Sex-related differences in the management and outcomes of patients hospitalized with ST-elevation myocardial infarction: a comparison within four European myocardial infarction registries.

Aims: Data on how differences in risk factors, treatments, and outcomes differ between sexes in European countries are scarce. We aimed to study sex-related differences regarding baseline characteristics, in-hospital managements, and mortality of ST-elevation myocardial infarction (STEMI) patients in different European countries. Methods and results: Patients over the age of 18 with STEMI who were treated in hospitals in 2014-17 and registered in one of the national myocardial infarction registers in Estonia (n = 5817), Hungary (n = 30 787), Norway (n = 33 054), and Sweden (n = 49 533) were included. Cardiovascular risk factors, hospital treatment, and recommendation of discharge medications were obtained from the infarction registries. The primary outcome was mortality, in-hospital, after 30 days and after 1 year. Logistic and cox regression models were used to study the associations of sex and outcomes in the respective countries. Women were older than men (70-78 and 62-68 years, respectively) and received coronary angiography, percutaneous coronary intervention, left ventricular ejection fraction assessment, and evidence-based drugs to a lesser extent than men, in all countries. The crude mortality in-hospital rates (10.9-15.9 and 6.5-8.9%, respectively) at 30 days (13.0-19.9 and 8.2-10.9%, respectively) and at 1 year (20.3-28.1 and 12.4-17.2%, respectively) after hospitalization were higher in women than in men. In all countries, the sex-specific differences in mortality were attenuated in the adjusted analysis for 1-year mortality. Conclusion: Despite improved awareness of the sex-specific inequalities on managing patients with acute myocardial infarction in Europe, country-level data from this study show that women still receive less guideline-recommended management.

Comparison of management and outcomes of ST-segment elevation myocardial infarction patients in Estonia, Hungary, Norway, and Sweden according to national ongoing registries.

AIMS: Describe the characteristics, management and outcomes of hospitalized ST-segment elevation myocardial infarction (STEMI) patients according to national ongoing myocardial infarction registries in Estonia, Hungary, Norway, and Sweden. METHODS AND RESULTS: Country-level aggregated data was used to study baseline characteristics, use of in-hospital procedures, medications at discharge, in-hospital complications, 30-day and 1-year mortality for all patients admitted with STEMI during 2014-2017 using data from EMIR (Estonia; n = 4584), HUMIR (Hungary; n = 23 685), NORMI (Norway; n = 12 414, data for 2013-2016), and SWEDEHEART (Sweden; n = 23 342). Estonia and Hungary had a higher proportion of women, patients with hypertension, diabetes, and peripheral artery disease compared to Norway and Sweden. Rates of reperfusion varied from 75.7% in Estonia to 84.0% in Sweden. Rates of recommendation of discharge medications were generally high and similar. However, Estonia demonstrated the lowest rates of dual antiplatelet therapy (78.1%) and statins (86.5%). Norway had the lowest rates of beta-blockers (80.5%) and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (61.5%). The 30-day mortality rates ranged between 9.9% and 13.4% remaining lowest in Sweden. One-year mortality rates ranged from 14.8% in Sweden and 16.0% in Norway to 20.6% in Hungary and 21.1% in Estonia. Age-adjusted lethality rates were highest for Hungary and lowest for Sweden. CONCLUSION: This inter-country comparison of data from four national ongoing European registries provides new insights into the risk factors, management and outcomes of patients with STEMI. There are several possible reasons for the findings, including coverage of the registries and variability of baseline-characteristics' definitions that need to be further explored.

Differences in characteristics, treatments and outcomes in patients with non-ST-elevation myocardial infarction: novel insights from four national European continuous real-world registries.

AIMS: To study baseline characteristics, in-hospital managements and mortality of non-ST-elevation myocardial infarction (NSTEMI) patients in different European countries. METHODS AND RESULTS: NSTEMI patients enrolled in the national myocardial infarction (MI) registries [EMIR; n = 5817 (Estonia), HUMIR; n = 30 787 (Hungary), NORMI; n = 33 054 (Norway), and SWEDEHEART; n = 49 533 (Sweden)] from 2014 to 2017 were included and presented as aggregated data. The median age at admission ranged from 70 to 75 years. Current smoking status was numerically higher in Norway (24%), Estonia (22%), and Hungary (19%), as compared to Sweden (17%). Patients in Hungary had a high rate of diabetes mellitus (37%) and hypertension (84%). The proportion of performed coronary angiographies (58% vs. 75%) and percutaneous coronary interventions (38% vs. 56%), differed most between Norway and Hungary. Prescription of dual antiplatelet therapy at hospital discharge ranged from 60% (Estonia) to 81% (Hungary). In-hospital death ranged from 3.5% (Sweden) to 9% (Estonia). The crude mortality rate at 1 month was 12% in Norway and 5% in Sweden (5%), whereas the 1-year mortality rates were similar (20-23%) in Hungary, Estonia, and Norway and 15% in Sweden. CONCLUSION: Cross-comparisons of four national European MI registries provide important data on differences in risk factors and treatment regiments that may explain some of the observed differences in death rates. A unified European continuous MI registry could be an option to better understand how implementation of guideline-recommended therapy can be used to reduce the burden of cardiovascular disease.

Adolescent Cranial Volume as a Sensitive Marker of Parental Investment: The Role of Non-material Resources?

Growth of different body parts in humans is sensitive to different resource constraints that are mediated by parental investment. Parental investment can involve the expenditure of material, cognitive, and emotional resources on offspring. Cranial volume, an important predictor of cognitive ability, appears understudied in this context. We asked (1) whether there are associations between growth and family structure, self-reported estimates for resource availability, and sibling number; and (2) whether these constraints relate to head and body growth in a similar manner. We assessed the associations between parental investment, height, and cranial volume in a cross-sectional study of Estonian children (born 1980-87, aged 11-17). Height correlated negatively with the number of siblings but this association became negligible in a model controlling for birthweight, parental heights, and mother's age at birth. Unlike height, cranial volume was unrelated to sibling number, but it was negatively associated with self-reported meat and general resource shortage. Cranial volume was related to family structure and paternal education. Children living with both birth-parents had larger heads than those living in families containing a step-parent. Since these family types did not differ with respect to meat or general resource shortage, our findings suggest that families including both genetic parents provide non-material benefits that stimulate predominantly cranial growth. For the studied developmental period, cranial volume appeared a more sensitive marker of growth constraints than height. The potential of using cranial volume for quantifying physical impact of non-material parental investment deserves further attention.

Meeting Report: The Role of Beliefs and Perception on Body Size. Proceedings of the 26th Aschauer Soiree, Held at Aschauhof, Altenhof, Germany, May 26th, 2018.

Thirty-one scientists met at Aschauhof, Germany to discuss the role of beliefs and self-perception on body size. In view of apparent growth stimulatory effects of dominance within the social group that is observed in social mammals, they discussed various aspects of competitive growth strategies and growth adjustments. Presentations included new data from Indonesia, a cohort-based prospective study from Merida, Yucatan, and evidence from recent meta-analyses and patterns of growth in the socially deprived. The effects of stress experienced during pregnancy and adverse childhood events were discussed, as well as obesity in school children, with emphasis on problems when using z-scores in extremely obese children. Aspects were presented on body image in African-American women, and body perception and the disappointments of menopause in view of feelings of attractiveness in different populations. Secular trends in height were presented, including short views on so called 'racial types' vs bio-plasticity, and historic data on early-life nutritional status and later-life socioeconomic outcomes during the Dutch potato famine. New tools for describing body proportions in patients with variable degrees of phocomelia were presented along with electronic growth charts. Bio-statisticians discussed the influence of randomness, community and network structures, and presented novel tools and methods for analyzing social network data.

Blood pressure loci identified with a gene-centric array.

Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.

HYPEST study: profile of hypertensive patients in Estonia.

BACKGROUND: More than one third of adult population in Estonia has problems with elevated blood pressure (BP). The Hypertension in Estonia (HYPEST) study represents the country's first hypertension-targeted sample collection aiming to examine the epidemiological and genetic determinants for hypertension (HTN) and related cardiovascular diseases (CVD) in Estonian population. The HYPEST subjects (n = 1,966) were recruited across Estonia between 2004-2007 including clinically diagnosed HTN cases and population-based controls. The present report is focused on the clinical and epidemiological profile of HYPEST cases, and gender-specific effects on the pathophysiology of hypertension. METHODS: Current analysis was performed on 1,007 clinically diagnosed HTN patients (617 women and 390 men) aged 18-85 years. The hypertensives were recruited to the study by BP specialists at the North Estonia Medical Center, Centre of Cardiology, Tallinn or at the Cardiology Clinic, Tartu University Hospital, Estonia. Longitudinal BP data was extracted retrospectively from clinical records. Current and retrospective data of patient's medical history, medication intake and lifestyle habits were derived from self-administrated questionnaire and each variable was examined separately for men and women. Eleven biochemical parameters were measured from fasting serum samples of 756 patients. RESULTS: The distribution of recruited men and women was 39% and 61% respectively. Majority of Estonian HTN patients (85%) were overweight (BMI ≥ 25 kg/m2) and a total of 79% of patients had additional complications with cardiovascular system. In men, the hypertension started almost 5 years earlier than in women (40.5 ± 14.5 vs 46.1 ± 12.7 years), which led to earlier age of first myocardial infarction (MI) and overall higher incidence rate of MI among male patients (men 21.2%, women 8.9%, P < 0.0001). Heart arrhythmia, thyroid diseases, renal tubulo-intestinal diseases and hyperlipidemia were more prevalent in hypertensive women compared to men (P < 0.0001). An earlier age of HTN onset was significantly associated with smoking (P = 0.00007), obesity (BMI ≥ 30 kg/m2; P = 0.0003), increased stress (P = 0.0003) and alcohol consumption (P = 0.004). CONCLUSION: Understanding the clinical profile of HTN patients contributes to CVD management. Estonian hypertension patients exhibited different disease and risk profiles of male and female patients. This well-characterized sample set provides a good resource for studying hypertension and other cardiovascular phenotypes.

Novel polymorphic AluYb8 insertion in the WNK1 gene is associated with blood pressure variation in Europeans.

Mutations in WNK1 and WNK4 cause familial hypertension, the Gordon syndrome. WNK1 and WNK4 conserved noncoding regions were targeted to polymorphism screening using DHPLC and DGGE. The scan identified an undescribed polymorphic AluYb8 insertion in WNK1 intron 10. Screening in primates revealed that this Alu-insertion has probably occurred in human lineage. Genotyping in 18 populations from Europe, Asia, and Africa (n = 854) indicated an expansion of the WNK1 AluYb8 bearing chromosomes out of Africa. The allele frequency in Sub-Saharan Africa was ~3.3 times lower than in other populations (4.8 vs. 15.8%; P = 9.7 × 10(-9) ). Meta-analysis across three European sample sets (n = 3,494; HYPEST, Estonians; BRIGHT, the British; CADCZ, Czech) detected significant association of the WNK1 AluYb8 insertion with blood pressure (BP; systolic BP, P = 4.03 × 10(-3) , effect 1.12; diastolic BP, P = 1.21 × 10(-2) , effect 0.67). Gender-stratified analysis revealed that this effect might be female-specific (n = 2,088; SBP, P = 1.99 × 10(-3) , effect 1.59; DBP P = 3.64 × 10(-4) , effect 1.23; resistant to Bonferroni correction), whereas no statistical support was identified for the association with male BP (n = 1,406). In leucocytes, the expressional proportions of the full-length WNK1 transcript and the splice-form skipping exon 11 were significantly shifted in AluYb8 carriers compared to noncarriers. The WNK1 AluYb8 insertion might affect human BP via altering the profile of alternatively spliced transcripts.

Hypervariable intronic region in NCX1 is enriched in short insertion-deletion polymorphisms and showed association with cardiovascular traits.

BACKGROUND: Conserved non-coding regions (CNR) have been shown to harbor gene expression regulatory elements. Genetic variations in these regions may potentially contribute to complex disease susceptibility. METHODS: We targeted CNRs of cardiovascular disease (CVD) candidate gene, Na(+)-Ca(2+) exchanger (NCX1) with polymorphism screening among CVD patients (n = 46) using DHPLC technology. The flanking region (348 bp) of the 14 bp indel in intron 2 was further genotyped by DGGE assay in two Eastern-European CVD samples: essential hypertension (HYPEST; 470 cases, 652 controls) and coronary artery disease, CAD (CADCZ; 257 cases, controls 413). Genotype-phenotype associations were tested by regression analysis implemented in PLINK. Alignments of primate sequences were performed by ClustalW2. RESULTS: Nine of the identified NCX1 variants were either singletons or targeted by commercial platforms. The 14 bp intronic indel (rs11274804) was represented with substantial frequency in HYPEST (6.82%) and CADCZ (14.58%). Genotyping in Eastern-Europeans (n = 1792) revealed hypervariable nature of this locus, represented by seven alternative alleles. The alignments of human-chimpanzee-macaque sequences showed that the major human variant (allele frequency 90.45%) was actually a human-specific deletion compared to other primates. In humans, this deletion was surrounded by other short (5-43 bp) deletion variants and a duplication (40 bp) polymorphism possessing overlapping breakpoints. This indicates a potential indel hotspot, triggered by the initial deletion in human lineage. An association was detected between the carrier status of 14 bp indel ancestral allele and CAD (P = 0.0016, OR = 2.02; Bonferroni significance level alpha = 0.0045), but not with hypertension. The risk for the CAD development was even higher among the patients additionally diagnosed with metabolic syndrome (P = 0.0014, OR = 2.34). Consistent with the effect on metabolic processes, suggestive evidence for the association with heart rate, serum triglyceride and LDL levels was detected (P = 0.04). CONCLUSIONS: Compared to SNPs targeted by large number of locus-specific and genome-wide assays, considerably less attention has been paid to short indel variants in the human genome. The data of genome dynamics, mutation rate and population genetics of short indels, as well as their impact on gene expressional profile and human disease susceptibility is limited. The characterization of NCX1 intronic hypervariable non-coding region enriched in human-specific indel variants contributes to this gap of knowledge.

Targeting 160 candidate genes for blood pressure regulation with a genome-wide genotyping array.

The outcome of Genome-Wide Association Studies (GWAS) has challenged the field of blood pressure (BP) genetics as previous candidate genes have not been among the top loci in these scans. We used Affymetrix 500K genotyping data of KORA S3 cohort (n = 1,644; Southern-Germany) to address (i) SNP coverage in 160 BP candidate genes; (ii) the evidence for associations with BP traits in genome-wide and replication data, and haplotype analysis. In total, 160 gene regions (genic region+/-10 kb) covered 2,411 SNPs across 11.4 Mb. Marker densities in genes varied from 0 (n = 11) to 0.6 SNPs/kb. On average 52.5% of the HAPMAP SNPs per gene were captured. No evidence for association with BP was obtained for 1,449 tested SNPs. Considerable associations (P<10(-3)) were detected for the genes, where >50% of HAPMAP SNPs were tagged. In general, genes with higher marker density (>0.2 SNPs/kb) revealed a better chance to reach close to significance associations. Although, none of the detected P-values remained significant after Bonferroni correction (P<0.05/2319, P<2.15 x 10(-5)), the strength of some detected associations was close to this level: rs10889553 (LEPR) and systolic BP (SBP) (P = 4.5 x 10(-5)) as well as rs10954174 (LEP) and diastolic BP (DBP) (P = 5.20 x 10(-5)). In total, 12 markers in 7 genes (ADRA2A, LEP, LEPR, PTGER3, SLC2A1, SLC4A2, SLC8A1) revealed considerable association (P<10(-3)) either with SBP, DBP, and/or hypertension (HYP). None of these were confirmed in replication samples (KORA S4, HYPEST, BRIGHT). However, supportive evidence for the association of rs10889553 (LEPR) and rs11195419 (ADRA2A) with BP was obtained in meta-analysis across samples stratified either by body mass index, smoking or alcohol consumption. Haplotype analysis highlighted LEPR and PTGER3. In conclusion, the lack of associations in BP candidate genes may be attributed to inadequate marker coverage on the genome-wide arrays, small phenotypic effects of the loci and/or complex interaction with life-style and metabolic parameters.

Polymorphisms in the WNK1 gene are associated with blood pressure variation and urinary potassium excretion.

WNK1--a serine/threonine kinase involved in electrolyte homeostasis and blood pressure (BP) control--is an excellent candidate gene for essential hypertension (EH). We and others have previously reported association between WNK1 and BP variation. Using tag SNPs (tSNPs) that capture 100% of common WNK1 variation in HapMap, we aimed to replicate our findings with BP and to test for association with phenotypes relating to WNK1 function in the British Genetics of Hypertension (BRIGHT) study case-control resource (1700 hypertensive cases and 1700 normotensive controls). We found multiple variants to be associated with systolic blood pressure, SBP (7/28 tSNPs min-p = 0.0005), diastolic blood pressure, DBP (7/28 tSNPs min-p = 0.002) and 24 hour urinary potassium excretion (10/28 tSNPs min-p = 0.0004). Associations with SBP and urine potassium remained significant after correction for multiple testing (p = 0.02 and p = 0.01 respectively). The major allele (A) of rs765250, located in intron 1, demonstrated the strongest evidence for association with SBP, effect size 3.14 mmHg (95%CI:1.23-4.9), DBP 1.9 mmHg (95%CI:0.7-3.2) and hypertension, odds ratio (OR: 1.3 [95%CI: 1.0-1.7]).We genotyped this variant in six independent populations (n = 14,451) and replicated the association between rs765250 and SBP in a meta-analysis (p = 7 x 10(-3), combined with BRIGHT data-set p = 2 x 10(-4), n = 17,851). The associations of WNK1 with DBP and EH were not confirmed. Haplotype analysis revealed striking associations with hypertension and BP variation (global permutation p<10(-7)). We identified several common haplotypes to be associated with increased BP and multiple low frequency haplotypes significantly associated with lower BP (>10 mmHg reduction) and risk for hypertension (OR<0.60). Our data indicates that multiple rare and common WNK1 variants contribute to BP variation and hypertension, and provide compelling evidence to initiate further genetic and functional studies to explore the role of WNK1 in BP regulation and EH.

Genome-wide scan identifies CDH13 as a novel susceptibility locus contributing to blood pressure determination in two European populations.

Hypertension is a complex disease that affects a large proportion of adult population. Although approximately half of the inter-individual variance in blood pressure (BP) level is heritable, identification of genes responsible for its regulation has remained challenging. Genome-wide association study (GWAS) is a novel approach to search for genetic variants contributing to complex diseases. We conducted GWAS for three BP traits [systolic and diastolic blood pressure (SBP and DBP); hypertension (HYP)] in the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) S3 cohort (n = 1644) recruited from general population in Southern Germany. GWAS with 395,912 single nucleotide polymorphisms (SNPs) identified an association between BP traits and a common variant rs11646213 (T/A) upstream of the CDH13 gene at 16q23.3. The initial associations with HYP and DBP were confirmed in two other European population-based cohorts: KORA S4 (Germans) and HYPEST (Estonians). The associations between rs11646213 and three BP traits were replicated in combined analyses (dominant model: DBP, P = 5.55 x 10(-5), effect -1.40 mmHg; SBP, P = 0.007, effect -1.56 mmHg; HYP, P = 5.30 x 10(-8), OR = 0.67). Carriers of the minor allele A had a decreased risk of hypertension. A non-significant trend for association was also detected with severe family based hypertension in the BRIGHT sample (British). The novel susceptibility locus, CDH13, encodes for an adhesion glycoprotein T-cadherin, a regulator of vascular wall remodeling and angiogenesis. Its function is compatible with the BP biology and may improve the understanding of the pathogenesis of hypertension.

SLC2A9 is a high-capacity urate transporter in humans.

BACKGROUND: Serum uric acid levels in humans are influenced by diet, cellular breakdown, and renal elimination, and correlate with blood pressure, metabolic syndrome, diabetes, gout, and cardiovascular disease. Recent genome-wide association scans have found common genetic variants of SLC2A9 to be associated with increased serum urate level and gout. The SLC2A9 gene encodes a facilitative glucose transporter, and it has two splice variants that are highly expressed in the proximal nephron, a key site for urate handling in the kidney. We investigated whether SLC2A9 is a functional urate transporter that contributes to the longstanding association between urate and blood pressure in man. METHODS AND FINDINGS: We expressed both SLC2A9 splice variants in Xenopus laevis oocytes and found both isoforms mediate rapid urate fluxes at concentration ranges similar to physiological serum levels (200-500 microM). Because SLC2A9 is a known facilitative glucose transporter, we also tested whether glucose or fructose influenced urate transport. We found that urate is transported by SLC2A9 at rates 45- to 60-fold faster than glucose, and demonstrated that SLC2A9-mediated urate transport is facilitated by glucose and, to a lesser extent, fructose. In addition, transport is inhibited by the uricosuric benzbromarone in a dose-dependent manner (Ki = 27 microM). Furthermore, we found urate uptake was at least 2-fold greater in human embryonic kidney (HEK) cells overexpressing SLC2A9 splice variants than nontransfected kidney cells. To confirm that our findings were due to SLC2A9, and not another urate transporter, we showed that urate transport was diminished by SLC2A9-targeted siRNA in a second mammalian cell line. In a cohort of men we showed that genetic variants of SLC2A9 are associated with reduced urinary urate clearance, which fits with common variation at SLC2A9 leading to increased serum urate. We found no evidence of association with hypertension (odds ratio 0.98, 95% confidence interval [CI] 0.9 to 1.05, p > 0.33) by meta-analysis of an SLC2A9 variant in six case-control studies including 11,897 participants. In a separate meta-analysis of four population studies including 11,629 participants we found no association of SLC2A9 with systolic (effect size -0.12 mm Hg, 95% CI -0.68 to 0.43, p = 0.664) or diastolic blood pressure (effect size -0.03 mm Hg, 95% CI -0.39 to 0.31, p = 0.82). CONCLUSIONS: This study provides evidence that SLC2A9 splice variants act as high-capacity urate transporters and is one of the first functional characterisations of findings from genome-wide association scans. We did not find an association of the SLC2A9 gene with blood pressure in this study. Our findings suggest potential pathogenic mechanisms that could offer a new drug target for gout.

N-acetyltransferase 8, a positional candidate for blood pressure and renal regulation: resequencing, association and in silico study.

BACKGROUND: Kidneys have an important function in blood pressure (BP) regulation and elevated BP may lead to kidney failure. Chr2p12-p13 region linked to BP traits in multiple studies harbours a potential candidate for BP and renal function, N-acetyltransferase 8 (NAT8) expressed in embryonic and adult kidney and associated with nephrotoxicity response. METHODS/RESULTS: We report the first study exploring NAT8 as a potential candidate gene for blood pressure and kidney function. The resequencing (n = 42, random Estonian samples) identified 15 NAT8 polymorphisms, including 6 novel variants. The diversity of NAT8 5' upstream region (pi/bp = 0.00320) exceeded up to 10 times the variation in the NAT8 genic region (pi/bp = 0.00037) as well as the average variation (pi/bp = 0.00040) for the promoters of 29 reference genes associated with hypertension. We suggest that a potential source for such high variation could be an active gene conversion process from NAT8B duplicate gene to NAT8. Similarly to NAT8, several reference genes with the most variable upstream regions have also duplicate copies. The NAT8 promoter SNPs were targeted with pilot quantitative association studies for blood pressure (n = 137, healthy unrelated individuals) and for the index of kidney function - estimated glomerular filtration rate (eGFR; n = 157 hypertensives with and without nephropathy). Minor alleles of these polymorphisms revealed a significant protective effect against elevated systolic BP as well as kidney failure in hypertension patients (p < 0.05; linear regression model, addictive effect). CONCLUSION: The full resequencing and pilot association study of a novel positional candidate gene for blood pressure and renal function, human N-acetyltransferase 8, suggested a contribution of highly variable NAT8 promoter polymorphisms in determination of systolic blood pressure and eGFR. Based on in silico analysis, we raise the hypothesis that the alternative SNP alleles of the NAT8 upstream region may have differential effect on gene expression.

Anthropometric parameters and sexual maturation in 12- to 15-year-old Estonian boys.

The aims of this study were 1. to fix main sexual maturation signs and anthropometric measurements, and 2. to investigate relations between maturational status and main anthropometric parameters (i.e. skinfolds, girths, lengths, breadths/lengths) in 12-15-year old boys. In total, 361 boys from Tartu, Estonia, were studied. Body height and weight, 9 skinfolds, 13 girths, 8 lengths and 8 breadths/lengths were measured. Pubertal stages were determined according to the criteria described by Tanner (1962). Self-assessment of pubic hair (PH1-PH5) was used. Genital development (G1-G5) was estimated by palpating the left testis and matching the size of wood ovoid of the Prader orchidometer. Finally, boys were asked about oigarche (= age at the first ejaculation of sperm). Most of the measured anthropometric variables were significantly different in boys of different chronological age and sexual maturity groups. By linear discriminant analysis, the safety of separation of the chronological age groups was higher than by sexual maturation variables. Nonlinear discriminant analysis allowed to separate sexual maturity groups by anthropometric variables up to 99% security. It was concluded that though the growth and development of a child is highly individual, on an average the anthropometric characteristics alter very constantly with the increase of age and biological maturation. Our results indicated that there were some significant differences in the anthropometrical parameters depending on the chronological age and biological maturation. Mostly length and breadth/length parameters change during the studied age period in respect to sexual development subgroups of boys. The skinfold thicknesses were not changed or even decreased.