Meta-analysis of four new genome scans for lipid parameters and analysis of positional candidates in positive linkage regions

Lipid levels in plasma strongly influence the risk for coronary heart disease. To localise and subsequently identify genes affecting lipid levels, we performed four genome-wide linkage scans followed by combined linkage/association analysis. Genome-scans were performed in 701 dizygotic twin pairs from four samples with data on plasma levels of HDL- and LDL-cholesterol and their major protein constituents, apolipoprotein AI (ApoAI) and Apolipoprotein B (ApoB). To maximise power, the genome scans were analysed simultaneously using a well-established meta-analysis method that was newly applied to linkage analysis. Overall LOD scores were estimated using the means of the sample-specific quantitative trait locus (QTL) effects inversely weighted by the standard errors obtained using an inverse regression method. Possible heterogeneity was accounted for with a random effects model. Suggestive linkage for HDL-C was observed on 8p23.1 and 12q21.2 and for ApoAI on 1q21.3. For LDL-C and ApoB, linkage regions frequently coincided (2p24.1, 2q32.1, 19p13.2 and 19q13.31). Six of the putative QTLs replicated previous findings. After fine mapping, three maximum LOD scores mapped within 1 cM of major candidate genes, namely APOB (LOD=2.1), LDLR (LOD=1.9) and APOE (LOD=1.7). APOB haplotypes explained 27% of the QTL effect observed for LDL-C on 2p24.1 and reduced the LOD-score by 0.82. Accounting for the effect of the LDLR and APOE haplotypes did not change the LOD score close to the LDLR gene but abolished the linkage signal at the APOE gene. In conclusion, application of a new meta-analysis approach maximised the power to detect QTLs for lipid levels and improved the precision of their location estimate.     

What evidence is there for the existence of individual genes with antagonistic pleiotropic effects?

Classical evolutionary theory predicts the existence of genes with antagonistic effects on longevity and various components of early-life fitness. Quantitative genetic studies have provided convincing evidence that such genes exist. However, antagonistic pleiotropic effects have rarely been attributed to individual loci. We examine several classes of longevity-assurance genes: those involved in regulation of the gonad; the insulin-like growth factor pathway; free-radical scavenging; heat shock proteins and apoptosis. We find initial evidence that antagonistic pleiotropic effects are pervasive in each of these classes of genes and in various model systems--although most studies lack explicit studies of fitness components. This is particularly true of human studies. Very little is known about the early-life fitness effects of longevity loci. Given the possible medical importance of such effects we urge their future study.     

Nonagenarian Siblings and Their Offspring Display Lower Risk of Mortality and Morbidity than Sporadic Nonagenarians: The Leiden Longevity Study

OBJECTIVES: To compare the risk of mortality of nonagenarian siblings with that of sporadic nonagenarians (not selected on having a nonagenarian sibling) and to compare the prevalence of morbidity in their offspring with that of the offsprings' partners.
DESIGN: Longitudinal (mortality risk) and cross-sectional (disease prevalence).
SETTING: Nationwide sample.
PARTICIPANTS: The Leiden Longevity Study consists of 991 nonagenarian siblings derived from 420 Caucasian families, 1,365 of their offspring, and 621 of the offsprings' partners. In the Leiden 85-plus Study, 599 subjects aged 85 were included, of whom 275 attained the age of 90 (sporadic nonagenarians).
MEASUREMENTS: All nonagenarian siblings and sporadic nonagenarians were followed for mortality (with a mean±standard deviation follow-up time of 2.7±1.4 years and 3.0±1.5 years, respectively). Information on medical history and medication use was collected for offspring and their partners.
RESULTS: Nonagenarian siblings had a 41% lower risk of mortality ( P <.001) than sporadic nonagenarians. The offspring of nonagenarian siblings had a lower prevalence of myocardial infarction (2.4% vs 4.1%, P =.03), hypertension (23.0% vs 27.5%, P =.01), diabetes mellitus (4.4% vs 7.6%, P =.004), and use of cardiovascular medication (23.0% vs 28.9%, P =.003) than their partners.
CONCLUSION: The lower mortality rate of nonagenarian siblings and lower prevalence of morbidity in their middle-aged offspring reinforce the notion that resilience against disease and death have similar underlying biology that is determined by genetic or familial factors.     

Influence of Bleeding Risk on Outcomes of Radial and Femoral Access for Percutaneous Coronary Intervention: An Analysis From the GLOBAL LEADERS Trial

BackgroundRadial artery access has been shown to reduce mortality and bleeding events, especially in patients with acute coronary syndromes. Despite this, interventional cardiologists experienced in femoral artery access still prefer that route for percutaneous coronary intervention. Little is known regarding the merits of each vascular access in patients stratified by their risk of bleeding.MethodsPatients from the Global Leaders trial were dichotomized into low or high risk of bleeding by the median of the PRECISE-DAPT score. Clinical outcomes were compared at 30 days.ResultsIn the overall population, there were no statistical differences between radial and femoral access in the rate of the primary end point, a composite of all-cause mortality, or new Q-wave myocardial infarction (MI) (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.42-1.15). Radial access was associated with a significantly lower rate of the secondary safety end point, Bleeding Academic Research Consortium (BARC) 3 or 5 bleeding (HR 0.55, 95% CI 0.36-0.84). Compared by bleeding risk strata, in the high bleeding score population, the primary (HR 0.47, 95% CI 0.26-0.85; P = 0.012; P_interaction = 0.019) and secondary safety (HR 0.57, 95% CI 0.35-0.95; P = 0.030; P_interaction = 0.631) end points favoured radial access. In the low bleeding score population, however, the differences in the primary and secondary safety end points between radial and femoral artery access were no longer statistically significant.ConclusionsOur findings suggest that the outcomes of mortality or new Q-wave MI and BARC 3 or 5 bleeding favour radial access in patients with a high, but not those with a low, risk of bleeding. Because this was not a primary analysis, it should be considered hypothesis generating.     

Percutaneous transradial coronary palmaz-schatz stent implantation,guided by intravascular ultrasound

Intravascular ultrasound (IVUS) allows accurate assessment of stent deployment, its use being confined to the use of 8 French (F) guiding catheters. We evaluated the feasibility of combining transradial artery Palmaz-Schatz stent implantation through 6F guiding catheters with IVUS for assessment of stent diameter after delivery at moderate inflation pressures (10-12 atmospheres [atm]) with compliant balloons and after high pressure dilatations with balloons of intermediate compliance. In 8 consecutive patients, 12 stents were delivered with Scimed® Express^TM balloon catheters at 10-12 atm followed by IVUS (EndoSonics® CathScanner; Visions® FX 3.5F 20 MHz transducer). An ultrasound study was repeated after high pressure dilatations (16-20 atm) with Schneider® Magical Speedy^TM balloon catheters. The balloon diameters were derived from manufacturer provided specifications. In all patients the transducer could easily be advanced through the guiding catheters. Reference diameter of the stented segment was 3.7 ± 0.5 mm (2.7-4.5) and the diameter of Scimed® Express^TM balloons during inflation was 4.0 ± 0.3 mm (3.6-4.7). Stent diameter was 3.0 ± 0.1 mm (2.8-3.2) (P < 0.001 compared to the reference and the balloon diameter). The diameter of the Schneide® Magical Speedy^TM balloons at secondary dilatations with 16 ± 3 atm (14-20) was 4.1 ± 0.4 mm (3.3-4.5) (P = 0.50 compared to the initial balloon diameter). Final stent diameter was 3.3 ± 0.4 mm (2.9-4.1) (P = 0.02 compared to the initial stent diameter). All stents were symmetrically deployed and well apposed. No damage to vessel or stents was detected after passage of the transducer. Thus ultrasound guided stenting via 6F guiding catheters is feasible, and high pressure dilatations with balloons of intermediate compliance results in better stent expansion than after 10-12 atm inflations with compliant balloon catheters.     

Meta-analysis of telomere length in 19?713 subjects reveals high heritability,stronger maternal inheritance and a paternal age effect

Telomere length (TL) has been associated with aging and mortality, but individual differences are also influenced by genetic factors, with previous studies reporting heritability estimates ranging from 34 to 82%. Here we investigate the heritability, mode of inheritance and the influence of parental age at birth on TL in six large, independent cohort studies with a total of 19 713 participants. The meta-analysis estimate of TL heritability was 0.70 (95% CI 0.64–0.76) and is based on a pattern of results that is highly similar for twins and other family members. We observed a stronger mother–offspring (r=0.42; P-value=3.60 × 10⁻⁶¹) than father–offspring correlation (r=0.33; P-value=7.01 × 10⁻⁵), and a significant positive association with paternal age at offspring birth (β=0.005; P-value=7.01 × 10⁻⁵). Interestingly, a significant and quite substantial correlation in TL between spouses (r=0.25; P-value=2.82 × 10⁻³⁰) was seen, which appeared stronger in older spouse pairs (mean age ≥55 years; r=0.31; P-value=4.27 × 10⁻²³) than in younger pairs (mean age<55 years; r=0.20; P-value=3.24 × 10⁻¹⁰). In summary, we find a high and very consistent heritability estimate for TL, evidence for a maternal inheritance component and a positive association with paternal age.     

The influence of clan structure on the genetic variation in a single Ghanaian village

Socioeconomic and cultural factors are thought to have an important role in influencing human population genetic structure. To explain such population structure differences, most studies analyse genetic differences among widely dispersed human populations. In contrast, we have studied the genetic structure of an ethnic group occupying a single village in north-eastern Ghana. We found a markedly skewed male population substructure because of an almost complete lack of male gene flow among Bimoba clans in this village. We also observed a deep male substructure within one of the clans in this village. Among all males, we observed only three Y-single-nucleotide polymorphism (SNP) haplogroups: E1b1a*-M2, E1b1a7a*-U174 and E1b1a8a*-U209, P277, P278. In contrast to the marked Y-chromosomal substructure, mitochondrial DNA HVS-1 sequence variation and autosomal short-tandem repeats variation patterns indicate high genetic diversities and a virtually random female-mediated gene flow among clans. On the extreme micro-geographical scale of this single Bimoba village, correspondence between the Y-chromosome lineages and clan membership could be due to the combined effects of the strict patrilocal and patrilineal structure. If translated to larger geographic scales, our results would imply that the extent of variation in uniparentally inherited genetic markers, which are typically associated with historical migration on a continental scale, could equally likely be the result of many small and different cumulative effects of social factors such as clan membership that act at a local scale. Such local scale effects should therefore be considered in genetic studies, especially those that use uniparental markers, before making inferences about human history at large.