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ObjectiveHeart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome. We aimed to derive HFpEF phenotype-based groups ('phenogroups') based on clinical and echocardiogram data using machine learning, and to compare clinical characteristics, proteomics and outcomes across the phenogroups.MethodsWe applied model-based clustering to 32 echocardiogram and 11 clinical and laboratory variables collected in stable condition from 320 HFpEF outpatients in the Karolinska-Rennes cohort study (56% female, median 78 years (IQR: 71–83)). Baseline proteomics and the composite end point of all-cause mortality or heart failure (HF) hospitalisation were used in secondary analyses.ResultsWe identified six phenogroups, for which significant differences in the prevalence of concomitant atrial fibrillation (AF), anaemia and kidney disease were observed (pConclusionsUsing machine learning we identified distinct HFpEF phenogroups with differential characteristics and outcomes, as well as differential levels of inflammatory and cardiovascular proteins.

BACKGROUND: Genome-wide association studies have identified numerous genetic regions that influence cross-sectional lung function. Longitudinal decline in lung function also includes a heritable component but the genetic determinants have yet to be defined.OBJECTIVES: We aimed to determine whether regions associated with cross-sectional lung function were also associated with longitudinal decline and to seek novel variants which influence decline.METHODS: We analysed genome-wide data from 4167 individuals from the Busselton Health Study cohort, who had undergone spirometry (12 695 observations across eight time points). A mixed model was fitted and weighted risk scores were calculated for the joint effect of 26 known regions on baseline and longitudinal changes in FEV1 and FEV1/FVC. Potential additional regions of interest were identified and followed up in two independent cohorts.RESULTS: The 26 regions previously associated with cross-sectional lung function jointly showed a strong effect on baseline lung function (p=4.44×10-16 for FEV1/FVC) but no effect on longitudinal decline (p=0.160 for FEV1/FVC). This was replicated in an independent cohort. 39 additional regions of interest (48 variants) were identified; these associations were not replicated in two further cohorts.CONCLUSIONS: Previously identified genetic variants jointly have a strong effect on cross-sectional lung function in adults but little or no effect on the rate of decline of lung function. It is possible that they influence COPD risk through lung development. Although no genetic variants have yet been associated with lung function decline at stringent genome-wide significance, longitudinal change in lung function is heritable suggesting that there is scope for future discoveries.

Objective To identify foetal susceptibility genes in Ro/SSA autoantibody-mediated congenital heart block on chromosome six. Methods Single nucleotide polymorphism (SNP) genotyping of individuals included in the Swedish Congenital Heart Block (CHB) study population was performed. Low resolution HLA-A, -Cw and -DRB1 allele typing was carried out in 86 families of the study population comprising 339 individuals (86 Ro/SSA autoantibody positive mothers, 71 fathers, 87 CHB index cases and 95 unaffected siblings). Results A case-control comparison between index cases and population-based out of study controls (n = 1710) revealed an association of CHB with fifteen SNPs in the 6p21.3 MHC locus at a chromosome-wide significance of p –6 (OR 2.21–3.12). In a family-based analysis between SNP markers as well as distinct MHC class I and II alleles with CHB we observed associations to HLA-DRB1*04 and HLA-Cw*05 variants that were significantly more often transmitted to affected individuals (p Conclusions Our study identifies HLA-DRB1*04 and HLA-Cw*05 as novel foetal HLA-allele variants that confer susceptibility to develop CHB in response to exposure to Ro/SSA autoantibodies, while DRB1*13 and Cw*06 emerged as protective alleles. For the first time, we also demonstrate paternal contribution to foetal susceptibility to CHB.

Objective Congenital heart block may develop in the fetus of Ro52 autoantibody positive women. The reported recurrence rate for autoantibody associated congenital heart block is however only 10–25%, indicating that other factors than maternal autoantibodies influence the disease development and fetal outcome. The most potent genetic influence on susceptibility to autoimmune diseases is the human leucocyte antigen (HLA) locus, and as there is a strong and well-known HLA-DR*03 allele association with systemic lupus erythematosus, Sjogren9s syndrome and production of Ro/SSA autoantibodies, the authors hypothesised that specific alleles of the HLA locus may render the fetus susceptible to congenital heart block induced by maternal autoantibodies. Methods Genotyping was performed for 561 490 single-nucleotide polymorphisms (SNPs) in DNA from Swedish Caucasian families with a Ro/SSA autoantibody positive mother and with at least one case of congenital heart block. Full HLA-A, HLA-C and HLA-DRB1 allele typing was performed by single specific primer PCR in 60 families with complete trios. Swedish Caucasian population-based healthy controls were used in case-control association analysis. Genetic linkage was analysed by transmission disequilibrium test. Results A case-control analysis between the index cases and population-based controls revealed an association of congenital heart block with six SNPs in the 6p21 major histocompatibility complex (MHC) locus at a genome-wide significance of p −8 (OR 2.57–3.12). In family-based association analysis of distinct MHC class I and II alleles the authors observed an association of the HLA-DR*04 (p=0.01), DR*13 (p=0.02) and Cw6 (p=0.03) alleles with congenital heart block. HLA-DR*04 was significantly more often transmitted to children who developed congenital heart block, while the opposite was true for HLA-DR*13 and Cw6. Conclusions This study identifies HLA-DRB1*04 as a novel fetal genetic variant that confers susceptibility to develop congenital heart block in response to exposure to Ro/SSA autoantibodies, while HLA-DR*13 and Cw6 provide resistance.