Marco Orru

Common variants at ten loci modulate the QT interval duration in the QTSCD Study

The QT interval, a measure of cardiac repolarization, predisposes to ventricular arrhythmias and sudden cardiac death (SCD) when prolonged or shortened. A common variant in NOS1AP is known to influence repolarization. We analyze genome-wide data from five population-based cohorts (ARIC, KORA, SardiNIA, GenNOVA and HNR) with a total of 15,842 individuals of European ancestry, to confirm the NOS1AP association and identify nine additional loci at P < 5 × 10−8. Four loci map near the monogenic long-QT syndrome genes KCNQ1, KCNH2, SCN5A and KCNJ2. Two other loci include ATP1B1 and PLN, genes with established electrophysiological function, whereas three map to RNF207, near LITAF and within NDRG4-GINS3-SETD6-CNOT1, respectively, all of which have not previously been implicated in cardiac electrophysiology. These results, together with an accompanying paper from the QTGEN consortium, identify new candidate genes for ventricular arrhythmias and SCD.

The GLUT9 gene is associated with serum uric acid levels in Sardinia and Chianti cohorts.

High serum uric acid levels elevate pro-inflammatory–state gout crystal arthropathy and place individuals at high risk for cardiovascular morbidity and mortality. Genome-wide scans in the genetically isolated Sardinian population identified variants associated with serum uric acid levels as a quantitative trait. They mapped within GLUT9, a Chromosome 4 glucose transporter gene predominantly expressed in liver and kidney. SNP rs6855911 showed the strongest association (p = 1.84 × 10−16), along with eight others (p = 7.75 × 10−16 to 6.05 × 10−11). Individuals homozygous for the rare allele of rs6855911 (minor allele frequency = 0.26) had 0.6 mg/dl less uric acid than those homozygous for the common allele; the results were replicated in an unrelated cohort from Tuscany. Our results suggest that polymorphisms in GLUT9 could affect glucose metabolism and uric acid synthesis and/or renal reabsorption, influencing serum uric acid levels over a wide range of values.

Variations in the G6PC2/ABCB11 genomic region are associated with fasting glucose levels

Identifying the genetic variants that regulate fasting glucose concentrations may further our understanding of the pathogenesis of diabetes. We therefore investigated the association of fasting glucose levels with SNPs in 2 genome-wide scans including a total of 5,088 nondiabetic individuals from Finland and Sardinia. We found a significant association between the SNP rs563694 and fasting glucose concentrations (P = 3.5 x 10(-7)). This association was further investigated in an additional 18,436 nondiabetic individuals of mixed European descent from 7 different studies. The combined P value for association in these follow-up samples was 6.9 x 10(-26), and combining results from all studies resulted in an overall P value for association of 6.4 x 10(-33). Across these studies, fasting glucose concentrations increased 0.01-0.16 mM with each copy of the major allele, accounting for approximately 1% of the total variation in fasting glucose. The rs563694 SNP is located between the genes glucose-6-phosphatase catalytic subunit 2 (G6PC2) and ATP-binding cassette, subfamily B (MDR/TAP), member 11 (ABCB11). Our results in combination with data reported in the literature suggest that G6PC2, a glucose-6-phosphatase almost exclusively expressed in pancreatic islet cells, may underlie variation in fasting glucose, though it is possible that ABCB11, which is expressed primarily in liver, may also contribute to such variation.

COL4A1 is associated with arterial stiffness by genome-wide association scan.

Background—Pulse wave velocity (PWV), a noninvasive index of central arterial stiffness, is a potent predictor of cardiovascular mortality and morbidity. Heritability and linkage studies have pointed toward a genetic component affecting PWV. We conducted a genome-wide association study to identify single-nucleotide polymorphisms (SNPs) associated with PWV. Methods and Results—The study cohort included participants from the SardiNIA study for whom PWV measures were available. Genotyping was performed in 4221 individuals, using either the Affymetrix 500K or the Affymetrix 10K mapping array sets (with imputation of the missing genotypes). Associations with PWV were evaluated using an additive genetic model that included age, age2, and sex as covariates. The findings were tested for replication in an independent internal Sardinian cohort of 1828 individuals, using a custom chip designed to include the top 43 nonredundant SNPs associated with PWV. Of the loci that were tested for association with PWV, the nonsynonymous SNP rs3742207 in the COL4A1 gene on chromosome 13 and SNP rs1495448 in the MAGI1 gene on chromosome 3 were successfully replicated (P=7.08×10−7 and P=1.06×10−5, respectively, for the combined analyses). The association between rs3742207 and PWV was also successfully replicated (P=0.02) in an independent population, the Old-Order Amish, leading to an overall P=5.16×10−8. Conclusions—A genome-wide association study identified a SNP in the COL4A1 gene that was significantly associated with PWV in 2 populations. Collagen type 4 is the major structural component of basement membranes, suggesting that previously unrecognized cell-matrix interactions may exert an important role in regulating arterial stiffness.

Key Modulatory Role of Presynaptic Adenosine A2A Receptors in Cortical Neurotransmission to the Striatal Direct Pathway

Basal ganglia processing results from a balanced activation of direct and indirect striatal efferent pathways, which are controlled by dopamine D1 and D2 receptors, respectively. Adenosine A2A receptors are considered novel antiparkinsonian targets, based on their selective postsynaptic localization in the indirect pathway, where they modulate D2 receptor function. The present study provides evidence for the existence of an additional, functionally significant, segregation of A2A receptors at the presynaptic level. Using integrated anatomical, electrophysiological, and biochemical approaches, we demonstrate that presynaptic A2A receptors are preferentially localized in cortical glutamatergic terminals that contact striatal neurons of the direct pathway, where they exert a selective modulation of corticostriatal neurotransmission. Presynaptic striatal A2A receptors could provide a new target for the treatment of neuropsychiatric disorders.

The central arterial burden of the metabolic syndrome is similar in men and women: the SardiNIA Study

AIMS We evaluated whether specific clusters of metabolic syndrome (MetS) components differentially impact on arterial structure and function, and whether the impact is similar in men and in women. METHODS AND RESULTS Components of the MetS and arterial properties were assessed in 6148 subjects, aged 14-102 in a cluster of four towns in Sardinia, Italy. MetS was defined in accordance with the ATP III criteria. Age groups were classified as: <35, 35-49, 50-64, and > or =65 years. Systolic blood pressure (BP), diastolic BP, pulse pressure, common carotid artery (CCA) diameter, intima-media thickness, distensibility, strain, stiffness index, wall stress, and aortic pulse wave velocity were measured. Common carotid artery plaque was defined as focal encroachment of the arterial wall and CCA calcification as acoustic shadowing. In any age group, subjects with MetS presented thicker, stiffer or less distensible, and wider large arteries than controls. The arterial burden of MetS increased as the number of altered MetS components increased. However, not all MetS components were associated with the same changes in arterial properties. In fact, specific clusters of MetS components, i.e. any combination of altered glucose tolerance, elevated BP, and elevated triglycerides (with or without abdominal obesity), dramatically increased age-associated arterial changes. The impact of MetS on arterial function was similar in men and women. CONCLUSION MetS accelerates age-associated arterial changes, even in older persons. However, not all the clusters of MetS components render the same burden on arterial structure and function.

Longitudinal Perspective on the Conundrum of Central Arterial Stiffness, Blood Pressure, and Aging

The age-associated increase in arterial stiffness has long been considered to parallel or to cause the age-associated increase in blood pressure (BP). Yet, the rates at which pulse wave velocity (PWV), a measure of arterial stiffness, and BP trajectories change over time within individuals who differ by age and sex have not been assessed and compared. This study determined the evolution of BP and aortic PWV trajectories during a 9.4-year follow-up in >4000 community-dwelling men and women of 20 to 100 years of age at entry into the SardiNIA Study. Linear mixed effects model analyses revealed that PWV accelerates with time during the observation period, at about the same rate over the entire age range in both men and women. In men, the longitudinal rate at which BP changed over time, however, did not generally parallel that of PWV acceleration: at ages >40 years the rates of change in systolic BP (SBP) and pulse pressure (PP) increase plateaued and then declined so that SBP, itself, also declined at older ages, whereas PP plateaued. In women, SBP, diastolic BP, and mean BP increased at constant rates across all ages, producing an increasing rate of increase in PP. Therefore, increased aortic stiffness is implicated in the age-associated increase in SBP and PP. These findings indicate that PWV is not a surrogate for BP and that arterial properties other than arterial wall stiffness that vary by age and sex also modulate the BP trajectories during aging and lead to the dissociation of PWV, PP, and SBP trajectories in men.

Associations of large artery structure and function with adiposity: Effects of age, gender, and hypertension. The SardiNIA Study

UNLABELLED In the context of obesity epidemic, no large population study has extensively investigated the relationships between total and abdominal adiposity and large artery structure and function nor have such relationships been examined by gender, by age, by hypertensive status. We investigated these potential relationships in a large cohort of community dwelling volunteers participating the SardiNIA Study. METHODS AND RESULTS Total and visceral adiposity and arterial properties were assessed in 6148 subjects, aged 14-102 in a cluster of 4 towns in Sardinia, Italy. Arterial stiffness was measured as aortic pulse wave velocity (PWV), arterial thickness and lumen as common carotid artery (CCA) intima-media thickness (IMT) and diameter, respectively. We reported a nonlinear relationship between total and visceral adiposity and arterial stiffness, thickness, and diameter. The association between adiposity and arterial properties was steeper in women than in men, in younger than in older subjects. Waist correlated with arterial properties better than BMI. Within each BMI quartile, increasing waist circumference was associated with further significant changes in arterial structure and function. CONCLUSION The relationship between total or abdominal adiposity and arterial aging (PWV and CCA IMT) is not linear as described in the current study. Therefore, BMI- and/or waist-specific reference values for arterial measurements might need to be defined.

Independent and additive effects of cytokine patterns and the metabolic syndrome on arterial aging in the SardiNIA Study

OBJECTIVE Metabolic syndrome (MetS) and its components accelerate age-associated increases in arterial stiffness and thickness. We investigated whether specific proinflammatory cytokines contribute to arterial aging, independent of age, sex, MetS, and other traditional CV risk factors. RESEARCH DESIGN AND METHODS MetS components (ATP III criteria) and arterial properties were assessed in 6148 subjects, aged 14-102 in Sardinia, Italy. Common carotid artery (CCA) diameter, intima-media thickness (IMT), and aortic pulse wave velocity (PWV), adiponectin, leptin, high-sensitivity C reactive protein (hsCRP), monocyte chemoattractant protein 1 (MCP1), and interleukin 6 (IL6) were measured. RESULTS While cytokine levels - except for MCP1 - were significantly higher (lower for adiponectin) in MetS than in control subjects, and the increased PWV and CCA IMT with aging were associated with MetS, this association was independent of cytokine levels (p<0.001 for both PWV and CCA IMT). Specific cytokines, however, were significantly associated with arterial stiffness (higher leptin, p<0.001, and higher hsCRP, p<0.001) or thickness (lower adiponectin, p<0.05, and higher IL6, p<0.001) - independent of age, sex, MetS and other traditional CV risk factors. The co-occurrence of both MetS and higher cytokines levels was associated with greater increases in arterial stiffness and thickness. CONCLUSION While MetS and specific cytokine patterns associated with arterial aging, the increases in arterial stiffness and thickness are greater when both MetS and higher cytokine levels are present, suggesting a possible synergistic effect of MetS and inflammation on the arterial wall.

Sex-Specific Correlates of Walking Speed in a Wide Age-Ranged Population

The goals of this cross-sectional study were to explore correlates of walking speed in a large wide age-ranged population and to identify factors affecting lower walking speed at older ages. Participants were 3,872 community-dwelling adults in the first follow-up of the SardiNIA study who completed a 4-m walking test. Sex-specific correlates of walking speed included marital status, height, waist circumference, pulse wave velocity, comorbidity, subjective health, strength, and personality. Effect modifiers of the age-walking speed association included extraversion (<55 years, p = .019) and education (<55 years, p = .021; > or =55 years, p = .012) in women, and openness (<55 years, p = .005), waist circumference (<55 years, p = .010), and subjective health (<55 years, p = .014) in men. The strong impact of personality suggests that certain personality traits may be associated with behaviors that affect physical performance and condition the reduced mobility mostly at younger ages. If these patterns are confirmed in longitudinal studies, personality may be an important target for prevention.