R.; Ladenvall, Claes; Vlachopoulou, Efthymia; Perola, Markus; Sinisalo, Juha; Salomaa, Veikko; Groop, Leif; Ripatti, Samuli (2020)
    BACKGROUND: Coronary artery disease (CAD) is accelerated in subjects with type 2 diabetes mellitus (T2D). METHODS: To test whether this reflects differential genetic influences on CAD risk in subjects with T2D, we performed a systematic assessment of genetic overlap between CAD and T2D in 66 643 subjects (27 708 with CAD and 24 259 with T2D). Variants showing apparent association with CAD in stratified analyses or evidence of interaction were evaluated in a further 117 787 subjects (16 694 with CAD and 11 537 with T2D). RESULTS: None of the previously characterized CAD loci was found to have specific effects on CAD in T2D individuals, and a genome-wide interaction analysis found no new variants for CAD that could be considered T2D specific. When we considered the overall genetic correlations between CAD and its risk factors, we found no substantial differences in these relationships by T2D background. CONCLUSIONS: This study found no evidence that the genetic architecture of CAD differs in those with T2D compared with those without T2D.
  • Said, M. Abdullah; Yeung, Ming Wai; van de Vegte, Yordi J.; Benjamins, Jan Walter; Dullaart, Robin P. F.; Ruotsalainen, Sanni; Ripatti, Samuli; Natarajan, Pradeep; Juarez-Orozco, Luis Eduardo; Verweij, Niek; van der Harst, P. (2021)
    Objective: Lipoprotein(a) (Lp[a]) is associated with coronary artery disease (CAD) but also to LDL (low-density lipoprotein) cholesterol. The genetic architecture of Lp(a) remains incompletely understood, as well as its independence of LDL cholesterol in its association to CAD. We investigated the genetic determinants of Lp(a) concentrations in a large prospective multiethnic cohort. We tested the association for potential causality between genetically determined higher Lp(a) concentrations and CAD using a multivariable Mendelian randomization strategy. Approach and Results: We studied 371 212 participants of the UK Biobank with available Lp(a) and genome-wide genetic data. Genome-wide association analyses confirmed 2 known and identified 37 novel loci (P Conclusions: This study supports an LDL cholesterol-independent causal link between Lp(a) and CAD. A rare missense variant in the LPA gene locus appears to be protective in people with the Lp(a) increasing variant of rs10455872. In the search for therapeutic targets of Lp(a), future work should focus on understanding the functional consequences of this missense variant.
  • Saleheen, Danish; Zhao, Wei; Young, Robin; Nelson, Christopher P.; Ho, WeangKee; Ferguson, Jane F.; Rasheed, Asif; Ou, Kristy; Nurnberg, Sylvia T.; Bauer, Robert C.; Goel, Anuj; Do, Ron; Stewart, Alexandre F. R.; Hartiala, Jaana; Zhang, Weihua; Thorleifsson, Gudmar; Strawbridge, Rona J.; Sinisalo, Juha; Kanoni, Stavroula; Sedaghat, Sanaz; Marouli, Eirini; Kristiansson, Kati; Zhao, Jing Hua; Scott, Robert; Gauguier, Dominique; Shah, Svati H.; Smith, Albert Vernon; van Zuydam, Natalie; Cox, Amanda J.; Willenborg, Christina; Kessler, Thorsten; Zeng, Lingyao; Province, Michael A.; Ganna, Andrea; Lind, Lars; Pedersen, Nancy L.; White, Charles C.; Joensuu, Anni; Kleber, Marcus Edi; Hall, Alistair S.; Maerz, Winfried; Salomaa, Veikko; O'Donnell, Christopher; Ingelsson, Erik; Feitosa, Mary F.; Erdmann, Jeanette; Bowden, Donald W.; Palmer, Colin N. A.; Gudnason, Vilmundur; Perola, Markus; PROMIS; Cardiogramplusc4D (2017)
    BACKGROUND: Common diseases such as coronary heart disease (CHD) are complex in etiology. The interaction of genetic susceptibility with lifestyle factors may play a prominent role. However, gene-lifestyle interactions for CHD have been difficult to identify. Here, we investigate interaction of smoking behavior, a potent lifestyle factor, with genotypes that have been shown to associate with CHD risk. METHODS: We analyzed data on 60 919 CHD cases and 80 243 controls from 29 studies for gene-smoking interactions for genetic variants at 45 loci previously reported to be associated with CHD risk. We also studied 5 loci associated with smoking behavior. Study-specific gene-smoking interaction effects were calculated and pooled using fixed-effects meta-analyses. Interaction analyses were declared to be significant at a P value of <1.0x10(-3) (Bonferroni correction for 50 tests). RESULTS: We identified novel gene-smoking interaction for a variant upstream of the ADAMTS7 gene. Every T allele of rs7178051 was associated with lower CHD risk by 12% in never-smokers (P= 1.3x10(-16)) in comparison with 5% in ever-smokers (P= 2.5x10(-4)), translating to a 60% loss of CHD protection conferred by this allelic variation in people who smoked tobacco (interaction P value= 8.7x10(-5)). The protective T allele at rs7178051 was also associated with reduced ADAMTS7 expression in human aortic endothelial cells and lymphoblastoid cell lines. Exposure of human coronary artery smooth muscle cells to cigarette smoke extract led to induction of ADAMTS7. CONCLUSIONS: Allelic variation at rs7178051 that associates with reduced ADAMTS7 expression confers stronger CHD protection in never-smokers than in ever-smokers. Increased vascular ADAMTS7 expression may contribute to the loss of CHD protection in smokers.
  • Tikkanen, Emmi; Jagerroos, Vilma; Holmes, Michael; Sattar, Naveed; Ala-Korpela, Mika; Jousilahti, Pekka; Lundqvist, Annamari; Perola, Markus; Salomaa, Veikko; Wurtz, Peter (2021)
    Background Peripheral artery disease (PAD) and coronary artery disease (CAD) represent atherosclerosis in different vascular beds. We used detailed metabolic biomarker profiling to identify common and discordant biomarkers and clarify pathophysiological differences for these vascular diseases. Methods and Results We used 5 prospective cohorts from Finnish population (FINRISK 1997, 2002, 2007, and 2012, and Health 2000; n=31 657; median follow-up time of 14 years) to estimate associations between >200 metabolic biomarkers and incident PAD and CAD. Metabolic biomarkers were measured with nuclear magnetic resonance, and disease events were obtained from nationwide hospital records. During the follow-up, 498 incident PAD and 2073 incident CAD events occurred. In age- and sex-adjusted Cox models, apolipoproteins and cholesterol measures were robustly associated with incident CAD (eg, hazard ratio [HR] per SD for higher apolipoprotein B/A-1 ratio, 1.30; 95% CI, 1.25-1.36), but not with incident PAD (HR per SD for higher apolipoprotein B/A-1 ratio, 1.04; 95% CI, 0.95-1.14; P-heterogeneity0.05). Lower proportion of polyunsaturated fatty acids relative to total fatty acids, and higher concentrations of monounsaturated fatty acids, glycolysis-related metabolites, and inflammatory protein markers were strongly associated with incident PAD, and many of these associations were stronger for PAD than for CAD (P-heterogeneity
  • Simonen, Piia; Arte, Elisa; Gylling, Helena (2021)
    Dietary modifications including plant stanol ester consumption are recommended measures to control serum and low-density lipoprotein (LDL)-cholesterol concentrations, but obesity can affect their responses. We investigated whether body mass index (BMI) affects serum cholesterol levels during plant stanol (mainly sitostanol) ester consumption. This ad hoc analysis was based on earlier results of a cross-over, randomized controlled trial of postmenopausal women consuming rapeseed oil-based margarine without or with plant stanol ester (3 g plant stanols/day) for seven weeks. We classified the subjects as normal-weight (BMI 25 kg/m(2), n = 11, mean 28.4 kg/m(2)), and recalculated the results, focusing on cholesterol absorption, cholesterol synthesis, and fecal steroid outputs. Serum cholesterol levels were similar in the groups during the control diet. Plant stanol ester reduced serum cholesterol by 0.63 +/- 0.19 mmol/L (11%) in normal-weight and by 0.75 +/- 0.13 mmol/L (12%) in overweight/obese subjects (p < 0.05 for both), and cholesterol absorption was reduced in both groups. However, relative and dietary cholesterol absorption were more effectively reduced in normal-weight subjects. In conclusion, overweight/obesity did not interfere with the serum cholesterol response to plant stanol ester consumption despite substantial differences in cholesterol metabolism between the groups.
  • FinnGen Project; Ripatti, Pietari; Rämö, Joel T.; Mars, Nina J.; Fu, Yu; Lin, Jake; Söderlund, Sanni; Benner, Christian; Surakka, Ida; Kiiskinen, Tuomo; Havulinna, Aki S.; Palta, Priit; Freimer, Nelson B.; Widén, Elisabeth; Salomaa, Veikko; Tukiainen, Taru; Pirinen, Matti; Palotie, Aarno; Taskinen, Marja-Riitta; Ripatti, Samuli (2020)
    Background: Hyperlipidemia is a highly heritable risk factor for coronary artery disease (CAD). While monogenic familial hypercholesterolemia associates with severely increased CAD risk, it remains less clear to what extent a high polygenic load of a large number of LDL (low-density lipoprotein) cholesterol (LDL-C) or triglyceride (TG)-increasing variants associates with increased CAD risk. Methods: We derived polygenic risk scores (PRSs) with approximate to 6M variants separately for LDL-C and TG with weights from a UK Biobank-based genome-wide association study with approximate to 324K samples. We evaluated the impact of polygenic hypercholesterolemia and hypertriglyceridemia to lipid levels in 27 039 individuals from the National FINRISK Study (FINRISK) cohort and to CAD risk in 135 638 individuals (13 753 CAD cases) from the FinnGen project (FinnGen). Results: In FINRISK, median LDL-C was 3.39 (95% CI, 3.38-3.40) mmol/L, and it ranged from 2.87 (95% CI, 2.82-2.94) to 3.78 (95% CI, 3.71-3.83) mmol/L between the lowest and highest 5% of the LDL-C PRS distribution. Median TG was 1.19 (95% CI, 1.18-1.20) mmol/L, ranging from 0.97 (95% CI, 0.94-1.00) to 1.55 (95% CI, 1.48-1.61) mmol/L with the TG PRS. In FinnGen, comparing the highest 5% of the PRS to the lowest 95%, CAD odds ratio was 1.36 (95% CI, 1.24-1.49) for the LDL-C PRS and 1.31 (95% CI, 1.19-1.43) for the TG PRS. These estimates were only slightly attenuated when adjusting for a CAD PRS (odds ratio, 1.26 [95% CI, 1.16-1.38] for LDL-C and 1.24 [95% CI, 1.13-1.36] for TG PRS). Conclusions: The CAD risk associated with a high polygenic load for lipid-increasing variants was proportional to their impact on lipid levels and partially overlapping with a CAD PRS. In contrast with a PRS for CAD, the lipid PRSs point to known and directly modifiable risk factors providing additional guidance for clinical translation.
  • Kerola, Anne M.; Palomäki, Antti; Rautava, Päivi; Nuotio, Maria; Kytö, Ville (2021)
    Background Evidence on the impact of sex on prognoses after myocardial infarction (MI) among older adults is limited. We evaluated sex differences in long-term cardiovascular outcomes after MI in older adults. Methods and Results All patients with MI >= 70 years admitted to 20 Finnish hospitals during a 10-year period and discharged alive were studied retrospectively using a combination of national registries (n=31 578, 51% men, mean age 79). The primary outcome was combined major adverse cardiovascular event within 10-year follow-up. Sex differences in baseline features were equalized using inverse probability weighting adjustment. Women were older, with different comorbidity profiles and rarer ST-segment-elevation MI and revascularization, compared with men. Adenosine diphosphate inhibitors, anticoagulation, statins, and high-dose statins were more frequently used by men, and renin-angiotensin-aldosterone inhibitors and beta blockers by women. After balancing these differences by inverse probability weighting, the cumulative 10-year incidence of major adverse cardiovascular events was 67.7% in men, 62.0% in women (hazard ratio [HR], 1.17; CI, 1.13-1.21; P= 80 years. Conclusions Older men had higher long-term risk of major adverse cardiovascular events after MI, compared with older women with similar baseline features and evidence-based medications. Our results highlight the importance of accounting for confounding factors when studying sex differences in cardiovascular outcomes.
  • Ala-Kauhaluoma, Marianne; Koskinen, Suvi M.; Silvennoinen, Heli; Vikatmaa, Pirkka; Nuotio, Krista; Ijäs, Petra; Relander, Kristiina; Lindsberg, Perttu J.; Soinne, Lauri; Summanen, Paula A. (2021)
    Purpose To compare subfoveal choroidal thickness (SFCT) and associated clinical variables in patients with carotid stenosis (CS) before and 6 months after carotid endarterectomy (CEA). Methods The prospective non-randomized Helsinki Carotid Endarterectomy Study - Brain and Eye Sub-sTudy included seventy patients (81% male, mean age 69 years) and 40 control subjects (77% male, 68 years), from March 2015 to December 2018. Ophthalmological examination included SFCT measured with enhanced-depth imaging-optical coherence tomography. Carotid stenosis (CS) was more severe (>= 70% stenosis in 92%) ipsilateral to the CEA than contralaterally ( Results At baseline, patients had thinner mean SFCT than control subjects in both eyes (ipsilateral, 222 versus 257 mu m and contralateral, 217 versus 258 mu m, p Conclusions Subfoveal choroidal thickness (SFCT) is thinner in patients with CS without association between SFCT and the grade of CS. Unchanged SFCT after CEA suggests, that choroidal vessels in severe CS are unable to react to increased blood flow. Bilaterally thin SFCT could be considered as yet another sign of CS.