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Antti Sajantila

Publications and source records attributed to Antti Sajantila.

At least 19 recordsLinked to original sources
PubMed2006

Characterizing genetically stable and unstable gastric cancers by microsatellites and array comparative genomic hybridization.

Gastric cancer (GCA) displays a variety of genomic aberrations, including DNA copy number alterations, microsatellite instability (MSI), and loss of heterozygosity (LOH). The main aim of the present work was to determine the copy number aberrations in tumors with and without MSI or LOH. Fifteen fresh-frozen GCA samples, 11 of the intestinal and 4 of the diffuse type, were grouped by microsatellite analysis into high-level MSI (MSI-H, n = 2), LOH (n = 5), and microsatellite stable, LOH not detected (MSS/LOH-N, n = 8) tumors. The DNA samples were subsequently analyzed by array comparative genomic hybridization with 16,000 cDNA clones. As expected, the LOH tumors showed more copy number changes; however, the frequency of small-size amplifications was similar across all tumor groups. In addition, the cDNA arrays detected two apparently single-gene amplicons, at 11q13 (CCND1) and 12p12.1 (K-RAS), the presence of which were confirmed using oligonucleotide arrays. A novel amplicon at 5q13.2 was found only in diffuse-type tumors, which were otherwise genetically stable. The results suggest that DNA copy number changes may also occur in gastric cancers that show genomic stability in microsatellite analysis.

Aged↗
PubMed2006

Deciphering the ancient and complex evolutionary history of human arylamine N-acetyltransferase genes.

The human N-acetyltransferase genes NAT1 and NAT2 encode two phase-II enzymes that metabolize various drugs and carcinogens. Functional variability at these genes has been associated with adverse drug reactions and cancer susceptibility. Mutations in NAT2 leading to the so-called slow-acetylation phenotype reach high frequencies worldwide, which questions the significance of altered acetylation in human adaptation. To investigate the role of population history and natural selection in shaping NATs variation, we characterized genetic diversity through the resequencing and genotyping of NAT1, NAT2, and the pseudogene NATP in a collection of 13 different populations with distinct ethnic backgrounds and demographic pasts. This combined study design allowed us to define a detailed map of linkage disequilibrium of the NATs region as well as to perform a number of sequence-based neutrality tests and the long-range haplotype (LRH) test. Our data revealed distinctive patterns of variability for the two genes: the reduced diversity observed at NAT1 is consistent with the action of purifying selection, whereas NAT2 functional variation contributes to high levels of diversity. In addition, the LRH test identified a particular NAT2 haplotype (NAT2*5B) under recent positive selection in western/central Eurasians. This haplotype harbors the mutation 341T-->C and encodes the "slowest-acetylator" NAT2 enzyme, suggesting a general selective advantage for the slow-acetylator phenotype. Interestingly, the NAT2*5B haplotype, which seems to have conferred a selective advantage during the past approximately 6,500 years, exhibits today the strongest association with susceptibility to bladder cancer and adverse drug reactions. On the whole, the patterns observed for NAT2 well illustrate how geographically and temporally fluctuating xenobiotic environments may have influenced not only our genome variability but also our present-day susceptibility to disease.

Acetylation↗
PubMed2006

DNA copy number aberrations in intestinal-type gastric cancer revealed by array-based comparative genomic hybridization.

Genomic instability can be divided into 2 categories: chromosomal instability (CIN) and microsatellite instability (MSI). CIN has been linked to aneuploidy and chromosomal aberrations, and high-level loss of heterozygosity (LOH-H) has been suggested to be an indicator of CIN. High-level MSI (MSI-H), which results from nonfunctional mismatch repair, has previously been suggested to be mutually exclusive with CIN. Four MSI-H and three LOH-H primary gastric tumors of intestinal histology were used for copy number analysis by array-based comparative genomic hybridization (aCGH) with 13,000 cDNA targets. The MSI-H group showed fewer gains (0-12, average 4.5) and losses (0-10, average 2.5) per tumor as compared to the LOH-H group (9-15 gains, average 11.6 and 1-6 losses, average 4). Two MSI-H tumors did not show any copy number changes and one showed only gains of whole chromosomes. The most common alterations were gains of 20q (5/7 samples), 1q, 8, and 10p (3/7 samples) and losses of 1p and 5p (3/7 samples). The minimal amplified regions in 1q and 20q were localized to 1q21.1 approximately q21.2, 1q21.3, 20q11.2, 20q13.12, and 20q13.3 approximately qter. No copy number change was found to be specific for MSI-H or LOH-H. The results suggest that the LOH-H phenotype revealed by microsatellite analysis predicts reliably copy number abnormalities on aCGH and that a subset of MSI-H and all LOH-H tumors share the CIN phenotype.

Aged↗
PubMed2006

How well does a national newspaper reporting system profile drowning?

In Finland, the Finnish Association for Swimming Instruction and Life Saving (SUH) and Statistics Finland (SF) both provide nationwide data on unintentional drowning. The SUH database relies on rapid reporting from a newspaper clipping service and additional local police information, whereas the SF database relies on the later release of the death certificate information, which is based on extensive medico-legal investigation. The aim of the study was to explore the main differences between the SUH and SF databases for drowning and to evaluate the capacity of the former to characterize drowning events in Finland from 1998 to 2000. Computerized files of death certificates tabulated by SF were linked with the SUH database by deterministic methods. SF and SUH databases allowed the identification of 704 and 567 unintentional drownings, respectively, giving an unintentional drowning rate of 4.5 and 3.6/100?000 per year. Of the 704 drownings described by SF, 418 (59.4%) were also found in the SUH database. The SUH database markedly underreported drowning fatalities in certain settings, such as bath, ditch and swimming pool drownings; fall- and land-traffic-related drownings; and drownings occurring in South Finland. The narrative text of SUH drownings contributed limited information to characterize the drowning events. It was concluded that the newspaper-based SUH data provide more timely data on individual drownings but are not representative of all drownings. Conversely, the SF vital statistics data are more accurate but may take up to 2 years to become available. Both SUH and SF data provide little detailed information on drowning events. A multidisciplinary national surveillance system for drowning is necessary to provide more accurate and timely drowning data, analyse risk factors and design follow-up studies for developing and monitoring prevention strategies.

Adolescent↗
PubMed2005

CYP2D6 and CYP2C19 genotypes and amitriptyline metabolite ratios in a series of medicolegal autopsies.

In a series of 202 postmortem toxicology cases, the CYP2D6 and CYP2C19 genes were genotyped, and the concentrations of amitriptyline (AT) and six metabolites were analyzed. The polymorphic CYP2D6 and CYP2C19 genes encode enzymes participating in the metabolism of several potentially toxic drugs, and mutations in these genes may lead to adverse drug reactions, possibly even intoxications. AT was chosen as the substrate of interest because it is mainly metabolized by these enzymes, is considered relatively toxic, and ranks among the major causes of fatal drug poisoning in Finland. Our objective was to evaluate genetically determined interindividual variation in conjunction with metabolite ratios of drugs found in toxicological analysis in a series of medicolegal autopsies. Positive correlations were found between the proportion of trans-hydroxylated metabolites and the number of functional copies of CYP2D6 and between the proportion of demethylated metabolites and the number of functional copies of CYP2C19. None of the accidental or undetermined AT poisonings coincided with the CYP2D6 or CYP2C19 genotype which predicts a poor metabolizer phenotype. However, an unusually high femoral blood concentration of AT, 60mg/l, was found in one suicide case with no functional CYP2D6 genes. Our study shows a concordance of AT metabolite patterns with CYP2D6 and CYP2C19 genotypes in the presence of confounding factors typical for postmortem material. This result demonstrates the feasibility of postmortem pharmacogenetic analysis and supports the dominant role of genes in drug metabolism.

Amitriptyline↗
PubMed2005

Differences in genomic instability between intestinal- and diffuse-type gastric cancer.

BACKGROUND: Microsatellite instability (MSI) and loss of heterozygosity (LOH) are lesions in the genome found with different frequencies in gastric carcinomas (GCAs). Despite a great body of studies, no systematic approach to the detailed classification of MSI and LOH in the two major types of GCA has been published. METHODS: Thirty-seven advanced GCAs, 25 intestinal-type (IGCAs) and 12 diffuse-type (DGCAs), were assayed with 15 autosomal tetranucleotide markers on 14 chromosomal arms. The observed frequencies and types of microsatellite alterations allowed stratification into subgroups, i.e., high- and low-grade MSI (MSI-H, MSI-L) or microsatellite-stable (MSS), and high- or low-grade, or non-detectable LOH (LOH-H, LOH-L, LOH-N). RESULTS: Collectively, the markers detected MSI-H tumors with sensitivity equal to that of BAT-26 (a single marker highly specific for MSI-H). Likewise, the markers detected LOH at chromosomal arms 5q, 18q, and 21q with a sensitivity equal to markers used previously. Seven (19%) MSI-H and six (16%) LOH-H tumors were found, with a significant association (P = 0.027) with IGCA: 92% of MSI-H and LOH-H occurred in IGCA patients only. Conversely, in DGCA, a significantly higher prevalence of a stable (LOH-N/MSS) phenotype was found as compared with IGCA (75.1% vs 28.0%; P = 0.035). The MSI-L phenotype was found in 57.9% of non-MSI-H IGCA tumors and was associated significantly (P = 0.015) with LOH-H. CONCLUSION: A clear difference in genomic instability between IGCA and DGCA was found. In IGCA, the MSI and LOH pathways were more commonly involved, whereas in DGCA, a stable phenotype was predominant. As a novel finding, MSI-L as a true phenomenon and its association with LOH was observed in IGCA.

Aged↗
PubMed2005

Fatal gunshot wounds between 1995 and 2001 in a highly populated region in Finland.

Gunshot injuries are a major problem worldwide from the human, medical, and economic perspectives. The number and characteristics of gunshot fatalities have been observed to vary significantly between countries. This study analyzes fatal gunshot wounds in the region of Uusimaa, Southern Finland, between 1995 and 2001. Gunshot wounds were typically found in suicides committed by men aged between 20 and 60 years. In most cases, a handgun was used. Mental disorders were present in the history of almost one quarter of the victims. Alcohol was identified in postmortem toxicology in half of the cases, but drugs of abuse were relatively uncommon. The autopsy rate in Finland is among the highest of the European Union countries, and a medicolegal investigation is performed in virtually all fatal gunshot incidents. This study is therefore representative of forensic investigations of gunshot fatalities in Finland overall.

Adult↗
PubMed2004

Mast cells in neovascularized human coronary plaques store and secrete basic fibroblast growth factor, a potent angiogenic mediator.

OBJECTIVE: Intraplaque neovascularization and hemorrhage may facilitate plaque progression. We studied expression of basic fibroblast growth factor (bFGF), a potent angiogenic mediator, by mast cells (MCs) in human coronary plaques with increasing degrees of atherosclerosis. METHODS AND RESULTS: Normal and atherosclerotic coronary segments were collected from 30 autopsied subjects. Immunohistochemical methods were used to detect MCs, bFGF, and microvessels. Both adventitial and intimal MCs showed intracytoplasmic granular staining for bFGF, and bFGF-positive extracellular granules were observed close to the MCs. Increased numbers of bFGF-positive MCs were detected in neovascularized areas of plaques, and there was a positive correlation between numbers of bFGF-positive MCs and microvessels in both the intima and adventitia. In plaques, the highly neovascularized areas contained increased numbers of bFGF-positive MCs compared with the adjacent nonvascularized areas, where only few MCs were present. Importantly, the proportion of intimal MCs expressing bFGF increased with increasing severity of atherosclerosis. CONCLUSIONS: The present work reveals a novel source of bFGF in human coronary arteries, the intimal and adventitial MCs. The association of bFGF-positive MCs with microvessels and with the severity of atherosclerosis suggests that coronary MCs, by releasing bFGF, may play a role in angiogenesis and progression of coronary plaques.

Adult↗
PubMed2004

Unintentional drowning in Finland 1970-2000: a population-based study.

BACKGROUND: While standard data on drowning reported by the World Health Organization (WHO) fails to provide a reliable picture of the burden of drowning in Finland, they suggest that the rates are much higher than those of other industrialized countries. AIM: To determine the true burden of drowning in Finland and factors related to its high rates. DESIGN: Descriptive, retrospective, population-based analysis of all deaths by drowning, among residents of all ages. SETTING: Finland, 1970-2000. MATERIAL AND METHODS: Mortality and population data furnished by Statistics Finland (SF) were used to determine age- and sex-specific drowning mortality rates using both nature- and cause-of-injury codes. Individual-level data from the death certificates were analysed and cross-linked to a nationwide postmortem toxicology database. RESULTS: From 1970 to 2000, 9279 unintentional drownings occurred (mean: 299.3/year SD 84.3, rate 6.1/100 000/year; M:F ratio = 8.6:1), accounting for 11.7% of all unintentional injury deaths. Drowning rates overall have decreased from 9.9/100 000/year in 1970-1972, to 4.5 in 1998-2000 (-2.7%/year; 95% CL: -3.0; -2.5). The most frequent activities related to drowning included boating (29.8%), falling (26.1%), swimming (25.0%), and activities on ice (12.4%). In non-boating-related drownings, 74.5% of males and 67.4% of females tested had a blood alcohol concentration (BAC) >/=50 mg/dl, while in boating-related drownings, the respective values were 78.1% and 71.4%. CONCLUSIONS: WHO statistics underestimate the true burden of drowning in Finland by up to 40-50%. Drowning rates and alcohol involvement in drowning are much higher than in other comparable developed countries. Broad-based countermeasures to reduce alcohol use in water activities are needed as part of any strategy to reduce drowning rates.

Adolescent↗
PubMed2004

Molecular diversity at the CYP2D6 locus in the Mediterranean region.

Despite the importance of cytochrome P450 in the metabolism of many drugs, several aspects of molecular variation at one of the main loci coding for it, CYP2D6, have never been analysed so far. Here we show that it is possible to rapidly and efficiently genotype the main European allelic variants at this locus by a SNaPshot method identifying chromosomal rearrangements and nine single-nucleotide polymorphisms. Haplotypes could be reconstructed from data on 494 chromosomes in six populations of the Mediterranean region. High levels of linkage disequilibrium were found within the chromosome region screened, suggesting that CYP2D6 may be part of a genomic recombination block, and hence that, aside from unequal crossingover that led to large chromosomal rearrangements, its haplotype diversity essentially originated through the accumulation of mutations. With the only, albeit statistically insignificant, exception of Syria, haplotype frequencies do not differ among the populations studied, despite the presence among them of three well-known genetic outliers, which could be the result of common selective pressures playing a role in shaping CYP2D6 variation over the area of Europe that we surveyed.

Cytochrome P-450 CYP2D6↗
PubMed2004

A comprehensive survey of human Y-chromosomal microsatellites.

We have screened the nearly complete DNA sequence of the human Y chromosome for microsatellites (short tandem repeats) that meet the criteria of having a repeat-unit size of > or = 3 and a repeat count of > or = 8 and thus are likely to be easy to genotype accurately and to be polymorphic. Candidate loci were tested in silico for novelty and for probable Y specificity, and then they were tested experimentally to identify Y-specific loci and to assess their polymorphism. This yielded 166 useful new Y-chromosomal microsatellites, 139 of which were polymorphic, in a sample of eight diverse Y chromosomes representing eight Y-SNP haplogroups. This large sample of microsatellites, together with 28 previously known markers analyzed here--all sharing a common evolutionary history--allowed us to investigate the factors influencing their variation. For simple microsatellites, the average repeat count accounted for the highest proportion of repeat variance (approximately 34%). For complex microsatellites, the largest proportion of the variance (again, approximately 34%) was explained by the average repeat count of the longest homogeneous array, which normally is variable. In these complex microsatellites, the additional repeats outside the longest homogeneous array significantly increased the variance, but this was lower than the variance of a simple microsatellite with the same total repeat count. As a result of this work, a large number of new, highly polymorphic Y-chromosomal microsatellites are now available for population-genetic, evolutionary, genealogical, and forensic investigations.

Chromosomes, Human, Y↗
PubMed2004

What is the incidence and significance of "dry-lungs" in bodies found in water?

BACKGROUND: Drowning without aspiration of liquid, generally attributed to death from asphyxia while submerged and in laryngospasm, has been reported to occur in approximately 10% to 15% of drowning victims. OBJECTIVES: The occurrence of "dry-drowning" recently has been questioned and the hypothesis developed that "dry-lungs" in bodies found dead in the water could conceal more natural deaths than previously recognized. METHODS: Based on 578 selected adult victims who presumably drowned, we analyzed the correlation between the cases with a low combined lung/pleura liquid weight (< 1000 g and < 750 g) and a wide set of individual, circumstantial, and postmortem (PM) variables, using multivariate logistic regression analysis. Victims with lung weight < 1000 g were screened for long-QT syndrome (LQTS) founder mutations in KCNQ1 and KCNH2 genes. RESULTS: Of the 578 victims, 120 (20.7%) had a lung weight of < 1000 g, and 22 of these (3.8%) of < 750 g. Multivariate analysis showed a significant correlation for women (P < 0.001), for women aged 65 years or older (P < 0.001), and for men with prolonged PM submersion time (P < 0.001). "Normal" lungs were found in only 8 (1.4%) victims. Low-weight (< 1000 g), overdistended lungs with no sign of liquid penetration were seen in 11 (1.9%). No LQTS founder mutations were detected. CONCLUSIONS: The actual incidence of death of persons found in water who have normal lungs or do not have penetration of liquid into their airways, based on our study, is much lower (below 2%) than currently assumed.

Adolescent↗
PubMed2004

Typing of XY (male) genotype from malignant neoplastic tissue by the amelogenin-based sex test.

DNA profiling of a cancer tissue can be problematic because of genomic instability. Here we have analyzed gastrointestinal cancer specimens from 46 males, of which seven (15%) showed aberrations in determination of gender by the widely used amelogenin test. The X-type amelogenin allele in all cases remained intact. All male tumor samples showing frequent autosomal loss of heterozygosity had a decreased signal of the Y allele from the amelogenin marker. When tested with an alternate set of primers for the amelogenin locus, the Y-type allele showed loss of heterozygosity in the same seven cases. However, when amplified with 15 Y-specific STR primers, all the cancerous tissue Y chromosomes seemed to be intact. These results indicate when malignant neoplastic tissue specimens are used, that amelogenin-based gender determination should be carefully interpreted.

Amelogenin↗
PubMed2003

Post-mortem SNP analysis of CYP2D6 gene reveals correlation between genotype and opioid drug (tramadol) metabolite ratios in blood.

Tramadol is an opioid drug metabolised in phase I by cytochrome P450 (CYP) enzymes, of which CYP2D6 is mainly responsible for the O-demethylation of tramadol, but is not involved in N-demethylation. Defects in the genes encoding drug metabolising enzymes (DMEs) may lead to adverse drug effects, even to death. To aid interpretation of the forensic toxicology results, we studied how the genetic variation of the CYP2D6 gene is reflected in tramadol metabolite ratios found in post-mortem samples. In 33 Finnish autopsy cases where tramadol was found, we analysed both the CYP2D6 genotype and the concentrations of tramadol and its metabolites O- and N-demethyltramadol. As expected, we found a correlation between the number of functional CYP2D6 alleles and the ratio of tramadol to O-demethyltramadol. We also found a correlation between the number of functional alleles and the ratio of tramadol to N-demethyltramadol. This can be explained by the complementary nature of the two main tramadol demethylation pathways. No known CYP2D6 inhibitors were associated with exceptional metabolic ratios. Furthermore, no accidental tramadol poisonings were associated with a defective CYP2D6 gene. Our results on the tramadol are among the first to demonstrate that genetic variation in drug metabolising enzymes can be analysed in post-mortem blood, and that it correlates well with the parent drug to metabolite ratios. The results also suggest that genetic factors play, in general, a dominant role over other factors in the metabolism of individual drugs.

Adult↗
PubMed2003

Molecular screening of selected long QT syndrome (LQTS) mutations in 165 consecutive bodies found in water.

The association of the long QT-syndrome (LQTS) with single accidental drowning or near-drowning cases has been recently emphasised, but no data on the prevalence of LQTS among drowning victims are currently available. In this study, we have retrospectively screened specific founder mutations in KCNQ1 (KVLQT1) and KCNH2 (HERG) genes in 165 consecutive bodies found in water in Finland. We found a KCNH2-Fin mutation in a 44-year-old woman whose death was classified as suicidal drowning, whereas no other carriers of the two LQTS founder mutations were identified among the remaining 164 victims. This study provides the first estimate of the minimum prevalence of LQTS (0.61%, CI(95): 0.02-3.33) in such a setting and demonstrates the value of genetic analysis of LQTS in putative drownings. The detection of a LQTS founder mutation in a body found in water is a relatively rare event based on our study sample. This finding is, however, of utmost medico-legal importance, since it broadens the spectrum of potential causes and manners of death.

Adolescent↗
PubMed2003

Recombination hotspots rather than population history dominate linkage disequilibrium in the MHC class II region.

Recombination, demographic history, drift and selection influence the extent of linkage disequilibrium (LD) in the human genome, but their relative contributions remain unclear. To investigate the effect of meiotic recombination versus population history on LD, three populations with different demographic histories (UK north Europeans, Saami and Zimbabweans) were genotyped for high-frequency single-nucleotide polymorphisms (SNPs) across a 75 kb DNA segment of the MHC class II region. This region spans three well-characterized recombination hotspots and a 60 kb long LD block. Despite a high level of underlying haplotype diversity and considerable divergence in haplotype composition between populations, all three populations showed very similar patterns of LD. Surprisingly, the entire 60 kb LD block was present even in Africans, although it was relatively difficult to detect owing to a systematic deficiency of high frequency SNPs. In contrast, DNA within recombination hotspots did not show this low nucleotide diversity in Africans. Thus, while population history has some influence on LD, our findings suggest that recombination hotspots play a major global role in shaping LD patterns as well as helping to maintain localized SNP diversity in this region of the MHC.

Female↗