Zijad Duraković

Genome-wide association of serum uric acid concentration: replication of sequence variants in an island population of the Adriatic coast of Croatia

A genome‐wide association study of serum uric acid (SUA) laevels was performed in a relatively isolated population of European descent from an island of the Adriatic coast of Croatia. The study sample included 532 unrelated and 768 related individuals from 235 pedigrees. Inflation due to relatedness was controlled by using genomic control. Genetic association was assessed with 2,241,249 single nucleotide polymorphisms (SNPs) in 1300 samples after adjusting for age and gender. Our study replicated four previously reported SUA loci (SLC2A9, ABCG2, RREB1, and SLC22A12). The strongest association was found with a SNP in SLC2A9 (rs13129697, P= 2.33×10−19), which exhibited significant gender‐specific effects, 35.76 μmol/L (P= 2.11×10−19) in females and 19.58 μmol/L (P= 5.40×10−5) in males. Within this region of high linkage disequilibrium, we also detected a strong association with a nonsynonymous SNP, rs16890979 (P= 2.24×10−17), a putative causal variant for SUA variation. In addition, we identified several novel loci suggestive of association with uric acid levels (SEMA5A, TMEM18, SLC28A2, and ODZ2), although the P‐values (P < 5×10−6) did not reach the threshold of genome‐wide significance. Together, these findings provide further confirmation of previously reported uric‐acid‐related genetic variants and highlight suggestive new loci for additional investigation.

Changes of the corrected Q-T interval in the electrocardiogram of patients with anorexia nervosa

Thirty patients with anorexia nervosa and 30 controls had an electrocardiogram with the corrected Q-T interval. The aim of the study was to analyse the corrected Q-T interval in patients with anorexia nervosa compared with the findings in the control group, to compare the body mass index between two groups and to measure underlying dispersion of the corrected Q-T interval in each of the 12 ECG leads in both groups. All corrected Q-T intervals were measured in each of the 12 ECG leads and the longest values of three consecutive intervals were used for this analysis. The prolonged corrected Q-T interval was found in 12 out of 30 patients with anorexia nervosa (40%), with the longest mean values of 0.421 s (range, 0.334-0.500 s), and in 2 out of 30 patients of the controls (7%), with the longest mean values of 0.390 s (range, 0.343-0.444 s). The difference was statistically significant (t = 4.453, P < 0.001). Relative risk for prolongation of the corrected Q-T interval in patients with anorexia nervosa was high: 12 compared with control subjects. The longest values of the corrected Q-T interval in both groups, and the longest values of the prolonged corrected Q-T interval in both groups were observed in the anteroseptal leads of the electrocardiograms. The mean serum potassium level in the group with anorexia nervosa was 3.97 and in the control group was 4.15 mmol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Common SNPs in FTO gene are associated with obesity related anthropometric traits in an island population from the eastern Adriatic coast of Croatia.

Background Multiple studies have provided compelling evidence that the FTO gene variants are associated with obesity measures. The objective of the study was to investigate whether FTO variants are associated with a broad range of obesity related anthropometric traits in an island population. Methodology/Principal Findings We examined genetic association between 29 FTO SNPs and a comprehensive set of anthropometric traits in 843 unrelated individuals from an island population in the eastern Adriatic coast of Croatia. The traits include 11 anthropometrics (height, weight, waist circumference, hip circumference, bicondilar upper arm width, upper arm circumference, and biceps, triceps, subscapular, suprailiac and abdominal skin-fold thicknesses) and two derived measures (BMI and WHR). Using single locus score tests, 15 common SNPs were found to be significantly associated with “body fatness” measures such as weight, BMI, hip and waist circumferences with P-values ranging from 0.0004 to 0.01. Similar but less significant associations were also observed between these markers and bicondilar upper arm width and upper arm circumference. Most of these significant findings could be explained by a mediating effect of “body fatness”. However, one unique association signal between upper arm width and rs16952517 (P-value = 0.00156) could not be explained by this mediating effect. In addition, using a principle component analysis and conditional association tests adjusted for “body fatness”, two novel association signals were identified between upper arm circumference and rs11075986 (P-value = 0.00211) and rs16945088 (P-value = 0.00203). Conclusions/Significance The current study confirmed the association of common variants of FTO gene with “body fatness” measures in an isolated island population. We also observed evidence of pleiotropic effects of FTO gene on fat-free mass, such as frame size and muscle mass assessed by bicondilar upper arm width and upper arm circumference respectively and these pleiotropic effects might be influenced by variants that are different from the ones associated with “body fatness”.

Poisoning with 2,4-dichlorophenoxyacetic acid treated by hemodialysis

In this paper four patients are presented who had been poisoned by 2,4-dichlorophenoxyacetic acid (2,4-D). The first patient, aged 51 years, had attempted to commit suicide by taking orally 400 ml of a 40% solution of 2,4-D. He was admitted in a coma, 6.5 h after poisoning. Extracorporal hemodialysis was performed and the course of the illness was satisfactory. The second patient, aged 80 years, had accidentally drunk 100 ml of a 40% solution of 2,4-D. He was admitted in a coma a few hours after poisoning. Hemodialysis and resin hemoperfusion were performed and the course of the illness was satisfactory. Prior to the above therapy the patient had a 2,4-D serum concentration of 177 mg/100 ml. 2,4-D clearance was 56,3 ml/min during this therapy. The third patient, aged 24 years, had drunk 200 ml of a 40% solution of 2,4-D in a suicide attempt, and paraquat poisoning was also suspected. He was admitted 10 h after poisoning and immediately hemodialysis and hemoperfusion were carried out: the course of the illness was satisfactory. On admittance the concentration of 2,4-D in serum was 122.5 mg/100 ml, and clearance was 72.9 ml/min during treatment.The fourth patient, aged 50 years, had accidentally drunk 100–200 ml of a 40% solution of 2,4-D. He was admitted in a coma 3 h after poisoning. Hemodialysis was performed and the course of the illness was satisfactory. On admittance the concentration of 2,4-D in serum was 37 mg/100 ml and clearance was 68.7 ml/min. On the fourth day after admittance clinical signs of 2,4-D poisoning appeared again, with a serum concentration of 43.9 ml/100 ml. The patients condition improved after further hemodialysis. In the first two patients there was a prolonged corrected Q-T interval during coma.

Q-T and JT dispersion in the elderly with urban hypothermia

Twenty elderly patients (12 females and 8 males, aged 65-88 years) were treated because of hypothermia: 11 suffered from moderate (35-32 degrees C) and nine from severe hypothermia (<32 degrees C). The control group consisted of 20 age and sex-matched healthy elderly persons. Twelve-channel electrocardiograms were recorded on admission and during hospitalization. In patients with moderate hypothermia Osborn wave was present in eight of 11, and minimal Osborn wave in three of 11; in severe hypothermia Osborn wave was seen in seven of nine, and minimal in two of nine. The corrected Q-T interval (Q-Tc) was analyzed according to the formula of Bazett: measured Q-T(s)/ radical R-R(s). The JT and the corrected JT interval (JTc) were measured according to the formula: JT=Q-T-QRS. The Q-T interval index (Q-TI) was measured according to the formula: (Q-TI:656)x(HR+100); and the JT interval index JTI: (JT:518)x(HR+100). The dispersion of the Q-Tc (JTc) was defined as the difference between maximum and minimum measured Q-Tc interval (JTc). The Q-Tc interval in the group with hypothermia was 651.41+/-130.06 ms, while in the control group it was 398.14+/-76.21 ms (P<0.001). The Q-Tc dispersion in the group with hypothermia was 91.39+/-51.98, and in the control group 33.21+/-10.25 ms (P<0.001). The Q-TcI in the group with hypothermia was 89.91+/-21.44, and in the control group 39.56+/-9.41 ms ((P<0.001). The JTc in the group with hypothermia was 542.66+/-132.74, in the control group: 328.06+/-76.92 (P<0.001). The JTc dispersion in the group with hypothermia was 79.35+/-46.22, and in the control group 28.53+/-7.99 (P<0.0001). The JTcI in the group with hypothermia was 93.06+/-17.38, in the control group it was 40.23+/-7.59 (P<0.001). The mean values of the Q-TcI were greater than Q-TI, and the mean values of the JTcI were greater than JTI, but the difference was not significant (P>0.10). The mean values of the JTcI were greater than Q-TcI, but the difference was not significant as well (P>0.05). There was no correlation between rectal temperature and dispersion of Q-T, Q-Tc, JT, JTc, and Osborn wave. The maximum Osborn wave and the maximum Q-T interval were registered in anteroseptal leads (V(2)-V(3)). The dispersion of the Q-Tc and of the JTc lasted more than Osborn wave. There was no correlation between rectal temperature and PR interval, RR interval and QRS duration. The prolonged dispersion of the Q-Tc (and JTc) last 24-48 h longer than Osborn wave.

Prevalence of metabolic syndrome and related metabolic traits in an island population of the Adriatic

Background: Metabolic syndrome, a constellation of risk factors associated with cardiovascular disease and Type 2 diabetes, has reached epidemic proportions worldwide. Epidemiological studies in transitional societies will provide insight into the underlying factors that interact in its manifestation. Aims: To estimate the prevalence of metabolic syndrome, provide a comparative analysis of two metabolic syndrome definitions and assess clustering and association of metabolic traits and cardiovascular diseases in an Adriatic island population. Subjects and methods: In a cross-sectional study, data on four anthropometric, blood pressure and 11 biochemical traits were obtained from 1430 adults from the island of Hvar. Results: Prevalence of metabolic syndrome was 25% and 38.5% based on Adult Treatment Panel III and International Diabetes Federation definitions, respectively. Rates of abdominal obesity, elevated blood glucose and hypertension were high. Among the traits not included in the definitions, levels of LDL, total cholesterol and fibrinogen were markedly elevated. The majority of the phenotypes were significantly associated with the syndrome, the strongest being waist circumference. Conclusion: The Croatian islanders are characterized by a high prevalence of metabolic abnormalities. Central obesity is the strongest contributor of the syndrome. With a high prevalence of dyslipidemia and pro-inflammatory factors, the population is at substantial risk for cardiovascular diseases.

Replication of genetic variants from genome-wide association studies with metabolic traits in an island population of the Adriatic coast of Croatia.

Twenty-two single-nucleotide polymorphisms (SNPs) in 10 gene regions previously identified in obesity and type 2 diabetes (T2D) genome-wide association studies (GWAS) were evaluated for association with metabolic traits in a sample from an island population of European descent. We performed a population-based study using 18 anthropometric and biochemical traits considered as continuous variables in a sample of 843 unrelated subjects (360 men and 483 women) aged 18–80 years old from the island of Hvar on the eastern Adriatic coast of Croatia. All eight GWAS SNPs in FTO were significantly associated with weight, body mass index, waist circumference and hip circumference; 20 of the 32 nominal P-values remained significant after permutation testing for multiple corrections. The strongest associations were found between the two TCF7L2 GWAS SNPs with fasting plasma glucose and HbA1c levels, all four P-values remained significant after permutation tests. Nominally significant associations were found between several SNPs and other metabolic traits; however, the significance did not hold after permutation tests. Although the sample size was modest, our study strongly replicated the association of FTO variants with obesity-related measures and TCF7L2 variants with T2D-related traits. The estimated effect sizes of these variants were larger or comparable to published studies. This is likely attributable to the homogenous genetic background of the relatively isolated study population.

Proteinuria in the Elderly

In a representative sample of 624 people, 65-84 years of age, from six regions of Croatia, Yugoslavia, proteinuria was investigated on the basis of certain medical characteristics. Established proteinuria was seen in 30.8% of females and 27.4% of males. Proteinuria was found to be significantly more common in people with urinary tract infections. Arterial hypertension with heart failure was more often seen in patients with than in patients without proteinuria, but the difference was not statistically significant.

The Effect of Cigarette Smoking History on Muscular and Cardiorespiratory Endurance

The purpose of this study was to investigate the effect of cigarette smoking history on physical fitness in younger adults. Small, insignificant differences in BMI between non-smokers and smokers were shown regardless of cigarette smoking history duration. Although the differences in muscular endurance increased in the samples with progressing cigarette smoking history duration, a highly significant difference in aerobic endurance was observed between the group of non-smokers and smokers with a history of smoking up to 5 years and persisted at the same level in smokers with a history of smoking for longer than 10 years.