Extent of height variability explained by known height-associated genetic variants in an isolated population of the Adriatic coast of Croatia

Background

Human height is a classical example of a polygenic quantitative trait. Recent large-scale genome-wide association studies (GWAS) have identified more than 200 height-associated loci, though these variants explain only 2∼10% of overall variability of normal height. The objective of this study was to investigate the variance explained by these loci in a relatively isolated population of European descent with limited admixture and homogeneous genetic background from the Adriatic coast of Croatia.

Methodology/Principal Findings

In a sample of 1304 individuals from the island population of Hvar, Croatia, we performed genome-wide SNP typing and assessed the variance explained by genetic scores constructed from different panels of height-associated SNPs extracted from five published studies. The combined information of the 180 SNPs reported by Lango Allen el al. explained 7.94% of phenotypic variation in our sample. Genetic scores based on 20∼50 SNPs reported by the remaining individual GWA studies explained 3∼5% of height variance. These percentages of variance explained were within ranges comparable to the original studies and heterogeneity tests did not detect significant differences in effect size estimates between our study and the original reports, if the estimates were obtained from populations of European descent.

Conclusions/Significance

We have evaluated the portability of height-associated loci and the overall fitting of estimated effect sizes reported in large cohorts to an isolated population. We found proportions of explained height variability were comparable to multiple reference GWAS in cohorts of European descent. These results indicate similar genetic architecture and comparable effect sizes of height loci among populations of European descent.     

Hypertrophic cardiomyopathy and sudden cardiac death due to physical exercise in Croatia in a 27-year period

The paper deals with the sudden cardiac death during physical exercise in males in Croatia. The data are a part of a retrospective study dealing with 69 sudden death due to physical activity in men in Croatia during 27 years: from January 1, 1984 to December 31, 2010. Three of them suddenly died during training and two of them died during recreational physical exercise, probably because of malignant ventricular arrhythmia due to hyperthrophic cardiomyopathy. One had an obstructive form of hypertrophic cardiomyopathy with i.v. septum of 40 mm and four had a non-obstructive forms of hyperthrophic cardiomyopathy with left ventricular wall of 18-20-22-25 mm. First athlete was a short trails runner, aged 24, with no any previous physical discomforts, who suddenly collapsed and died during training. The second athlete was a soccer player aged 18, with no any previous physical discomfort, who suddenly collapsed and died during training. The third aged 15, was a school boy, basketball player, with no any previous physical discomfort, who collapsed and died during training. Two aged 25 and 34, were with no physical discomfort during exercise and died suddenly during recreational soccer games. A sudden cardiac death due to physical exercise in young athletes in Croatia suffered of hyperthropic cardiomyopathy reached 0.06/100 000 yearly (p = 0.00000) in 27 years, in teenagers 0.26/100 000 (p = 0.00226), in teenagers suffered of hypertrophic cardiomyopathy reached 0.10/100 000 (p = 0.00000), in all young athletes suffered of other heart diseases reached 0.19/100 000 (p = 0.00005), and in the total male population aged 15 or more, engaged in sports and recreational physical exercise: 0.71/100.0000 (p = 0.00001).     

Host-derived Langerhans cells persist after MHC-matched allografting independent of donor T cells and critically influence the alloresponses mediated by donor lymphocyte infusions

Mouse models of minor histocompatibility Ag-mismatched bone marrow transplantation were used to study donor dendritic cell (DC) reconstitution after conditioning, variables influencing the persistence of residual host DCs in different compartments, their phenotype, and their role in governing donor lymphocyte infusion (DLI)-mediated alloresponses. Reconstitution of all splenic DC subsets occurred rapidly after bone marrow transplantation and before T cell reconstitution. However, in contrast to MHC-mismatched chimeras, residual host-derived DCs persisted in the cutaneous lymph nodes (CLNs) of MHC-matched chimeras despite the presence or addition of donor T cells to the graft. The phenotype of these residual host-derived DCs in CLNs was consistent with Langerhans' cells (LCs). We confirmed their skin origin and found near-complete preservation of host-derived LCs in the skin. Host-derived LCs retained their ability to continuously traffic to the CLNs, expressed homogeneously increased levels of costimulatory molecules, and could capture and carry epicutaneously applied Ags. To determine the role of residual host LCs in governing DLI-mediated alloresponses, we administered DLI alone or after topical application of the TLR7 ligand imiquimod, which is known to enhance the LC emigration from the skin. DLI administration resulted in a decrease in host-derived DCs in the CLNs and increased recruitment of donor-derived DCs to the skin, whereas imiquimod augmented their alloreactivity. These results suggest uniqueness of the MHC-matched setting in relation to the persistence of host-derived DCs in the skin and points to a previously unrecognized role of host-derived LCs in the induction of DLI-mediated graft-vs-host alloresponses.     

Acute cardiovascular complications due to physical exercise in male teenagers

Five sudden cardiac deaths in male adolescents (age 14-18 years) were detected in a 5-year period in Croatia. Two of them had been engaged in physical exercise at school, one as a professional soccer player, one in recreational swimming, and the fifth had just finished secondary school and was working at the site. All of them were autopsied and in three congenital cardiovascular diseases was found. Two had hypoplastic coronary arteries. The third had hypertrophic cardiomyopathy with interventricular wall of 40 mm. The fourth had normal heart findings including coronaries, but had bilateral pneumonia with a possible altitude (non-cardiogenic) pulmonary edema. The fifth had a chronic myopericarditis with an aneurysm of the left ventricle. All of them had not reported definite symptoms at exertion. According to this data, the death rate in adolescent males in Croatia during or after recreational physical exercise was 1/100,000 per year or 5/500,000 in five years. Thorough preparticipation medical examination including indicated laboratory tests and avoidance of heavy exertion at the time of respiratory infection might have helped to avoid some of the lethal events.     

Physical activity and sudden cardiac death in elders--a Croatian study

The paper deals with the sudden cardiac death in elders due to physical activity in Croatia and to compare it to other population groups who practice physical activity. The data are a part of a retrospective study dealing with 59 sudden death due to physical activity in men in Croatia: from January 1, 1988 to December 31, 2008. Fifteen aged 65 to 82 years were recreationally engaged in physical activity: six in swimming, four in tennis, one in driving a bicycle, one in jogging, two in bowling and one died during sexual act. Only one had symptoms of pectoral angina, two suffered from arterial hypertension, and two had congestive heart failure. Eleven were without symptoms before exercise. At forensic autopsy, fourteen had coronary heart disease, seven had critical coronary artery stenosis, three had occluded left descendens anterior coronary artery and four critical coronary stenosis, four had a recent myocardial infarctions, and eleven had myocardial scars due to previous myocardial infarctions. Twelve of them had left ventricular hypertrophy: 15-25 mm. In Croatia, about 7per cent of the entire male population undertake recreational physical activity, while 13 per cent of them are elders. A sudden cardiac death due to recreational physical activity in elders reached 1.71/100 000 yearly, in the entire male population engaged in recreational physical exercise: 0.75/100 000 (p = 0.05730), in the total male population aged 15-40 engaged in sports and recreational physical exercise: 0.57/100.0000 (p = 0.00387), in young athletes: 0.15/100 000 (p = 0.00000). Medical examination of all elderly persons has to be done before starting of recreational physical activity: by clinical examination, searching for risk factors for atherosclerosis, performing ECG at rest, stress ECG, and echocardiography and to repeat the medical examination at least once a year Physical activity should start with a warm-up period and with a gradually increasing load, and usually not to exceed 6-7 metabolic equivalents (METs).     

Finding Missing Heritability in Less Significant Loci and Allelic Heterogeneity: Genetic Variation in Human Height

Genome-wide association studies (GWAS) have identified many common variants associated with complex traits in human populations. Thus far, most reported variants have relatively small effects and explain only a small proportion of phenotypic variance, leading to the issues of ‘missing’ heritability and its explanation. Using height as an example, we examined two possible sources of missing heritability: first, variants with smaller effects whose associations with height failed to reach genome-wide significance and second, allelic heterogeneity due to the effects of multiple variants at a single locus. Using a novel analytical approach we examined allelic heterogeneity of height-associated loci selected from SNPs of different significance levels based on the summary data of the GIANT (stage 1) studies. In a sample of 1,304 individuals collected from an island population of the Adriatic coast of Croatia, we assessed the extent of height variance explained by incorporating the effects of less significant height loci and multiple effective SNPs at the same loci. Our results indicate that approximately half of the 118 loci that achieved stringent genome-wide significance (p-value<5×10⁻⁸) showed evidence of allelic heterogeneity. Additionally, including less significant loci (i.e., p-value<5×10⁻⁴) and accounting for effects of allelic heterogeneity substantially improved the variance explained in height.     

Myopericarditis and sudden cardiac death due to physical exercise in male athletes

In the period 1998-, we registered four sudden and unexpected cardiac deaths in male athletes due to myopericarditis during or after physical exercise. Three of them were professional soccer players and the fourth was engaged in swimming. One aged 29, had symptoms of tiredness, heart enlargement and left ventricular premature beats during training. Three of them, aged 17-18-18, were without symptoms. Three died during training and the fourth died in the hospital after head trauma at training. In the first one, aged 29, forensic autopsy showed chronic myopericarditis, thickening of the left ventricular wall of 15 mm and enlargement of the whole heart. The second one, aged 17, had subacute diffuse myopericarditis, suppurative tonsillitis and narrowed ascending aorta. The third, aged 18, had chronic myopericarditis and cardiac aneurysm of the left ventricle. The fourth, aged 18, had fibrinous pericarditis, thickening of the left ventricle 20 mm, hypoplastic ascending aorta, bilateral bronchopneumonia and cerebral contusion with edema. In Croatia, death rate among athletes, including all its causes, reached 0.15/100,000, in athletes suffering from myopericarditis it was 0.34/100,000, in others who practice exercise recreatively it amounted to 0.57/100,000 (p=0.0068), and in all males who practice exercise it measured 0.75/100,000 (p=0.0014). Physical exercise has to be contraindicated in cases of myopericarditis for at least six months from the onset of the illness.     

Does chronological age reduce working ability?

Definitions of so-called older age often are based on a chronological age of 65 years and over, although by some authors aging is the process that starts after the 30th year of life. At the beginning occur changes in the organ functions, followed by anatomical changes as well. Some organs age faster, some slower. For example, kidneys decrease for one third, lungs do not change, liver shrinks a little, prostate increases twice. In some cross-sectional studies, muscle mass in men aged 65 is on average 12 kg less than in the so-called middle age, and in women it is approximately 5 kg less. In the heart the amount of connective tissue increases, lipofuscin is deposited in cardiac muscle, the strength of which is decreasing. In the respiratory tract the number of pathways cilia decreases, along with the alveolar surface, muscles involved in breathing change, lung elasticity is also diminished. But, in regard with the previous body capacity, "physiological aging" can be divided into three types of elderly: the "older" elderly have the highest functional capacity of 2-3 MET (MET--metabolic unit, i.e. the oxygen consumption of 3.5 ml/kg body mass in a minute), the "younger" elderly are the persons of older age having maximal functional capacity of 5-7 MET, while the "sport" elderly have the functional capacity of 9-10 MET, disregarding chronological age. The brain weight diminishes for approximately 7% compared to younger age. In temporal gyrus and area striata even 20-40% of cells are being lost, vacuolar and neuroaxonal degeneration occurs, lipofuscin is being accumulated. The brain blood flow, which is in normal conditions 50-60 ml/min/100 g of tissue, with the increase of biological age decreases to about 40 ml/min/100 g of tissue. However, this usually is not the consequence of biological age but of disease. A chronological age of 65 for the beginning of "elder hood" is a sociopolitical construct developed by social security systems and government organizations to decide an arbitrary age at which benefits should be paid. Thus, it neither a border nor do changes designating old age occurs exactly with that "age border". The changes in the organism during the so-called aging are individual. So, the functional capacity of an organism, both physical and intellectual, must be evaluated individually, having in mind biological age.