Janne Hulkkonen

Genetic association between interleukin‐10 promoter region polymorphisms and primary Sjögren's syndrome

OBJECTIVE To determine whether the haplotypes formed on the basis of single-base-exchange polymorphisms at positions -1082, -819, or -592 of the interleukin-10 (IL-10) gene predispose subjects to primary Sjögrens syndrome (SS). METHODS The frequency of IL-10 polymorphisms was analyzed in 62 patients with primary SS and in 400 healthy subjects. These data were assessed for correlations with the concentration of IL-10 in the plasma. RESULTS The frequency of the IL-10 GCC haplotype (G at position -1082, C at position -819, and C at position -592 of the IL-10 gene) was increased (P < 0.05, odds ratio [OR] 1.90, 95% confidence interval [95% CI] 0.955-3.62) and the frequency of the ACC haplotype decreased (P < 0.05, OR 0.443, 95% CI 0.257-0.764) in primary SS patients compared with healthy controls. Moreover, the frequency of the ATA haplotype was similar in primary SS patients and healthy controls, but the incidence of the GCC/ATA genotype was elevated in the primary SS patients (P < 0.05, OR 2.19, 95% CI 1.19-4.03). The concentration of plasma IL-10 was significantly higher in patients carrying the GCC haplotype than in non-carriers of GCC. CONCLUSION These results suggest that the presence of the GCC haplotype or the GCC/ATA genotype and the absence of the ACC haplotype of the IL-10 gene are associated with an increased susceptibility to primary SS. This effect is probably mediated by the increased capability to produce IL-10 among carriers of the GCC haplotype.

Lifetime Risk Factors and Arterial Pulse Wave Velocity in Adulthood The Cardiovascular Risk in Young Finns Study

Limited and partly controversial data are available regarding the relationship of arterial pulse wave velocity and childhood cardiovascular risk factors. We studied how risk factors identified in childhood and adulthood predict pulse wave velocity assessed in adulthood. The study cohort consisted of 1691 white adults aged 30 to 45 years who had risk factor data available since childhood. Pulse wave velocity was assessed noninvasively by whole-body impedance cardiography. The number of conventional childhood and adulthood risk factors (extreme quintiles for low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, body mass index, and smoking) was directly associated with pulse wave velocity in adulthood (P=0.005 and P<0.0001, respectively). In multivariable regression analysis, independent predictors of pulse wave velocity were sex (P<0.0001), age (P<0.0001), childhood systolic blood pressure (P=0.002) and glucose (P=0.02), and adulthood systolic blood pressure (P<0.0001), insulin (P=0.0009), and triglycerides (P=0.003). Reduction in the number of risk factors (P<0.0001) and a favorable change in obesity status (P=0.0002) from childhood to adulthood were associated with lower pulse wave velocity in adulthood. Conventional risk factors in childhood and adulthood predict pulse wave velocity in adulthood. Favorable changes in risk factor and obesity status from childhood to adulthood are associated with lower pulse wave velocity in adulthood. These results support efforts for a reduction of conventional risk factors both in childhood and adulthood in the primary prevention of atherosclerosis.

Coronary Artery Disease–Associated Locus on Chromosome 9p21 and Early Markers of Atherosclerosis

Background—Genome-wide association studies have recently identified a locus on chromosome 9p21 that influences risk of coronary artery disease (CAD). The effect of the locus on early markers of atherosclerosis is unknown. We examined its association with carotid intima-media thickness (CIMT) and brachial flow-mediated dilatation (FMD). Methods and Results—We genotyped 2277 individuals, age 24 to 39 years, from the Cardiovascular Risk in Young Finns Study with CIMT and FMD measurements and 1295 individuals, age 46 to 76 years, from the Health 2000 Survey with CIMT for rs1333049, the chromosome 9p21 variant showing the strongest association with CAD. Both mean and maximum CIMT were significantly higher (P<0.001) in the older subjects of the Health 2000 Survey compared with the Young Finns Study. However, there was no association of the rs1333049 genotype with either mean or maximum CIMT at either age (P=0.959 and 0.977 for the 2 phenotypes in the Young Finns Study and P=0.714 and 0.725 in the Health 2000 Survey). Similarly, there was no association of the locus with variation in FMD in the Young Finns cohort (P=0.521). Conclusions—The chromosome 9p21 locus does not influence CAD risk through a mechanism that also affects CIMT or induces early changes in FMD.

Interleukin-10 gene promoter region polymorphism is associated with eosinophil count and circulating immunoglobulin E in adult asthma.

Background IL‐10 has several functional effects relevant to asthma. It can modulate IgE production and induce apoptosis in eosinophils. Polymorphisms of IL‐10 gene have been shown to affect IL‐10 production.

The balance of inhibitory and excitatory cytokines is differently regulated in vivo and in vitro among therapy resistant epilepsy patients

PURPOSE Excessive neuronal activity and seizures directly stimulate cytokine expression. In this study we investigated cytokine production in circulating blood and peripheral blood mononuclear cells (PBMC) in order to assess the cellular origin of these cytokines in patients with therapy resistant epilepsy. METHODS We compared the levels of plasma IL-1beta, IL-1Ra and IL-6 in 10 patients with therapy resistant localization-related epilepsy and in healthy volunteers. The spontaneous and exogenously stimulated production of these cytokines was studied in PBMC cultures using EIA. Moreover, cell-specific cytokine production was studied using flow cytometry. RESULTS Highly pro-inflammatory cytokine profile (high IL-6, low IL-1Ra and low IL-1Ra/IL-1beta ratio) was observed in plasma from patients with epilepsy. Spontaneous and LPS stimulated cytokine release was similar in PBMC cultures of patients and control subjects. When cells were stimulated with OKT3 the cytokine response profiles in patients with epilepsy were almost opposite (anti-inflammatory) to the profile which was observed in circulating blood. Low IL-6 was observed in cell cultures of patients when stimulated with PDBu + A23187. Flow cytometric analysis revealed that the percentages of IL-1beta, IL-1Ra and IL-6 positive monocytes were similar in patients and control subjects. CONCLUSIONS Patients with therapy resistant epilepsy display a pro-inflammatory profile of plasma cytokines without any evidence of increased production from PBMC. These results suggest that the most likely origin for these cytokines is the brain, where cytokines can exert neuromodulatory functions.

Polymorphism in the IL10 promoter region and early markers of atherosclerosis: The Cardiovascular Risk in Young Finns Study

OBJECTIVE Inflammatory factors modify the risk of coronary heart disease. Pleiotropic cytokine interleukin-10 (IL-10) has been suggested as modifying risk for atherosclerosis. Promoter region genetic polymorphism of IL-10 gene (IL10) is known to be associated with the variation of IL-10 production. We investigated whether single-base exchange polymorphisms -1082 G>A (rs1800896), -819 C>T (rs1800871) and -592 C>A (rs1800872) at IL10 gene are associated with risk factors and early markers of atherosclerosis in young subjects. METHODS AND RESULTS As a part of the Cardiovascular Risk in Young Finns Study, we determined carotid artery compliance (CAC), stiffness index (SI) and Youngs elastic modulus (YEM), intima media thickness (IMT), IL10 genotype and atherosclerosis risk parameters for 2260 subjects aged 24-39 years. In male subjects CAC was lower in carriers of IL-10 high- to intermediate-producer haplotype -1082 G; -819 C; -592 C (GCC+, 1.96+/-0.67) than in noncarriers (GCC-, 2.10+/-0.62, %/10 mmHg, mean+/-SD, p=0.0010). An inverse association was observed in SI (GCC+, 5.76+/-2.12 and GCC-, 5.26+/-1.46, p=0.0034) and YEM (GCC+, 347+/-165 and GCC-, 305+/-110, mm Hg.mm, p=0.0005). Associations remained significant when adjusted to age, BMI, smoking and serum lipids as well as fasting glucose and insulin levels. The genetic effect size for these parameters was not significant in women. CONCLUSIONS IL10 promoter region high- to intermediate-producer haplotype GCC associates with decreased arterial elasticity in men. These results are in disconcordance with the supposed antiatheromatous properties of IL-10.

The IL1A genotype is associated with nasal polyposis in asthmatic adults

Background: Nasal polyposis (NP) is a chronic inflammatory disease often found coexisting with asthma. As this disorder tends to cluster in families, a genetic predisposition has been suggested. Interleukin‐1 (IL‐1) has been proposed to play a role in the pathogenesis of NP.

Interleukin-6 promoter polymorphism and cardiovascular risk factors: the Health 2000 Survey.

OBJECTIVE Inflammatory factors modify the risk of cardiovascular diseases and atherosclerosis. The single base genetic polymorphism in the promoter region of inflammatory cytokine interleukin-6 (IL6 -174 G>C, rs1800795) is associated with the variation of IL-6 production. The aim of this study was to investigate whether IL6 -174 G>C is associated with the risk factors and early markers of atherosclerosis. METHODS As part of Finnish Health 2000 Study, we performed carotid artery ultrasound examinations, IL6 -174 G>C genotyping and cardiovascular risk factor determination for 1334 subjects aged 46-76 years. RESULTS In men, serum total cholesterol was higher in IL6 -174 GG (5.70+/-0.88mmol/L) than in the GC (5.51+/-0.98mmol/L) or CC (5.38+/-0.97mmol/L, mean+/-SD, p=0.0059) groups. The same order was seen in LDL-C (GG 3.64+/-0.83mmol/L, GC 3.41+/-0.88mmol/L, CC 3.30+/-0.91mmol/L, p=0.0017). The opposite association was observed with plasma fasting glucose levels (GG 5.93+/-0.97, GC 6.11+/-1.34, CC 6.34+/-1.59mmol/L, p=0.043) and BMI (GG 26.8+/-3.42, GC 27.5+/-4.32, CC 28.0+/-3.81kg/m(2), p=0.027). IL6 -174 allele C homozygous men indicated a trend towards higher systolic blood pressure. IL6 -174 G>C was not associated with carotid artery compliance, intima media thickness or CRP. The effect size of IL6 -174 G>C on cardiovascular risk factors was not significant in women. These results suggest that IL6 -174 G>C modifies the levels of several metabolic risk factors of atherosclerosis in men.

Polymorphism in the IL6 promoter region is associated with the risk factors and markers of subclinical atherosclerosis in men: The Cardiovascular Risk in Young Finns Study

OBJECTIVE Inflammatory factors modify the risk of coronary heart disease. Promoter region genetic polymorphism of inflammatory cytokine interleukin-6 (IL6 -174 G>C) is associated with the variation of IL-6 production. We investigated whether IL6 -174 G>C associates with the risk factors of atherosclerosis and carotid artery compliance (CAC) in young subjects. METHODS AND RESULTS As part of the Cardiovascular Risk in Young Finns Study, we performed carotid artery ultrasound examinations, IL6 -174 G>C genotyping and coronary heart disease risk factor determination for 2228 subjects aged 24-39 years. In men CAC was higher for IL6 -174 GG (2.10+/-0.65) than for GC (2.00+/-0.68) or CC (1.95+/-0.63, %/10mmHg, mean+/-S.D., p=0.0221). A similar association was observed for HDL cholesterol (GG 1.22+/-0.29, GC 1.15+/-0.27 and CC 1.14+/-0.28mmol/L, p=0.0015) and apolipoprotein A1 (apoA1) (GG 1.44+/-0.21, GC 1.40+/-0.20, CC 1.38+/-0.21mmol/L, p=0.0118). The opposite genotype effect was present in systolic (GG 127+/-13.1, GC 129+/-13.1, CC 130+/-14.3mmHg, p=0.0382) and diastolic blood pressure (GG 73.8+/-9.14, GC 75.1+/-8.68, CC 75.9+/-9.70mmHg, p=0.0374). The genetic effect size for these parameters was not significant in women. CONCLUSIONS IL6 -174 allele G homozygozity associates with beneficial profile of early predictors of atherosclerosis such as high CAC, HDL-C and apoA1 as well as low systolic and diastolic blood pressure in men.

Allergic rhinitis and polymorphisms of the interleukin 1 gene complex.

BACKGROUND Allergic rhinitis is a chronic inflammatory disease with a genetic background. Inflammatory reactions are regulated by cytokines. Cytokine genes are polymorphic and have been implicated as candidate genes in allergy. OBJECTIVES To study the significance of the interleukin 1 (IL-1) gene complex in allergic rhinitis. METHODS Population-based, cross-sectional study. We studied the polymorphisms of 3 IL-1 gene complex genes, IL1A (+4845G>T), IL1B (-511 degrees C>T), and IL1RN (variable number of tandem repeats; IVS2, 86 bp, duplicates 2 to 5), in patients with allergic rhinitis. The study group consisted of 405 nonasthmatic individuals of whom 56 had allergic rhinitis. RESULTS The genotype distribution differed significantly in all cytokine genes studied between subjects with and without allergic rhinitis. The difference was mainly due to an increased number of IL1A allele G homozygotes (67.9% vs 43.2%; odds ratio [OR], 2.8; 95% confidence interval [CI], 1.5-5.1), IL1B heterozygotes (72.2% vs 47.4%; OR, 2.8; 95% CI, 1.5-5.3), and IL1RN allele 2 homozygotes (18.5% vs 7.5%; OR, 2.8; 95% CI, 1.3-6.2) in allergic rhinitis. Haplotype analysis revealed a significant difference in the distribution of IL-1 gene complex haplotypes between subjects with and without allergic rhinitis (P = 0.005, 10 df). CONCLUSIONS The IL-1 gene complex polymorphism is strongly associated with allergic rhinitis in nonasthmatic individuals.