| 1. |
- Broberg Palmgren, Karin, et al.
(författare)
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Association between polymorphisms in RMI1, TOP3A, and BLM and risk of cancer, a case-control study.
- 2009
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 9:May 11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Mutations altering BLM function are associated with highly elevated cancer susceptibility (Bloom syndrome). Thus, genetic variants of BLM and proteins that form complexes with BLM, such as TOP3A and RMI1, might affect cancer risk as well. METHODS: In this study we have studied 26 tagged single nucleotide polymorphisms (tagSNPs) in RMI1, TOP3A, and BLM and their associations with cancer risk in acute myeloid leukemia/myelodysplatic syndromes (AML/MDS; N = 152), malignant melanoma (N = 170), and bladder cancer (N = 61). Two population-based control groups were used (N = 119 and N = 156). RESULTS: Based on consistency in effect estimates for the three cancer forms and similar allelic frequencies of the variant alleles in the control groups, two SNPs in TOP3A (rs1563634 and rs12945597) and two SNPs in BLM (rs401549 and rs2532105) were selected for analysis in breast cancer cases (N = 200) and a control group recruited from spouses of cancer patients (N = 131). The rs12945597 in TOP3A and rs2532105 in BLM showed increased risk for breast cancer. We then combined all cases (N = 584) and controls (N = 406) respectively and found significantly increased risk for variant carriers of rs1563634 A/G (AG carriers OR = 1.7 [95%CI 1.1-2.6], AA carriers OR = 1.8 [1.2-2.8]), rs12945597 G/A (GA carriers OR = 1.5 [1.1-1.9], AA carriers OR = 1.6 [1.0-2.5]), and rs2532105 C/T (CT+TT carriers OR = 1.8 [1.4-2.5]). Gene-gene interaction analysis suggested an additive effect of carrying more than one risk allele. For the variants of TOP3A, the risk increment was more pronounced for older carriers. CONCLUSION: These results further support a role of low-penetrance genes involved in BLM-associated homologous recombination for cancer risk.
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| 2. |
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| 3. |
- Engström, Karin, et al.
(författare)
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Arsenic metabolism is influenced by polymorphisms in genes involved in one-carbon metabolism and reduction reactions.
- 2009
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Ingår i: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis. - : Elsevier BV. - 1879-2871 .- 0027-5107. ; 667, s. 4-14
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The susceptibility to arsenic (As)-induced diseases differs greatly between individuals, probably to a large extent due to genetic differences in arsenic metabolism. The aim for this study was to identify genetic variants affecting arsenic metabolism. METHODS: We evaluated the association between urinary metabolite pattern and polymorphisms in three gene-groups related to arsenic metabolism: (1) methyltransferases, (2) other genes involved in one-carbon metabolism and (3) genes involved in reduction reactions. Forty-nine polymorphisms were successfully genotyped in indigenous women (N=104) from northern Argentina, exposed to approximately 200mug/L of arsenic in drinking water, with a unique metabolism with low percent monomethylated arsenic (%MMA) and high percent dimethylated As (%DMA). RESULTS: Genetic factors affecting arsenic metabolite pattern included two polymorphisms in arsenic (+III) methyltransferase (AS3MT) (rs3740400, rs7085104), where carriers had lower %MMA and higher %DMA. These single nucleotide polymorphisms (SNPs) were in strong linkage disequilibrium (LD) with three intronic AS3MT SNPs, previously reported to be associated with arsenic metabolism, indicating the existence of a strongly methylating, population-specific haplotype. The CYP17A1 rs743572, 27kilobasepairs (kbs) upstream of AS3MT, was in strong LD with the AS3MT SNPs and thus had similar effects on the metabolite profile. Smaller effects were also seen for one-carbon metabolism genes choline dehydrogenase (CHDH) (rs9001, rs7626693) and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) (rs1801394) and genes involved in reduction reactions, glutaredoxin (GLRX) (rs3822751) and peroxiredoxin 2 (PRDX2) (rs10427027, rs12151144). Genotypes associated with more beneficial arsenic metabolite profile (low %MMA and/or high %DMA in urine) were more common in this population, which has been exposed to arsenic in drinking water for thousands of years. CONCLUSIONS: Polymorphisms in AS3MT and in genes involved in one-carbon metabolism and reduction reactions affects arsenic metabolism.
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| 4. |
- Engström, Karin, et al.
(författare)
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Genetic polymorphisms influencing arsenic metabolism: evidence from Argentina.
- 2007
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Ingår i: Environmental Health Perspectives. - : Environmental Health Perspectives. - 1552-9924 .- 0091-6765. ; 115:4, s. 599-605
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Tidskriftsartikel (refereegranskat)abstract
- The susceptibility to arsenic-induced diseases differs greatly between individuals, possibly due to interindividual variations in As metabolism that affect retention and distribution of toxic metabolites. To elucidate the role of genetic factors in As metabolism, we studied how polymorphisms in six genes affected the urinary metabolite pattern in a group of indigenous women (n = 147) in northern Argentina who were exposed to approximately 200 mu g/L As in drinking water. These women had low urinary percentages of monomethylated As (MMA) and high percentages of dimethylated As (DMA). MMA has been associated with adverse health effects, and DMA has the lowest body retention of the metabolites. The genes studied were arsenic(+ 111) methyltransferase (AS3MT), glutathione S-transferase omega 1 (GSTO1), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), methylenetetrahydrofolate reductase (MTHFR), and glutathione S-transferases mu I (GSTM1) and theta I (GSTT1). We found three intronic polymorphisms in AS3MT (G12390C, C14215T, and G35991A) associated with a lower percentage of MMA (%MMA) and a higher percentage of DMA (%DMA) in urine. The variant homozygotes showed approximately half the %MMA compared with wild-type homozygotes. These polymorphisms were in strong linkage, with high allelic frequencies (72-76%) compared with other populations. We also saw minor effects of other polymorphisms in the multivariate regression analysis with effect modification for the deletion genotypes for GSTM1 (affecting %MMA) and GSTT1 (affecting %MMA and %DMA). For pregnant women, effect modification was seen for the folate-metabolizing genes MTR and MTHFA In conclusion, these findings indicate that polymorphisms in AS3MT-and possibly GSTM1, GSTT1, MTR, and MTHFR-are responsible for a large part of the interindividual variation in As metabolism and susceptibility.
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| 5. |
- Engström, Karin, et al.
(författare)
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Genetic variation in glutathione-related genes and body burden of methylmercury
- 2008
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Ingår i: Journal of Environmental Health Perspectives. - Research Triangle Park, N.C. : Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 116:6, s. 734-739
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Exposure to toxic methylmercury (MeHg) through fish consumption is a large problem worldwide, and it has led to governmental recommendations of reduced fish consumption and blacklisting of mercury-contaminated fish. The elimination kinetics of MeHg varies greatly among individuals. Knowledge about the reasons for such variation is of importance for improving the risk assessment for MeHg. One possible explanation is hereditary differences in MeHg metabolism. MeHg is eliminated from the body as a glutathione (GSH) conjugate. OBJECTIVES: We conducted this study to assess the influence of polymorphisms in GSH-synthesizing [glutamyl-cysteine ligase modifier subunit (GCLM-588) and glutamyl-cysteine ligase catalytic subunit (GCLC-129)] or GSH-conjugating [glutathione S-transferase pi 1 (GSTP1-105 and GSTP1-114)] genes on MeHg retention. METHODS: Based on information obtained from questionnaires, 292 subjects from northern Sweden had a high consumption of fish (lean/fat fish two to three times per week or more). We measured total Hg in erythrocytes (Ery-Hg) and long-chain n-3 polyunsaturated fatty acids in plasma (P-PUFA; an exposure marker for fish intake). RESULTS: The GSTP1 genotype modified Ery-Hg; effects were seen for GSTP1-105 and -114 separately, and combining them resulted in stronger effects. We found evidence of effect modification: individuals with zero or one variant allele demonstrated a steeper regression slope for Ery-Hg (p = 0.038) compared with individuals with two or more variant alleles. The GCLM-588 genotype also influenced Ery-Hg (p = 0.035): Individuals with the GCLM-588 TT genotype demonstrated the highest Ery-Hg, but we saw no evidence of effect modification with increasing P-PUFA. CONCLUSIONS: These results suggest a role of GSH-related polymorphisms in MeHg metabolism.
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| 6. |
- Harari, Raul, et al.
(författare)
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Exposure and Toxic Effects of Elemental Mercury in Gold Mining Activities
- 2009
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Ingår i: Epidemiology. - : Ovid Technologies (Wolters Kluwer Health). - 1044-3983. ; 20:6, s. 264-265
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Tidskriftsartikel (refereegranskat)abstract
- Elemental mercury (Hg0) is widely used in gold-mining activities in South America, Africa and Asia. Miners use Hg0 to extract gold, and are exposed by inhalation when burning the gold amalgam to get rid of the Hg0. Burning is usually performed only once per 1–3 weeks. Gold buyers again burn the gold to be sure that they only buy gold. Hg0 affects the central nervous system (CNS), but the exposure-response relationship for discrete but important effects is not well known. As indicators of exposure, Hg levels in blood, plasma and urine are useful. It is usually assumed that there is a simple relationship between exposure and these biomarkers. However, recent data indicate that genetic traits may modify the retention of Hg. Also, there is a possibility that such factors may influence the exposure-response curves.
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| 7. |
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| 8. |
- Jönsson, Lena S, et al.
(författare)
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Gene expression in nasal lavage from hairdressers exposed to persulphate.
- 2009
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Ingår i: International Archives of Occupational and Environmental Health. - : Springer Science and Business Media LLC. - 1432-1246 .- 0340-0131. ; 82, s. 1261-1266
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Many hairdressers experience work-related symptoms from the airways caused by bleaching powder. This contains persulphates, which could be irritating to the mucous membrane and also may evoke an allergic reaction. However, specific IgE antibodies are difficult to detect. We found earlier that hairdressers with work-related bleaching powder-associated nasal symptoms reacted to persulphate, but that atopics also did and that the mechanism appeared to be similar in the two groups. In this study, we analysed gene expression of cytokines in the nose in order to further investigate the mechanism for work-related bleaching powder-associated nasal symptoms. METHODS: The study subjects belonged to either hairdressers with work-related bleaching powder-associated nasal symptoms (S; n = 6), hairdressers without work-related bleaching powder-associated symptoms (WS; n = 7) or atopics (A; n = 6). Nasal lavage was performed before and during (up to 4 h after the last challenge) provocation with potassium persulphate. Expression of two genes involved in allergic inflammation [interleukin 5 (IL5) and IL13] and one involved in cell-mediated immunity (interferon-gamma; IFNG) were analysed in nasal lavage with quantitative PCR. RESULTS: The change of IL5 in the S group differed when compared to the WS group (P = 0.0051), in the A group when compared to the WS group (P = 0.014), but not in the S group when compared to the A group (P = 0.82). The change of IL13 in the A group differed when compared to the S (P = 0.041) and WS (P = 0.014) groups, but no difference was noticed between the S and WS groups (P = 0.30). The relative level of IFNG increased from before challenge to during challenge in the S group (P = 0.031). CONCLUSIONS: Symptomatic hairdressers showed increased expression of IL5 and IFNG, but not IL13, during challenge. Hairdressers without work-related bleaching powder-associated nasal symptoms showed no markedly changed reaction. Atopics showed increased expression of IL5 and IL13. Thus, this may indicate a difference in the mechanism of symptoms between symptomatic hairdressers and atopics. However, due to the low number of participants, further studies are needed to elucidate the mechanism for persulphate-associated nasal symptoms.
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| 9. |
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| 10. |
- Björk, Jonas, et al.
(författare)
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Smoking as a risk factor for myelodysplastic syndromes and acute myeloid leukemia and its relation to cytogenetic findings: A case-control study.
- 2009
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Ingår i: Leukemia Research: A Forum for Studies on Leukemia and Normal Hemopoiesis. - : Elsevier BV. - 1873-5835. ; Nov 17, s. 788-791
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Tidskriftsartikel (refereegranskat)abstract
- In this case-control study, interview data on smoking habits were available for 179 de novo cases (116 with cytogenetic data) of acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). Smoking habits were compared with a pooled set of population controls and hospital controls (diagnosed with malignant melanoma). Each pack-year of smoking increased the risk of MDS with 1.3% (95% CI 0.1-2.6%), corresponding to an estimated excess risk of 71% (95% CI 3-180%) for 40 pack-years. Associations between smoking and the specific aberrations -5/5q-, -7/7q-, and +8 in AML and MDS were indicated but the estimates were imprecise.
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