ANGPTL8 protein-truncating variant associated with lower serum triglycerides and risk of coronary disease

Protein-truncating variants (PTVs) affecting dyslipidemia risk may point to therapeutic targets for cardiometabolic disease. Our objective was to identify PTVs that were associated with both lipid levels and the risk of coronary artery disease (CAD) or type 2 diabetes (T2D) and assess their possible associations with risks of other diseases. To achieve this aim, we leveraged the enrichment of PTVs in the Finnish population and tested the association of low-frequency PTVs in 1,209 genes with serum lipid levels in the Finrisk Study (n = 23,435). We then tested which of the lipid-associated PTVs were also associated with the risks of T2D or CAD, as well as 2,683 disease endpoints curated in the FinnGen Study (n = 218,792). Two PTVs were associated with both lipid levels and the risk of CAD or T2D: triglyceride-lowering variants in ANGPTL8 (-24.0[-30.4 to -16.9] mg/dL per rs760351239-T allele, P = 3.4 x 10(-9)) and ANGPTL4 (-14.4[-18.6 to -9.8] mg/dL per rs746226153-G allele, P = 4.3 x 10(-9)). The risk of T2D was lower in carriers of the ANGPTL4 PTV (OR = 0.70[0.60-0.81], P = 2.2 x 10(-6)) than noncarriers. The odds of CAD were 47% lower in carriers of a PTV in ANGPTL8 (OR = 0.53[0.37-0.76], P = 4.5 x 10(-4)) than noncarriers. Finally, the phenome-wide scan of the ANGPTL8 PTV showed that the ANGPTL8 PTV carriers were less likely to use statin therapy (68,782 cases, OR = 0.52[0.40-0.68], P = 1.7 x 10(-6)) compared to noncarriers. Our findings provide genetic evidence of potential long-term efficacy and safety of therapeutic targeting of dyslipidemias. Author summary Studying the health impacts of protein-truncating variants (PTVs) enables detecting the health impact of drugs that inhibit these same genes. Our study aimed to expand our knowledge of genes associated with cardiometabolic disease, along with the side effects of these genes. To detect PTVs associated with cardiometabolic disease, we first performed a genome-wide scan of PTVs associated with serum lipid levels in Finns. We found PTVs in two genes highly enriched in Finns, which were associated with both serum lipid levels and a lower risk of type 2 diabetes or coronary artery disease: ANGPTL4 and ANGPTL8. To evaluate the other health effects of these PTVs, we performed an association scan between the PTVs and 2,683 disease endpoints curated in the FinnGen Study (n = 218,792). We demonstrate that using human populations with PTV-enrichment, such as Finns, offers considerable boosts in statistical power to detect potential long-term efficacy and safety of pharmacologically targeting genes.Peer reviewe

Obstructive sleep apnoea and the risk for coronary heart disease and type 2 diabetes : a longitudinal population-based study in Finland

Objective To evaluate if obstructive sleep apnoea (OSA) modifies the risk of coronary heart disease, type 2 diabetes (T2D) and diabetic complications in a gender-specific fashion. Design and setting A longitudinal population-based study with up to 25-year follow-up data on 36 963 individuals (>500 000 person years) from three population-based cohorts: the FINRISK study, the Health 2000 Cohort Study and the Botnia Study. Main outcome measures Incident coronary heart disease, diabetic kidney disease, T2D and all-cause mortality from the Finnish National Hospital Discharge Register and the Finnish National Causes-of-Death Register. Results After adjustments for age, sex, region, high-density lipoprotein (HDL) and total cholesterol, current cigarette smoking, body mass index, hypertension, T2D baseline and family history of stroke or myocardial infarction, OSA increased the risk for coronary heart disease (HR=1.36, p=0.0014, 95% CI 1.12 to 1.64), particularly in women (HR=2.01, 95% CI 1.31 to 3.07, p=0.0012). T2D clustered with OSA independently of obesity (HR=1.48, 95% CI 1.26 to 1.73, p=9.11x10(-7)). The risk of diabetic kidney disease increased 1.75-fold in patients with OSA (95% CI 1.13 to 2.71, p=0.013). OSA increased the risk for coronary heart disease similarly among patients with T2D and in general population (HR=1.36). All-cause mortality was increased by OSA in diabetic individuals (HR=1.35, 95% CI 1.06 to 1.71, p=0.016). Conclusion OSA is an independent risk factor for coronary heart disease, T2D and diabetic kidney disease. This effect is more pronounced even in women, who until now have received less attention in diagnosis and treatment of OSA than men.Peer reviewe

A data-driven medication score predicts 10-year mortality among aging adults

Health differences among the elderly and the role of medical treatments are topical issues in aging societies. We demonstrate the use of modern statistical learning methods to develop a data-driven health measure based on 21 years of pharmacy purchase and mortality data of 12,047 aging individuals. The resulting score was validated with 33,616 individuals from two fully independent datasets and it is strongly associated with all-cause mortality (HR 1.18 per point increase in score; 95% CI 1.14-1.22; p=2.25e-16). When combined with Charlson comorbidity index, individuals with elevated medication score and comorbidity index had over six times higher risk (HR 6.30; 95% CI 3.84-10.3; AUC=0.802) compared to individuals with a protective score profile. Alone, the medication score performs similarly to the Charlson comorbidity index and is associated with polygenic risk for coronary heart disease and type 2 diabetes.Peer reviewe

Joint effects of alcohol use, smoking and body mass index as an explanation for the alcohol harm paradox : causal mediation analysis of eight cohort studies

Background and aims Lower socio-economic status (SES) is associated with higher alcohol-related harm despite lower levels of alcohol use. Differential vulnerability due to joint effects of behavioural risk factors is one potential explanation for this 'alcohol harm paradox'. We analysed to what extent socio-economic inequalities in alcohol-mortality are mediated by alcohol, smoking and body mass index (BMI), and their joint effects with each other and with SES. DesignCohort study of eight health examination surveys (1978-2007) linked to mortality data. Setting Finland.ParticipantsA total of 53 632 Finnish residents aged 25+ years.MeasurementsThe primary outcome was alcohol-attributable mortality. We used income as an indicator of SES. We assessed the joint effects between income and mediators (alcohol use, smoking and BMI) and between the mediators, adjusting for socio-demographic indicators. We used causal mediation analysis to calculate the total, direct, indirect and mediated interactive effects using Aalen's additive hazards models. Findings During 1 085 839 person-years of follow-up, we identified 865 alcohol-attributable deaths. We found joint effects for income and alcohol use and income and smoking, resulting in 46.8 and 11.4 extra deaths due to the interaction per 10 000 person-years. No interactions were observed for income and BMI or between alcohol and other mediators. The lowest compared with the highest income quintile was associated with 5.5 additional alcohol deaths per 10 000 person-years (95% confidence interval = 3.7, 7.3) after adjusting for confounders. The proportion mediated by alcohol use was negative (-69.3%), consistent with the alcohol harm paradox. The proportion mediated by smoking and BMI and their additive interactions with income explained 18.1% of the total effect of income on alcohol-attributable mortality. Conclusions People of lower socio-economic status appear to be more vulnerable to the effects of alcohol use and smoking on alcohol-attributable mortality. Behavioural risk factors and their joint effects with income may explain part of the alcohol harm paradox.Peer reviewe

Characterising the loss-of-function impact of 5' untranslated region variants in 15,708 individuals

Upstream open reading frames (uORFs) are tissue-specific cis-regulators of protein translation. Isolated reports have shown that variants that create or disrupt uORFs can cause disease. Here, in a systematic genome-wide study using 15,708 whole genome sequences, we show that variants that create new upstream start codons, and variants disrupting stop sites of existing uORFs, are under strong negative selection. This selection signal is significantly stronger for variants arising upstream of genes intolerant to loss-of-function variants. Furthermore, variants creating uORFs that overlap the coding sequence show signals of selection equivalent to coding missense variants. Finally, we identify specific genes where modification of uORFs likely represents an important disease mechanism, and report a novel uORF frameshift variant upstream of NF2 in neurofibromatosis. Our results highlight uORF-perturbing variants as an under-recognised functional class that contribute to penetrant human disease, and demonstrate the power of large-scale population sequencing data in studying non-coding variant classes. Upstream open reading frames (uORFs), located in 5' untranslated regions, are regulators of downstream protein translation. Here, Whiffin et al. use the genomes of 15,708 individuals in the Genome Aggregation Database (gnomAD) to systematically assess the deleteriousness of variants creating or disrupting uORFs.Peer reviewe

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Gender differences in health care use among the elderly population in areas of Norway and Finland. A cross-sectional analysis based on the HUNT study and the FINRISK Senior Survey

BACKGROUND: The aim of the study was to examine gender differences in the self-reported use of health care services by the elderly in rural and metropolitan areas of two Nordic countries with slightly different health care systems: Finland and Norway. METHODS: Population based, cross-sectional surveys conducted in Nord-Tröndelag Norway (1995–97) and in rural and metropolitan areas of Finland (1997) were employed. In the Norwegian data, a total of 7,919 individuals, aged 65–74 years old were included, and the Finnish data included 1,500 individuals. The outcome variables comprised whether participants had visited a general practitioner or a specialist, or had received hospital care or physiotherapy during the past 12 months. Gender differences in the use of health care services were analysed by multiple logistic regression, controlling for health status and socio-demographic characteristics. RESULTS: In Norway, elderly women visited a specialist or were hospitalised less often than men. In Finland, elderly women used all health care services except hospital care more often than men. In Norway, less frequent use of specialist care by women was not associated with self-reported health or chronic diseases. CONCLUSION: The findings revealed differences in self-reported use of secondary care among different genders in areas of Norway and Finland