Kirsi Määttä

A functional variant in the serine-threonine kinase coding gene is associated with hypertension: a case-control study in a Finnish population, the Tampere adult population cardiovascular risk study.

Objectives: Hypertension raises the risk of cardiovascular consequences to two-fold or three-fold. The incidence of hypertension is increasing worldwide. Genetic causes of blood pressure are estimated to cause half of the hypertension effect, but the genes behind this are still fairly unclear. Polymorphisms in gene STK39 (serine/threonine kinase) have in some studies been associated with hypertension, but results have differed according to genetic population. We screened the STK39 polymorphism rs6749447 in a Finnish cohort to see if it was associated with hypertension. Methods: The study included 447 hypertensive cases and 771 controls. All participants were 50-year-old Finnish patients and the data was collected from the Tampere adult population cardiovascular risk study (TAMRISK). Genotypes were determined by polymerase chain reaction using DNAs extracted from buccal swabs. Results: The risk for hypertension among G-allele carriers was 1.4-fold compared with controls (P = 0.006, 95% CI = 1.10–1.79). The genetic effect of the G-allele was even more significant when the strong effect of BMI on hypertension was taken into account: for normal weight patients (BMI < 25) the risk was two-fold (P = 0.003, 95% CI 1.3–3.1) and for normal weight or slightly overweight patients (BMI < 30), the risk was 1.6-fold (P = 0.001, 95% CI 1.2–2.2). Conclusion: In conclusion, there was a significant association between STK39 genetic variant rs6749447 and hypertension in a Finnish cohort.

Genetic variant coding for iron regulatory protein HFE contributes to hypertension, the TAMRISK study.

AbstractIron is essential for body homeostasis, but iron overload may lead to metabolic abnormalities and thus increase the risk for atherosclerosis and many other diseases. Major histocompatibility complex class I-like transmembrane protein (HFE) is involved in body iron metabolism. The gene coding for HFE has 3 well-known polymorphic sites of which H63D (rs1799945, C > G) has recently been associated with hypertension in a genome-wide association study (GWAS) study. In the present study, we wanted to clarify whether the genetic variant associates with hypertension in a Finnish cohort consisting of 50-year-old men and women.The study included 399 hypertensive cases and 751 controls from the Tampere adult population cardiovascular risk study (TAMRISK) cohort. Genotyping of polymorphisms was done by polymerase chain reaction using DNAs extracted from buccal swabs.We found that individuals with the mutated form of the H63D polymorphic site (G-allele) had a 1.4-fold risk (P = 0.037, 95% confidence interval [CI] 1.02–1.89) for hypertension at the age of 50 years compared with the CC genotype carriers. When obese subjects (body mass index > 30 kg/m2) were analyzed in their own group, the risk for hypertension was even stronger (odds ratio 4.15, P < 0.001, 95% CI 1.98–8.68). We also noticed that the blood pressure (BP) readings were higher in those with the minor G-allele when compared to ones having a normal genotype already at the age of 35 years. Means of systolic/diastolic BPs were 127/81 mm Hg for CC and 131/83 mm Hg for CG + GG groups (P < 0.001 for systolic and P = 0.005 for diastolic pressure).In conclusion, HFE genetic variant H63D was associated with essential hypertension in Finnish subjects from the TAMRISK cohort confirming a previous GWAS study. The effect of this SNP on BP was also confirmed from a longitudinal study.

Periodic cohort health examinations in the TAMRISK study show untoward increases in body mass index and blood pressure during 15 years of follow-up.

BackgroundObesity is a significant risk factor for hypertension and diabetes. A cohort of 50-year-old voluntary periodic health examination (PHE) participants was analyzed 15 years retrospectively. Our aim was to evaluate changes in body mass index (BMI) and blood pressure in subjects diagnosed with hypertension and/or diabetes in comparison with healthy controls.MethodsVoluntary periodic health examinations (PHE) of the citizens have been carried out by the city of Tampere, Finland. Health data, including body mass index (BMI) and blood pressure, were recorded every five years, starting at the age of 35 (baseline). A total of 339 subjects from the 50-year-old cohort having hypertension and/or diabetes were chosen to the study group. The control group included 604 subjects from the 50-year-old cohort who had the same follow-up information but were not diagnosed with hypertension and/or diabetes.ResultsIn the study group the mean BMI had increased from 26.1 at baseline to 28.5 at the final 15-year follow-up examination. The corresponding increase in the control group was from 23.8 at baseline to 25.5 at the final follow-up. The difference in change with time between the groups was statistically significant (p = 0.04). On the average, the controls gained 4.9 kilograms, whereas subjects in the study group gained 7.0 kilograms over the 15 years of follow-up. Systolic and diastolic blood pressures were also higher in the study group already at baseline and systolic blood pressure increased with time more in the study group than in the control group (p = 0.004).ConclusionsBMI and blood pressure were higher in the study group in comparison with the controls already at baseline at 35 years, and the differences were not favorably changed during the follow-up. Apparently, the effect of PHE had not been as efficient as planned on subjects in the study group, who were already slightly overweight at baseline.

Genetic Polymorphisms of Transcription Factor NRF2 and of its Host Gene Sulfiredoxin (SRXN1) are Associated with Cerebrovascular Disease in a Finnish Cohort, the TAMRISK Study

Oxidative stress is involved in the pathophysiology of many cardiovascular disorders, such as hypertension and atherosclerosis. NRF2 is the primary transcriptional regulator of several antioxidant genes, including that of sulfiredoxin (SRXN1). The association of genotypes of NRF2 and SRXN1 with cardiovascular conditions was studied in a Finnish cohort of 336 subjects with diagnosed hypertension and 480 normotensive controls from the Tampere adult population cardiovascular risk study (TAMRISK). Samples were genotyped for four SNPs (rs1962142, rs2706110, rs6721961 and rs6706649) in the NRF2 gene region and four SNPs (rs6053666, rs6116929, rs2008022, rs6085283) in the SRXN1 gene region using Competitive Allele Specific PCR (KASP) technique. Cardiovascular diseases were followed up from 2005 to 2014 using the Finnish National Hospital Discharge Registry (HILMO). Four out of eight studied polymorphisms: rs6721961, rs1962142, rs2706110 of NRF2, and rs6053666 of SRXN1 were associated with cerebrovascular disease. NRF2 polymorphism rs6721961 showed association with hypertension. NRF2 and SRXN1 polymorphisms, previously thought to be associated with human disease, appear to be associated particularly with cerebrovascular disease.

Functional Inducible Nitric Oxide Synthase Gene Variants Associate With Hypertension: A Case–Control Study in a Finnish Population—The TAMRISK Study

AbstractIncreased inducible nitric oxide synthase (iNOS) activity and expression has been associated with hypertension, but less is known whether the 2 known functional polymorphic sites in the iNOS gene (g.–1026 C/A (rs2779249), g.2087 G/A (rs2297518)) affect susceptibility to hypertension. The objective of this study was to investigate the association between the genetic variants of iNOS and diagnosed hypertension in a Finnish cohort.This study included 320 hypertensive cases and 439 healthy controls. All participants were 50-year-old men and women and the data were collected from the Tampere adult population cardiovascular risk study (TAMRISK). DNA was extracted from buccal swabs and iNOS single nucleotide polymorphisms (SNPs) were analyzed using KASP genotyping PCR. Data analysis was done by logistic regression.At the age of 50 years, the SNP rs2779249 (C/A) associated significantly with hypertension (P = 0.009); specifically, subjects carrying the A-allele had higher risk of hypertension compared to those carrying the CC genotype (OR = 1.47; CI = 1.08–2.01; P = 0.015). In addition, a 15-year follow-up period (35, 40, and 45 years) of the same individuals showed that carriers of the A-allele had more often hypertension in all of the studied age-groups. The highest risk for developing hypertension was obtained among 35-year-old subjects (odds ratio [OR] 3.83; confidence interval [CI] = 1.20–12.27; P = 0.024). Those carrying variant A had also significantly higher readings of both systolic (P = 0.047) and diastolic (P = 0.048) blood pressure during the follow-up. No significant associations between rs2297518 (G/A) variants alone and hypertension were found. However, haplotype analysis of rs2779249 and rs2297518 revealed that individuals having haplotype H3 which combines both A alleles (CA–GA, 19.7% of individuals) was more commonly found in the hypertensive group than in the normotensive group (OR = 2.01; CI = 1.29–3.12; P = 0.002).In conclusion, there was a significant association between iNOS genetic variant (rs2779249) and hypertension in the genetically homogenous Finnish population. Those who carried the rare A-allele of the gene had higher risk for hypertension already at the age of 35 years.

Minor variant of rs 16827043 in the iron regulator hemojuvelin gene (HJV) contributes to hypertension: The TAMRISK study.

Abstract It is known that iron overload may lead to an increased risk for many diseases. According to GWAS studies, iron regulatory protein HFE gene variant H63D (rs1799945) was associated with hypertension, an observation which we were able to confirm also in our TAMRISK cohort. Thus, it is possible that abnormalities in iron homeostasis may predispose to hypertension. This prompted us to study whether there is an association between hypertension and another iron overload-associated gene, hemojuvelin (HJV), which has 2 common polymorphic sites (rs 16827043, rs7536827). The study included 336 hypertensive cases and 480 controls. All participants were 50- year-old Finnish men and women, and the data was collected from the Tampere adult population cardiovascular risk study (TAMRISK). Genotypes were determined using Competitive Allelic Specific PCR (KASP). We found that the minor variant of the HJV polymorphic site rs16827043 (G-allele) is a statistically significant factor associated with hypertension among 50 year-old individuals compared with the AA genotype carriers (OR = 1.66, 95% CI: 1.06 – 2.60, P = 0.03). The risk was even higher when overweight subjects (BMI>30) were excluded from the analyses. For the other polymorphic variant rs7536827, association with hypertension was found only among normal or slightly overweight A-allele carriers. In conclusion, HJV genetic variants were associated with essential hypertension in Finnish subjects from the TAMRISK cohort. Previous studies together with the present one indicate that individuals with possible dysregulation of iron metabolism may have higher risk for hypertension than those with normal iron homeostasis.

Whole-exome sequencing of Finnish hereditary breast cancer families

A remarkable proportion of factors causing genetic predisposition to breast cancer (BC) are unknown in non-BRCA1/2 families. Exome sequencing was performed for 13 high-risk Finnish hereditary breast and/or ovarian cancer (HBOC) families to detect variants contributing to BC susceptibility. After filtering, 18 candidate variants in DNA damage response (DDR) pathway genes were screened in 129 female HBOC patients, up to 989 female controls, and 31 breast tumours by Sanger sequencing/TaqMan assays. In addition, two variants were further studied in 49 male BC patients and 909 male controls. Second, all variants predicted to affect function in six early-onset BC patients were analysed in detail. Variants in ATM, MYC, PLAU, RAD1, and RRM2B were enriched in female HBOC patients compared with controls (odds ratio 1.16–2.16). A rare nonsynonymous variant in RAD50 was detected in a male BC patient. In addition, a very rare BRCA1 variant was identified in a single high-risk family. None of the variants showed wild-type allele loss in breast tumours. Furthermore, novel variants predicted to affect function were detected in early-onset patients in genes, which target DNA repair and replication, signalling, apoptosis, and cell cycle pathways. Family-specific enrichment of multiple DDR pathway gene defects likely explains BC predisposition in the studied families. These findings provide new information on potential BC-related pathways and an excellent premise for future studies.

Glucuronic Acid Epimerase (GLCE) Variant rs3865014 (A>G) Is Associated with BMI, Blood Hemoglobin, Hypertension, and Cerebrovascular Events, the TAMRISK Study

Heparan sulfate proteoglycans modulate many physiological systems, and genes responsible for proteoglycan assembly and disassembly may affect their interaction. We sought to determine whether polymorphisms of the glucuronic acid epimerase (GLCE) rs3865014 and sulfatase‐2 (SULF2) rs2281279, genes coding for enzymes participating in heparan sulfate side chain activity, associate with hypertension, selected cardiometabolic risk factors and cardiovascular events in the Tampere adult population cardiovascular risk study. A Finnish cohort of 339 subjects with diagnosed hypertension and 441 controls was analyzed. Samples were genotyped for GLCE rs3865014 (A>G) and SULF2 rs2281279 (T>C) polymorphisms using competitive allele‐specific PCR (KASP) technique. Prevalence of ischemic heart diseases (I20–I25) and incidence of cerebrovascular diseases (I60–I69) and transient cerebral ischemic attacks (TIA) (G45) were followed up until the subjects were on the average 60 years old. GLCE rs3865014 G allele showed negative association with hypertension (p = 0.022), waist circumference (p = 0.032), BMI (p = 0.048), and positive association with hemoglobin (p = 0.029), low‐density lipoprotein cholesterol (p = 0.031), and frequency of cerebrovascular events (p = 0.011). SULF2 rs2281279 showed no association with the studied parameters. The GLCE gene polymorphism rs3865014 appears to have biological relevance in human pathophysiology.