Polymorphisms at the F12 and KLKB1 loci have significant trait association with activation of the renin-angiotensin system

BACKGROUND: Plasma coagulation Factor XIIa (Hageman factor; encoded by F12) and kallikrein (KAL or Fletcher factor; encoded by KLKB1) are proteases of the kallikerin-kinin system involved in converting the inactive circulating prorenin to renin. Renin is a key enzyme in the formation of angiotensin II, which regulates blood pressure, fluid and electrolyte balance and is a biomarker for cardiovascular, metabolic and renal function. The renin-angiotensin system is implicated in extinction learning in posttraumatic stress disorder. METHODS & RESULTS: Active plasma renin was measured from two independent cohorts- civilian twins and siblings, as well as U.S. Marines, for a total of 1,180 subjects. Genotyping these subjects revealed that the carriers of the minor alleles at the two loci- F12 and KLKB1 had a significant association with reduced levels of active plasma renin. Meta-analyses confirmed the association across cohorts. In vitro studies verified digestion of human recombinant pro-renin by kallikrein (KAL) to generate active renin. Subsequently, the active renin was able to digest the synthetic substrate angiotensinogen to angiotensin-I. Examination of mouse juxtaglomerular cell line and mouse kidney sections showed co-localization of KAL with renin. Expression of either REN or KLKB1 was regulated in cell line and rodent models of hypertension in response to oxidative stress, interleukin or arterial blood pressure changes. CONCLUSIONS: The functional variants of KLKB1 (rs3733402) and F12 (rs1801020) disrupted the cascade of enzymatic events, resulting in diminished formation of active renin. Using genetic, cellular and molecular approaches we found that conversion of zymogen prorenin to renin was influenced by these polymorphisms. The study suggests that the variant version of protease factor XIIa due to the amino acid substitution had reduced ability to activate prekallikrein to KAL. As a result KAL has reduced efficacy in converting prorenin to renin and this step of the pathway leading to activation of renin affords a potential therapeutic target

The transcriptional landscape of age in human peripheral blood

Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.Peer reviewe

A Novel Interaction between Tryptophan Hydroxylase 2 (TPH2) Gene Polymorphism (rs4570625) and BDNF Val66Met Predicts a High-Risk Emotional Phenotype in Healthy Subjects.

Poor inhibitory processing of negative emotional content is central to many psychiatric disorders, including depression and anxiety. Moreover, increasing evidence suggests that core aspects of emotion-inhibitory processing are largely inherited and as such may represent a key intermediate or risk-related phenotype for common affective diseases (e.g., unipolar depressive, anxiety disorders). The current study employed a candidate-gene approach in order to most effectively examine this complex behavioral phenotype. We examined the novel interaction between BDNF (Val66Met) and TPH2 (rs4570625) polymorphisms and their influence on behavioral inhibition of negative emotion in two independent investigations of healthy adults. BDNF Met carriers consistently report greater symptoms of affective disease and display corresponding behavioral rigidity, while TPH2 T carriers display poor inhibitory processing. These genotypes are traditionally perceived as 'risk' genotypes when compared to their respective major Val and G homozygous genotypes, but evidence is mixed. Recent studies in humans and mutant mouse models suggest biological epistasis between BDNF and genes involved in serotonin regulation. Moreover, polymorphisms in the TPH2 gene may have greater influence on serotonergic function than other more commonly studied polymorphisms (e.g., 5-HTTLPR). We observed consistent evidence across two different emotion-inhibition paradigms, one with high internal validity (Study 1, n = 119) and one with high ecological validity (Study 2, n = 115) that the combination of Val/Val and G/G genotypes was clearly associated with impaired inhibition of negative emotional content. This was followed by individuals carrying the BDNF-Met allele (including Met/Val and Met/Met) when combined with the TPH2-T allele (including T/G and T/T combinations). The consistency of these results across tasks and studies suggests that these two groups may be particularly vulnerable to the most common psychiatric disorders and should be targets for future clinical investigation

Negative emotions expressed during positive contexts.

<p>Reported and coded emotion scores from subjects in Study 2 were standardized to z-scores and combined yielding one score for negative emotion during the positive films. Negative emotion of Val/Val–T Carriers was significantly lower than those exhibited by Val/Val–G/Gs (F(1,68) = 6.49, p<0.01) and by Met Carrier–T Carriers (F(1,47) = 4.11, p<0.05). Negative emotion of Val/Val–T Carriers was not significantly different from Met Carrier–G/Gs (F(1,62) = 1.75, p = 0.19). Val/Val–G/Gs were not significantly different from Met Carrier–G/Gs (F(1,60) = 1.65, p = 0.20) nor from Met Carrier–T Carriers (F(1,45) = 0.02, p = 0.90). Met Carrier–G/Gs were also not significantly different from Met Carrier–T Carriers (F(1,39) = 0.96, p = 0.33. All data are presented as mean ± SEM.</p

Reaction time to negative words in the Emotion-word Stroop task.

<p>Subjects from Study 1 that were Val/Val–G/G had significantly increased reaction times to negative words compared to Val/Val–T Carriers (F(1,80) = 10.87, p<0.001) and Met Carrier–G/Gs (F(1,68) = 13.28, p<0.001). There was also a trend for an increased reaction time of Val/Val–G/Gs compared to Met Carrier–T Carriers (F(1,55) = 2.72, p = 0.11). Met Carrier–G/Gs were not significantly different from Val/Val–T Carriers (F(1,56) = 0.11, p = 0.74) nor from Met Carrier–T Carriers (F(1,31) = 0.70, p = 0.41). Val/Val–T Carriers were also not significantly different from Met Carrier–T Carriers (F(1,43) = 0.22, p = 0.64). All data are presented as mean ± SEM.</p

A Novel Interaction between Tryptophan Hydroxylase 2 (TPH2) Gene Polymorphism (rs4570625) and BDNF Val⁶⁶Met Predicts a High-Risk Emotional Phenotype in Healthy Subjects - Table 1

A Novel Interaction between Tryptophan Hydroxylase 2 (TPH2) Gene Polymorphism (rs4570625) and BDNF Val⁶⁶Met Predicts a High-Risk Emotional Phenotype in Healthy Subjects - Table

The transcriptional landscape of age in human peripheral blood

Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts