| 1. |
- Sandholm, Niina, et al.
(författare)
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New susceptibility loci associated with kidney disease in type 1 diabetes
- 2012
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Ingår i: PLOS Genetics. - San Francisco, USA : Public Library of Science, PLOS. - 1553-7390 .- 1553-7404. ; 8:9, s. e1002921-
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Tidskriftsartikel (refereegranskat)abstract
- Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genomewide association studies (GWAS) of T1D DN comprising similar to 2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2 x 10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 x 10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-beta 1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1 x 10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.
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| 2. |
- Lehto, Markku
(författare)
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Search for MODY and Type 2 diabetes genes
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Diabetes is a heterogeneous disease influenced by both environmental and genetic factors. Maturity-onset diabetes of the young (MODY) is considered as a subform of Type 2 diabetes, which is inherited in an autosomal dominant fashion and expressed at childhood or early adult life. The aims of the study was to a) search for susceptibility loci for Type 2 diabetes in 26 Finnish families with late-onset diabetes by using a genome scan approach, b) clone and search for mutations in the genes causing maturity-onset diabetes of the young (MODY) in Scandinavian families with early-onset diabetes, and c) perform phenotypic characterization of MODY families. As a result of the genome wide scan, a subset of Type 2 diabetic families, presenting with an insulin secretory defect, were positively linked to the MODY3 region on chromosome 12, which was named NIDDM2. In the search for MODY-mutations in Scandinavian families with early-onset diabetes, we identified 2 families with mutations in the hepatocyte nuclear factor (HNF) -4a (MODY1) gene, 4 families with mutations in the glucokinase (MODY2) gene and 12 families with a mutations in the HNF-1a (MODY3) gene. Notable, a mutational hot spot was identified in exon 4 of the HNF-1a gene. In addition, three families with early-onset diabetes were found to carry a specific mutation (A3243G) in the mitochondrial tRNALeu(UUR) gene. Both MODY1 and MODY3 mutation carriers had impaired insulin secretion suggesting defects in pancreatic b-cell function. Distinct from common Type 2 diabetes, MODY mutation carriers had no signs of dyslipidemia or insulin resistance. Of note, patients with MODY1 exhibit also low triglyceride and apoCIII concentrations even after long duration of diabetes. Therefore, mutations in the HNF-4a gene could also affect lipid metabolism. Absence of antibodies against glutamic acid decarboxylase (GAD) suggests that autoimmunity does not play a major role in the development of MODY diabetes. Conclusions: In Scandinavian populations, the MODY3 locus on chromosome 12 is associated with both early- and late-onset forms of diabetes. The underlying genetic defect in NIDDM2 remains to be determined. Among the Scandinavian families with early-onset diabetes, mutations in the HNF-1a (MODY3) gene were the most common cause of MODY.
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| 3. |
- Lindgren, Cecilia, et al.
(författare)
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Contribution of known and unknown susceptibility genes to early-onset diabetes in scandinavia: evidence for heterogeneity.
- 2002
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 51:5, s. 1609-1617
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Tidskriftsartikel (refereegranskat)abstract
- In an attempt to identify novel susceptibility genes predisposing to early-onset diabetes (EOD), we performed a genome-wide scan using 433 markers in 222 individuals (119 with diabetes) from 29 Scandinavian families with ≥2 members with onset of diabetes ≤45 years. The highest nonparametric linkage (NPL) score, 2.7 (P < 0.01), was observed on chromosome 1p (D1S473/D1S438). Six other regions on chromosomes 3p, 7q, 11q, 18q, 20q, and 21q showed a nominal P value <0.05. Of the EOD subjects in these 29 families, 20% were GAD antibody positive and 68% displayed type 1 diabetes HLA risk alleles (DQB*02 or 0302). Mutations in maturity-onset diabetes of the young (MODY) 1–5 genes and the A3243G mitochondrial DNA mutation were detected by single-strand conformation polymorphism and direct sequencing. To increase homogeneity, we analyzed a subsample of five families with autosomal dominant inheritance of EOD (greater than or equal to two members with age at diagnosis ≤35 years). The highest NPL scores were found on chromosome 1p (D1S438–D1S1665; NPL 3.0; P < 0.01) and 16q (D16S419; NPL 2.9; P < 0.01). After exclusion of three families with MODY1, MODY3, and mitochondrial mutations, the highest NPL scores were observed on chromosomes 1p (D1S438; NPL 2.6; P < 0.01), 3p (D3S1620; NPL 2.2; P < 0.03), 5q (D5S1465; NPL 2.1; P < 0.03), 7q (D7S820; NPL 2.0; P < 0.03), 18q (D18S535; NPL 1.9; P < 0.04), 20q (D20S195; NPL 2.5; P < 0.02), and 21q (D21S1446; NPL 2.2; P < 0.03). We conclude that considerable heterogeneity exists in Scandinavian subjects with EOD; 24% had MODY or maternally inherited diabetes and deafness, and ∼60% were GAD antibody positive or had type 1 diabetes-associated HLA genotypes. Our data also point at putative chromosomal regions, which could harbor novel genes that contribute to EOD.
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| 4. |
- Pirinen, Jani, et al.
(författare)
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Are 12-lead ECG findings associated with the risk of cardiovascular events after ischemic stroke in young adults?
- 2016
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Ingår i: Annals of medicine. - : Informa UK Limited. - 1365-2060 .- 0785-3890. ; 48:7, s. 532-540
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Tidskriftsartikel (refereegranskat)abstract
- Ischemic stroke (IS) in a young patient is a disaster and recurrent cardiovascular events could add further impairment. Identifying patients with high risk of such events is therefore important. The prognostic relevance of ECG for this population is unknown.A total of 690 IS patients aged 15-49 years were included. A 12-lead ECG was obtained 1-14 d after the onset of stroke. We adjusted for demographic factors, comorbidities, and stroke characteristics, Cox regression models were used to identify independent ECG parameters associated with long-term risks of (1) any cardiovascular event, (2) cardiac events, and (3) recurrent stroke.Median follow-up time was 8.8 years. About 26.4% of patients experienced a cardiovascular event, 14.5% had cardiac events, and 14.6% recurrent strokes. ECG parameters associated with recurrent cardiovascular events were bundle branch blocks, P-terminal force, left ventricular hypertrophy, and a broader QRS complex. Furthermore, more leftward P-wave axis, prolonged QTc, and P-wave duration>120ms were associated with increased risks of cardiac events. No ECG parameters were independently associated with recurrent stroke.A 12-lead ECG can be used for risk prediction of cardiovascular events but not for recurrent stroke in young IS patients. KEY MESSAGES ECG is an easy, inexpensive, and useful tool for identifying young ischemic stroke patients with a high risk for recurrent cardiovascular events and it has a statistically significant association with these events even after adjusting for confounding factors. Bundle branch blocks, P-terminal force, broader QRS complex, LVH according to Cornell voltage duration criteria, more leftward P-wave axis, prolonged QTc, and P-wave duration >120ms are predictors for future cardiovascular or cardiac events in these patients. No ECG parameters were independently associated with recurrent stroke.
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| 5. |
- Pirinen, Jani, et al.
(författare)
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Twelve-lead electrocardiogram and mortality in young adults after ischaemic stroke
- 2017
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Ingår i: European Stroke Journal. - : SAGE Publications. - 2396-9873 .- 2396-9881. ; 2:1, s. 77-86
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Ischaemic stroke at young age carries an increased risk for mortality in comparison to the general population, but factors associated with mortality have been poorly studied. We studied the role of electrocardiogram in mortality risk stratification in young stroke patients. Patients and methods: The Helsinki Young Stroke Registry encompasses 1008 patients aged <50 years with ischaemic stroke. We included 690 patients for this electrocardiogram substudy. Our endpoints were all-cause and cardiovascular mortality. Cox regression models – adjusted for clinical and demographic characteristics – were used to identify the electrocardiogram parameters associated with these endpoints. Results: At a mean follow-up of 8.8 years, cumulative all-cause and cardiovascular mortality were 16.1 and 9.1%, respectively. Factors associated with both endpoints included diabetes (type 1 for all-cause, type 2 for cardiovascular mortality), heavy drinking, malignancy, as well as stroke severity and aetiology. Of the electrocardiogram parameters, higher heart rate (hazard ratio 1.35 per 10/min, 95% confidence interval 1.21–1.49), a shorter P-wave (hazard ratio 0.78 per 10 ms decrement, 0.64–0.92) and longer QTc interval (1.09 per 10 ms, 1.03–1.16) were associated with increased all-cause mortality. Only a higher heart rate (1.42 per 10/min, 1.24–1.60) was associated with death from cardiovascular causes. Conclusions: A higher heart rate during the subacute phase after stroke is associated with an elevated risk of all-cause and cardiovascular mortality in young adults. A longer QTc interval is associated only with higher all-cause mortality. P-wave characteristics and their possible association with mortality need further studies.
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| 6. |
- Pirttiniemi, Anniina, et al.
(författare)
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Long-chain polyphosphates inhibit type I interferon signaling and augment LPS-induced cytokine secretion in human leukocytes.
- 2023
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Ingår i: Journal of Leukocyte Biology. - : Oxford University Press (OUP). - 0741-5400 .- 1938-3673. ; 114:3, s. 250-265
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Tidskriftsartikel (refereegranskat)abstract
- Inorganic polyphosphates are evolutionarily conserved bioactive phosphate polymers found as various chain lengths in all living organisms. In mammals, polyphosphates play a vital role in the regulation of cellular metabolism, coagulation, and inflammation. Long-chain polyphosphates are found along with endotoxins in pathogenic gram-negative bacteria and can participate in bacterial virulence. We aimed to investigate, whether exogenously administered polyphosphates modulate human leukocyte function in vitro by treating the cells with three different chain lengths of polyphosphates (P14, P100, and P700). The long-chain polyphosphates, P700, had a remarkable capacity to downregulate type I interferon signaling dose dependently in THP1-Dual cells while only a slight elevation could be observed in the NF-κB pathway with the highest dose of P700. P700 treatment decreased LPS-induced IFNβ transcription and secretion, STAT1 phosphorylation, and downregulated subsequent interferon stimulated gene expression in primary human peripheral blood mononuclear cells. P700 also augmented LPS-induced secretion of IL-1α, IL-1β, IL-4, IL-5, IL-10, and IFNγ. Furthermore, P700 has previously been reported to increase the phosphorylation of several intracellular signaling mediators, such as AKT, mTOR, ERK, p38, GSK3α/β, HSP27, and JNK pathway components, which was supported by our findings. Taken together, these observations demonstrate the extensive modulatory effects P700 has on cytokine signaling, and the inhibitory effects specifically targeted to type I interferon signaling in human leukocytes.
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| 7. |
- Schmidt, Florian, et al.
(författare)
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Ammonia in breath and emitted from skin
- 2013
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Ingår i: Journal of Breath Research. - : IOP Publishing. - 1752-7155 .- 1752-7163. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Ammonia concentrations in exhaled breath (eNH(3)) and skin gas of 20 healthy subjects were measured on-line with a commercial cavity ring-down spectrometer and compared to saliva pH and plasma ammonium ion (NH4+), urea and creatinine concentrations. Special attention was given to mouth, nose and skin sampling procedures and the accurate quantification of ammonia in humid gas samples. The obtained median concentrations were 688 parts per billion by volume (ppbv) for mouth-eNH(3), 34 ppbv for nose-eNH3, and 21 ppbv for both mouth-and nose-eNH(3) after an acidic mouth wash (MW). The median ammonia emission rate from the lower forearm was 0.3 ng cm(-2) min(-1). Statistically significant (p < 0.05) correlations between the breath, skin and plasma ammonia/ammonium concentrations were not found. However, mouth-eNH(3) strongly (p < 0.001) correlated with saliva pH. This dependence was also observed in detailed measurements of the diurnal variation and the response of eNH(3) to the acidic MW. It is concluded that eNH(3) as such does not reflect plasma but saliva and airway mucus NH4+ concentrations and is affected by saliva and airway mucus pH. After normalization with saliva pH using the Henderson-Hasselbalch equation, mouth-eNH(3) correlated with plasma NH4+, which points to saliva and plasma NH4+ being linked via hydrolysis of salivary urea.
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| 8. |
- Simonsen, Johan R, et al.
(författare)
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Genetic factors affect the susceptibility to bacterial infections in diabetes
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Diabetes increases the risk of bacterial infections. We investigated whether common genetic variants associate with infection susceptibility in Finnish diabetic individuals. We performed genome-wide association studies and pathway analysis for bacterial infection frequency in Finnish adult diabetic individuals (FinnDiane Study; N = 5092, Diabetes Registry Vaasa; N = 4247) using national register data on antibiotic prescription purchases. Replication analyses were performed in a Swedish diabetic population (ANDIS; N = 9602) and in a Finnish non-diabetic population (FinnGen; N = 159,166). Genome-wide data indicated moderate but significant narrow-sense heritability for infection susceptibility (h2 = 16%, P = 0.02). Variants on chromosome 2 were associated with reduced infection susceptibility (rs62192851, P = 2.23 × 10-7). Homozygotic carriers of the rs62192851 effect allele (N = 44) had a 37% lower median annual antibiotic purchase rate, compared to homozygotic carriers of the reference allele (N = 4231): 0.38 [IQR 0.22-0.90] and 0.60 [0.30-1.20] respectively, P = 0.01). Variants rs6727834 and rs10188087, in linkage disequilibrium with rs62192851, replicated in the FinnGen-cohort (P < 0.05), but no variants replicated in the ANDIS-cohort. Pathway analysis suggested the IRAK1 mediated NF-κB activation through IKK complex recruitment-pathway to be a mediator of the phenotype. Common genetic variants on chromosome 2 may associate with reduced risk of bacterial infections in Finnish individuals with diabetes.
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| 9. |
- Tammi, Markku, et al.
(författare)
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EGF regulates HAS-2 expression, controls epidermal thickness and stimulates keratinocyte migration
- 2002
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Ingår i: Hyaluronan, Vol 1: Chemical, Biochemical and Biological Aspects. - Great Britain : Woodhead Publishing Limited. - 1855735709 ; , s. 561-570
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Konferensbidrag (refereegranskat)abstract
- High concentrations of hyaluronan reside in the small space between the vital kertinocyte layers of human and animal epidermis and influence keratinocyte interactions, including growth, mobility and differentiation. We have previously found that the content of epidermal hyaluronan in human skin organ cultures is decreased and increased by cortisol and retinoic acid, and associated with enhanced and retarded terminal differentiation, respectively. To further substantiate this idea, we incubated epidermal keratinocytes with epidermal growth factor (EGF), and found a marked increase in hyaluronan synthesis which correlated with faster migration in an in vitro wounding assay of keratinocyte monolayers. EGF increased hyaluronan also in stratified, differentiated organotypic cultures, and increased the height of vital epidermis and reduced the thickness of the cornified layers, findings in line with an inhibition of terminal differentiation of keratinocytes. The stimulation of hyaluronan synthesis by EGF was due to upregulation of hyaluronan synthase 2 (HAS2) but not HAS1 or HAS3. A part of the EGF influence on the structure of epidermis, and on skin wound healing, is thus mediated through its control of HAS2 expression.
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| 10. |
- van Dongen, Myrna Marita Elisabeth, et al.
(författare)
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Use of Statins After Ischemic Stroke in Young Adults and Its Association With Long-Term Outcome.
- 2019
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Ingår i: Stroke. - 1524-4628. ; 50:12, s. 3385-3392
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose- Knowledge of the use of secondary preventive medication in young adults is limited. We studied the use of statins and its association with subsequent vascular events in young adults with ischemic stroke-a patient group with a known low burden of atherosclerosis. Methods- The study population included 935 first-ever 30-day ischemic stroke survivors aged 15 to 49 years from the Helsinki Young Stroke Registry, 1994 to 2007. Follow-up data until 2012 were obtained from the Social Insurance Institution of Finland (Drug Prescription Register), the Finnish Care Register, and Statistics Finland. The association of the use of statins (defined as at least 2 purchases) with all-cause mortality, recurrent stroke, and other recurrent vascular events was assessed through adjusted Cox regression analyses. We further compared propensity score-matched statin users with nonusers. Results- Of our 935 patients, 46.8% used statins at some point during follow-up. Higher age, dyslipidemia, heavy alcohol use, and hypertension were significantly associated with purchasing statins. Statin users exhibited lower risk of all-cause mortality (hazard ratio, 0.38 [95% CI, 0.25-0.58]) and recurrent stroke (hazard ratio, 0.29 [95% CI, 0.19-0.44]) than nonusers, after adjustment for dyslipidemia, stroke subtype, and other confounders. These results remained unchanged after propensity score-matched comparison. Conclusions- Less than half of young ischemic stroke patients used statins; use was affected by age and risk factor profile. Statin use was independently associated with lower risk of all-cause mortality and recurrent stroke.
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| 11. |
- Weng, Jianping, et al.
(författare)
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An automated fluorescent single strand conformation polymorphism technique for high throughput mutation screening
- 2001
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Ingår i: Chinese Medical Journal. - 0366-6999. ; 114:11, s. 1147-1150
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To develop a high throughput mutational detection method by multiple fluorescence-labeled polymerase chain reaction (PCR) products. METHODS: A total of 27 known mutations including 22 substitutions, 3 insertions (1, 2 and 7 bp) and 2 deletions (1 and 2 bp) in the hepatocyte nuclear factor (HNF)-4 alpha, glucokinase and HNF-1 alpha genes were tested. During nested PCR, amplified fragments were labeled with three fluorescent dyes. PCR products were visualized with an ABI-377 fluorescence sequencer using 5% glycerol or 10% sucrose in non-denaturing gel conditions. RESULTS: Twenty-five of 27 variants (93%) could be detected by combining 5% glycerol and 10% sucrose gel matrix conditions. Twenty-two of 27 (82%) and 18 of 27 (67%) variants were identified using 5% glycerol and 10% sucrose conditions, respectively. CONCLUSION: This fluorescence-based PCR single strand conformation polymorphism technique represents a simple, non-hazardous, time-saving and sensitive method for high throughput mutation detection.
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| 12. |
- Weng, Jianping, et al.
(författare)
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Screening for MODY mutations, GAD antibodies, and type 1 diabetes--associated HLA genotypes in women with gestational diabetes mellitus.
- 2002
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 25:1, s. 68-71
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To investigate whether genetic susceptibility to type 1 diabetes or maturity-onset diabetes of the young (MODY) increases susceptibility to gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: We studied mutations in MODY1-4 genes, the presence of GAD antibodies, and HLA DQB1 risk genotypes in 66 Swedish women with GDM and a family history of diabetes. An oral glucose tolerance test was repeated in 46 women at 1 year postpartum. RESULTS: There was no increase in type 1 diabetes-associated HLA-DQB1 alleles or GAD antibodies when compared with a group of type 2 diabetic patients (n = 82) or healthy control subjects (n = 86). Mutations in known MODY genes were identified in 3 of the 66 subjects (1 MODY2, 1 MODY3, and 1 MODY4). Of the 46 GDM subjects, 2 had diabetes (4%) and 17 had impaired glucose tolerance (IGT) (37%) at 1 year postpartum. Of the two subjects who developed manifest diabetes, one carried a MODY3 mutation (A203H in the hepatocyte nuclear factor-1alpha gene). There was no increase in high-risk HLA alleles or GAD antibodies in the women who had manifest diabetes or IGT at 1 year postpartum. CONCLUSIONS: MODY mutations but not autoimmunity contribute to GDM in Swedish women with a family history of diabetes and increase the risk of subsequent diabetes.
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