| 1. |
- Arking, D. E., et al.
(författare)
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Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization
- 2014
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 46:8, s. 826-836
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Tidskriftsartikel (refereegranskat)abstract
- The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼ 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD. © 2014 Nature America, Inc.
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| 6. |
- Koivisto, U M, et al.
(författare)
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The familial hypercholesterolemia (FH)-North Karelia mutation of the low density lipoprotein receptor gene deletes seven nucleotides of exon 6 and is a common cause of FH in Finland
- 1992
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Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 90:1, s. 219-228
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Tidskriftsartikel (refereegranskat)abstract
- A mutation of the LDL receptor gene very common among Finnish patients with heterozygous familial hypercholesterolemia (FH) was identified. This mutation, designated as FH-North Karelia, deletes seven nucleotides from exon 6 of the LDL receptor gene, causes a translational frameshift, and is predicted to result in a truncated receptor protein. Only minute quantities of mRNA corresponding to the deleted gene were detected. Functional studies using cultured fibroblasts from the patients revealed that the FH-North Karelia gene is associated with a receptor-negative (or binding-defective) phenotype of FH. Carriers of the FH-North Karelia gene showed a typical xanthomatous form of FH, with mean serum total and LDL cholesterol levels of 12 and 10 mmol/liter, respectively. This mutation was found in 69 (34%) out of 201 nonrelated Finnish FH patients and was especially abundant (prevalence 79%) in patients from the eastern Finland. These results, combined with our earlier data on another LDL receptor gene deletion (FH-Helsinki), demonstrate that two "Finnish-type" mutant LDL receptor genes make up about two thirds of FH mutations in this country, reflecting a founder gene effect. This background provides good possibilities to examine whether genetic heterogeneity affects the clinical presentation or responsiveness to therapeutic interventions in FH.
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| 7. |
- Kontula, K, et al.
(författare)
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Apolipoprotein E polymorphism determined by restriction enzyme analysis of DNA amplified by polymerase chain reaction : convenient alternative to phenotyping by isoelectric focusing
- 1990
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Ingår i: Clinical Chemistry. - 0009-9147 .- 1530-8561. ; 36:12, s. 2087-2092
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Tidskriftsartikel (refereegranskat)abstract
- Three common alleles determine six apolipoprotein E (apo E) phenotypes that are associated with variations in serum cholesterol in the population. This genetic variation results from single nucleotide alterations at two DNA loci encoding the amino acid residues 112 and 158 of apo E. We compared results of apo E phenotyping carried out by isoelectric focusing with those of apo E genotyping accomplished by direct DNA analysis. In the latter, the target DNA was amplified by the polymerase chain reaction (PCR) and subsequently analyzed by digestion with the restriction enzyme Hha I, followed by polyacrylamide gel electrophoresis of the cleavage products. With one exception, these two techniques yielded similar results from all 40 samples tested. In addition, a rare variant form of apo E (phenotype E1) was analyzed separately and incorrectly diagnosed as E2 by the Hha I digestion method; the anticipated mutation in the codon 127 was, however, confirmed by demonstration of a new Taq I restriction site in this variant gene. These data confirm that the common isoforms of apo E usually arise from genetic variation of the codons 112 and 158 and demonstrate the feasibility of the PCR technique in apo E genotyping.
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| 9. |
- Rivas, Manuel A., et al.
(författare)
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A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis
- 2016
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Ingår i: Nature Communications. - London, United Kingdom : Nature Publishing Group. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 × 10(-7), odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain.
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| 10. |
- Suviolahti, E, et al.
(författare)
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The SLC6A14 gene shows evidence of association with obesity
- 2003
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Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 112:11, s. 1762-1772
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Tidskriftsartikel (refereegranskat)abstract
- In our previous genome-wide scan of Finnish nuclear families, obesity was linked to chromosome Xq24. Here we analyzed this 15-Mb region by genotyping 9 microsatellite markers and 36 single nucleotide polyp morphisms (SNPs) for 11 positional and functional candidate genes in an extended sample of 218 obese Finnish sibling pairs (sibpairs) (BMI > 30 kg/m(2)). Evidence of linkage emerged mainly from the obese male sibpairs, suggesting a gender-specific effect for the underlying gene. By constructing haplotypes among the obese male sibpairs, we restricted the region from 15 Mb to 4 Mb, between markers DXS8088 and DXS8067. Regional functional candidate genes were tested for association in an initial sample of 117 cases and 182 controls. Significant evidence was observed for association for an SNP in the 3'-untranslated region of the solute carrier family 6 member 14 (SLC6A14) gene (P = 0.0002) and for SNP haplotypes of the SLC6A14 gene (P = 0.0007-0.006). Furthermore, an independent replication study sample of 837 cases and 968 controls from Finland and Sweden also showed significant differences in allele frequencies between obese and non-obese individuals (P = 0.003). The SLC6A14 gene is an interesting novel candidate for obesity because it encodes an amino acid transporter, which potentially regulates tryptophan availability for serotonin synthesis and thus possibly affects appetite control.
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| 11. |
- Syvänen, Ann-Christine, et al.
(författare)
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A primer-guided nucleotide incorporation assay in the genotyping of apolipoprotein E
- 1990
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Ingår i: Genomics. - 0888-7543 .- 1089-8646. ; 8:4, s. 684-692
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Tidskriftsartikel (refereegranskat)abstract
- We describe a new technique by which single base changes in human genes can be conveniently detected. In this method the DNA fragment of interest is first amplified using the polymerase chain reaction with an oligonucleotide primer biotinylated at its 5'-end. The amplified 5'-biotinylated DNA is immobilized on an avidin matrix and rendered single-stranded. The variable nucleotide in the immobilized DNA is identified by a one-step primer extension reaction directed by a detection step primer, which anneals to the DNA immediately upstream of the site of variation. In this reaction a single labeled nucleoside triphosphate complementary to the nucleotide at the variable site is incorporated. The method is highly sensitive, allowing the use of nucleoside triphosphates labeled with radioisotopes of low specific activity (3H) as well as nonradioactive markers (digoxigenin). The procedure consists of few and simple operations and is thus applicable to the analysis of large numbers of samples. Here we applied it to the analysis of the three-allelic polymorphism of the human apolipoprotein E gene. We were able to correctly identify all possible combinations of the three apo E alleles.
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| 12. |
- Syvänen, Ann-Christine, et al.
(författare)
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Direct sequencing of affinity-captured amplified human DNA application to the detection of apolipoprotein E polymorphism
- 1989
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Ingår i: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 258:1, s. 71-74
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Tidskriftsartikel (refereegranskat)abstract
- We describe a method for the direct sequencing of DNA amplified by the polymerase chain reaction (PCR). Biotin is introduced into one strand of the amplified DNA using a 5'-biotinylated PCR primer. The synthesized fragment is captured on an avidin-matrix and rendered single stranded, whereafter the nucleotide sequence of the immobilized strand is determined by the chain termination method. The method involves few and simple operations and is thus applicable to the analysis of human genes for routine diagnostic purposes. Here we applied the method for determination of the three-allelic polymorphism of the apolipoprotein E (apo E) gene. We were able to correctly identify the alleles in both homozygous and heterozygous samples.
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| 13. |
- Chittani, Martina, et al.
(författare)
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TET2 and CSMD1 genes affect SBP response to hydrochlorothiazide in never-treated essential hypertensives.
- 2015
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Ingår i: Journal of Hypertension. - 1473-5598. ; 33:6, s. 1301-1309
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Tidskriftsartikel (refereegranskat)abstract
- Thiazide diuretics have been recommended as a first-line antihypertensive treatment, although the choice of 'the right drug in the individual essential hypertensive patient' remains still empirical. Essential hypertension is a complex, polygenic disease derived from the interaction of patient's genetic background with the environment. Pharmacogenomics could be a useful tool to pinpoint gene variants involved in antihypertensive drug response, thus optimizing therapeutic advantages and minimizing side effects.
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| 15. |
- French, K M, et al.
(författare)
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Strategies for the introduction of human papillomavirus vaccination: modelling the optimum age- and sex-specific pattern of vaccination in Finland
- 2007
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 1532-1827 .- 0007-0920. ; 96:3, s. 514-518
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Tidskriftsartikel (refereegranskat)abstract
- Phase III trials have demonstrated the efficacy of human papillomavirus (HPV) vaccines in preventing transient and persistent high-risk (hr) HPV infection and precancerous lesions. A mathematical model of HPV type 16 infection and progression to cervical cancer, parameterised to represent the infection in Finland, was used to explore the optimal age at vaccination and pattern of vaccine introduction. In the long term, the annual proportion of cervical cancer cases prevented is much higher when early adolescents are targeted. Vaccinating against hr HPV generates greater long-term benefits if vaccine is delivered before the age at first sexual intercourse. However, vaccinating 12 year olds delays the predicted decrease in cervical cancer, compared to vaccinating older adolescents or young adults. Vaccinating males as well as females has more impact on the proportion of cases prevented when vaccinating at younger ages. Implementing catch-up vaccination at the start of a vaccination programme would increase the speed with which a decrease in HPV and cervical cancer incidence is observed.
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| 18. |
- Parmar, A S, et al.
(författare)
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Association of celiac disease genes with inflammatory bowel disease in Finnish and Swedish patients
- 2012
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Ingår i: Genes and Immunity. - : Nature Publishing Group. - 1466-4879 .- 1476-5470. ; 13:6, s. 474-480
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Tidskriftsartikel (refereegranskat)abstract
- Some genetic loci may affect susceptibility to multiple immune system-related diseases. In the current study, we investigated whether the known susceptibility loci for celiac disease (CelD) also associate with Crohn's disease (CD) and/or ulcerative colitis (UC), the two main forms of inflammatory bowel disease (IBD), in Finnish patients. A total of 45 genetic markers were genotyped in a Finnish data set comprising 699 IBD patients and 2482 controls. Single-marker association with IBD and its subphenotypes was tested. A meta-analysis with a Swedish UC data set was also performed. A total of 12 single-nucleotide polymorphisms associated with CD and/or UC (P<0.05). In the subphenotype analysis, rs6974491-ELMO1 (P=0.0002, odds ratio (OR): 2.20) and rs2298428-UBE2L3 (P=5.44 × 10(-5), OR: 2.59) associated with pediatric UC and CD, respectively. In the meta-analysis, rs4819388-ICOSLG (P=0.00042, OR: 0.79) associated with UC. In the subphenotype meta-analysis, rs1738074-TAGAP (P=7.40 × 10(-5), OR: 0.61), rs6974491-ELMO1 (P=0.00052, OR: 1.73) and rs4819388-ICOSLG (P=0.00019, OR: 0.75) associated with familial UC, pediatric UC and sporadic UC, respectively. Multiple CelD risk loci also confer susceptibility for CD and/or UC in the Finnish and Swedish populations. Certain genetic risk variants may furthermore predispose an individual for developing a particular disease phenotype.
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