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ABSTRACT: A large number of genes, including several not previously implicated in SLE susceptibility, have recently been identified or confirmed by genome-wide association studies (GWAS). In this study, we sought to replicate some of these results in Finnish SLE patients (n = 275) and control individuals (n = 356).
We genotyped 32 single nucleotide polymorphisms (SNPs) in 12 of the best-supported GWAS-identified SLE genes and loci. We further investigated gene-gene interactions between the loci included in the study.
The strongest evidence of association was found at the IRF5-TNPO3 locus, with the most significant P-value being 2.0 × 10(-7) and an odds ratio of 1.95 (95% CI 1.51, 2.50). Association between SLE and TNFAIP3, FAM167A-BLK, BANK1 and KIAA1542 was also confirmed, although at a lower significance level and contribution to individual risk. No significant association was found with 1q25.1, PXK, ATG5, ICA1, XKR6, LYN and SCUBE1. Furthermore, no significant gene-gene interactions were detected.
Replication of previous GWAS findings across diverse populations is of importance to validate these associations and to get a better understanding of potential genetic heterogeneity between populations in SLE susceptibility. Our results attest the importance of B-cell receptor pathway and IFN signalling in SLE pathogenesis.
Rheumatology (Oxford, England) 01/2012; 51(1):87-92. · 4.24 Impact Factor
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ABSTRACT: Chronic kidney disease (CKD) patients are especially prone to vitamin D insufficiency. Narrow-band ultraviolet B (NB-UVB) treatment increases serum 25-hydroxyvitamin D [25(OH)D] in dermatological patients, and we studied whether it also improves vitamin D balance in CKD patients on haemodialysis.
Fifteen dialysis patients (mean age 48.3 years) and 12 healthy subjects (mean age 43.6 years) received nine NB-UVB exposures on the upper body. Serum 25(OH)D and 1,25(OH)(2)D were measured before and after the exposures. From skin biopsy specimen messenger RNA (mRNA) expression levels of CYP24A1 and CYP27B1, two enzymes needed for hydroxylation of vitamin D into its active metabolites, and of antimicrobial peptide cathelicidin, were examined.
Before NB-UVB, mean serum 25(OH)D was 32.5 ± 10.2 nmol/L in the dialysis patients and 60.2 ± 18.0 nmol/L in the healthy subjects (P < 0.001). After eight NB-UVB exposures, serum 25(OH)D increased by 13.8 nmol/L (43%; P < 0.001) and serum 1,25(OH)(2)D by 3.3 pmol/L (27%; P = 0.002) in the dialysis patients. After NB-UVB exposures, CYP27B1 mRNA was increased (P = 0.04), whereas cathelicidin mRNA was decreased (P < 0.0001) compared to non-treated healthy subjects. One and 2 months after NB-UVB exposure, serum 25(OH)D was still 10% higher than initially in the dialysis patients.
The present study shows that a short course of NB-UVB exposure increases significantly serum 25(OH)D and 1,25(OH)(2)D in dialysis patients. The effect is, however, short lasting suggesting that the patients need cyclic NB-UVB exposure to maintain their improved vitamin D concentration.
Nephrology Dialysis Transplantation 12/2011; 27(6):2435-40. · 3.40 Impact Factor
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Acta Dermato-Venereologica 06/2011; 91(4):463-4.
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Leena Ackermann,
Kristiina Aalto-Korte,
Kristiina Alanko, Taina Hasan,
Riitta Jolanki,
Kaija Lammintausta,
Antti Lauerma,
Arja Laukkanen,
Jussi Liippo,
Riitta Riekki,
Anna-Maija Vuorela,
Tapio Rantanen
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ABSTRACT: Antimicrobials constitute the second most common cause of contact allergy to cosmetics. Methylisothiazolinone (MI), previously always used together with methylchloroisothiazolinone (MCI), has recently been approved in the EU for use on its own in cosmetics and also various industrial products. MCI has been classified as an extreme-strong and MI as a strong-moderate sensitizer.
To study the frequency of positive patch test reactions to MI, and its relevance and relation to MCI/MI sensitivity, in Finland.
Over a period of 3 years (2006-2008), MI 0.1% (1000 ppm) and 0.03% (300 ppm) were patch tested in 10,821 patients at eight Finnish dermatological clinics. During 2008, patients with positive reactions to MI were asked to take part in a repeated open application test (ROAT).
Of the patients tested, 1.4% and 0.6% showed positive patch test reactions to 0.1% and 0.03% MI, respectively. Sixty-six per cent of those who were MI-positive were also positive to 100 ppm MCI/MI. Thirty-three agreed to undergo the use test, and 10 of these gave positive results (30%).
Our data show that MI used alone also potentially induces contact allergy. Careful monitoring is needed to determine whether or not this antimicrobial is safe to use in cosmetics.
Contact Dermatitis 01/2011; 64(1):49-53. · 3.51 Impact Factor
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Acta Dermato-Venereologica 09/2010; 90(5):553-4.
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ABSTRACT: Thiourea derivatives in rubber products may induce contact sensitization and allergic contact dermatitis. Sensitization is most often from neoprene rubber, but the multitude of possible sensitizing products has remained poorly characterized.
The aim of this study was to collect information on the occurrence of thiourea-related contact allergy and to show novel sources of sensitization.
A mixture of dibutyl-, diethyl-, and diphenylthiourea was included in patch test baseline series in five Finnish dermatology clinics during 2002-2007. In addition, an extended series of rubber chemicals was tested in patients with suspected rubber allergy. Sources of sensitization to thioureas were analysed in sensitized patients.
Thiourea mix yielded positive patch test reactions in 59 of 15,100 patients (0.39%); 33/59 patients were also tested with individual rubber chemicals. Diethylthiourea was positive in 24/33, diphenylthiourea in 5, and dibutylthiourea in 1 patient. The most common sources of sensitization included various neoprene-containing orthopaedic braces, sports equipment, and foot wear.
The sources of sensitization to thiourea chemicals were detected in most cases. These sources comprise a heterogenous group of products extending from orthopaedic materials to sports equipment.
Contact Dermatitis 07/2010; 63(1):37-41. · 3.51 Impact Factor
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ABSTRACT: Chairs and sofas imported from China to Europe were shown to contain dimethyl fumarate (DMF), a sensitizing, volatile chemical. Many of the sensitized patients also had positive patch test reactions to acrylates.
To analyse the occurrence and strength of DMF sensitization and the appearance of concomitant reactions.
Patch testing with DMF in concentrations of 0.1-0.00001% was carried out in 37 patients. Diethyl fumarate (DEF), diethyl maleate (DEM), dimethyl maleate (DMM), ethyl acrylate (EA), methyl acrylate (MA), and methyl methacrylate (MMA) were also tested with a dilution series at equimolar concentrations.
The lowest concentration of DMF eliciting a reaction varied between 0.0001% and 0.1% and all but four patients reacted concurrently to DEF. DEM elicited positive patch test reactions in 21/37 patients and DMM reactions were seen in all 9 patients tested. EA elicited positive reactions in 13/37 patients and a positive MA reaction was seen in 7/37 patients, 2 of whom also reacted to MMA.
The strength of the sensitization to DMF showed variation and concurrent reactions were common. Concurrent reactions to (meth)acrylates were seen in patients, who reacted to lower (0.001% or less) DMF concentration probably elicited by cross-reactivity.
Contact Dermatitis 02/2010; 62(2):88-96. · 3.51 Impact Factor
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ABSTRACT: Lupin, a legume with good nutritional value, is used in food production today, most often in bakery products. In Finland, lupin is a labelled ingredient in very few products. Clinically relevant lupin allergy, even anaphylaxis, often occurs in patients without atopic background or other food allergies, whereas lupin sensitization without clinical relevancy most commonly seems to represent cross reactivity to other legumes. Lupin allergy should be suspected and studied in patients with adverse reactions to food, and patients with allergy to other legumes should be advised about possible lupin allergy, as well.
Duodecim; lääketieteellinen aikakauskirja 01/2010; 126(12):1393-9.
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Tiina M Järvinen,
Anna Hellquist,
Sari Koskenmies,
Elisabet Einarsdottir,
Jaana Panelius, Taina Hasan,
Heikki Julkunen,
Leonid Padyukov,
Marika Kvarnström,
Marie Wahren-Herlenius,
Filippa Nyberg,
Mauro D'Amato,
Juha Kere,
Ulpu Saarialho-Kere
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ABSTRACT: Lupus erythematosus (LE) is a heterogeneous disease ranging from mainly skin-restricted manifestations (discoid LE [DLE] and subacute cutaneous LE) to a progressive multisystem disease (systemic LE [SLE]). Genetic association studies have recently identified several strong susceptibility genes for SLE, including integrin alpha M (ITGAM), also known as CD11b, whereas the genetic background of DLE is less clear.
To specifically investigate whether ITGAM is a susceptibility gene not only for SLE, but also for cutaneous DLE, we genotyped 177 patients with DLE, 85 patients with sporadic SLE, 190 index cases from SLE families and 395 population control individuals from Finland for nine genetic markers at the ITGAM locus. SLE patients were further subdivided by the presence or absence of discoid rash and renal involvement. In addition, 235 Finnish and Swedish patients positive for Ro/SSA-autoantibodies were included in a subphenotype analysis. Analysis of the ITGAM coding variant rs1143679 showed highly significant association to DLE in patients without signs of systemic disease (P-value = 4.73×10(-11), OR = 3.20, 95% CI = 2.23-4.57). Significant association was also detected to SLE patients (P-value = 8.29×10(-6), OR = 2.14, 95% CI = 1.52-3.00), and even stronger association was found when stratifying SLE patients by presence of discoid rash (P-value = 3.59×10(-8), OR = 3.76, 95% CI = 2.29-6.18).
We propose ITGAM as a novel susceptibility gene for cutaneous DLE. The risk effect is independent of systemic involvement and has an even stronger genetic influence on the risk of DLE than of SLE.
PLoS ONE 01/2010; 5(12):e14212. · 4.09 Impact Factor
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Tiina M Järvinen,
Anna Hellquist,
Sari Koskenmies,
Elisabet Einarsdottir,
Lotta L E Koskinen,
Leila Jeskanen,
Linda Berglind,
Jaana Panelius, Taina Hasan,
Annamari Ranki,
Juha Kere,
Ulpu Saarialho-Kere
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ABSTRACT: Lupus erythematosus (LE) is a heterogeneous disease ranging from skin-restricted manifestations to a progressive multisystem disease. The specific skin lesions include chronic cutaneous, subacute cutaneous and acute cutaneous LE. Both genetic and environmental factors are involved in the development of LE. However, reports on the genetic background of cutaneous lupus erythematosus (CLE) forms, namely discoid (DLE) and subacute cutaneous lupus erythematosus (SCLE), are sparse. We investigated whether the known systemic LE (SLE) susceptibility genes also predispose to CLE. Altogether, 219 Finnish patients with DLE or SCLE and 356 healthy controls were recruited. Single nucleotide polymorphisms tagging reported risk genes were genotyped. Tyrosine kinase 2 (TYK2) rs2304256 was associated with increased risk of DLE (P = 0.012, OR = 1.47, 95% CI = 1.01-1.98). Expression of TYK2 was demonstrated by immunohistochemistry in macrophage-like cells and neutrophils and interferon regulatory factor 5 (IRF5) in macrophage- and fibroblast-like cells of DLE, SCLE and SLE skin. IRF5 rs10954213 showed association with DLE (P = 0.017, OR = 1.40, 95% CI = 1.06-1.86) and SCLE (P = 0.022, OR = 1.87, 95% CI = 1.09-3.21). A haplotype of cytotoxic T-lymphocyte-associated protein 4 (CTLA4) showed association with DLE (P = 0.0065, OR = 2.51, 95% CI = 1.25-5.04). Our results show that the TYK2, IRF5 and CTLA4 genes previously associated with SLE also confer risk for DLE and SCLE, suggesting that different LE subphenotypes may share pathogenetic pathways.
Experimental Dermatology 09/2009; 19(2):123-31. · 3.54 Impact Factor
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ABSTRACT: Lupin, a legume with good nutritional value, is used in food production today, most often in bakery products. Lupin sensitization is often seen among patients with reactions to legumes, but the number of reports describing lupin anaphylaxis is also increasing.
To investigate the occurrence of lupin sensitization, cross-reactivity, and lupin allergy among patients with suspected food allergy in Finland, where lupin is a labeled ingredient in few products.
The occurrence of positive skin prick test (SPT) reactions to lupin seed flour was studied among 1522 patients with suspected food allergy from November 1, 2005, through December 31, 2007. Clinical histories and diagnostic SPT results were analyzed among patients with positive SPT results to lupin. For 1 patient, ImmunoSpot and lupin radioallergosorbent test inhibition methods were used.
Lupin sensitization was shown in 25 of 1522 patients (1.6%), and probable lupin allergy was diagnosed in 7 of 25 patients, in whom the clinical symptoms varied from anaphylaxis and respiratory symptoms to contact urticaria and itchy mouth. Cross-reactions or concurrent reactions to other legumes were seen in 18 of 25 patients.
Clinically relevant lupin allergy often occurs in patients without atopic background or other food allergies, although lupin sensitization most commonly seems to represent cross-reactivity to other legumes. The occurrence of lupin allergy in a country where lupin has not been traditionally used is surprisingly common, suggesting that short-term use of modest amounts of lupin can cause serious allergic reactions.
Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 09/2009; 103(3):233-7. · 2.83 Impact Factor
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Anna Hellquist,
Tiina M Järvinen,
Sari Koskenmies,
Marco Zucchelli,
Christina Orsmark-Pietras,
Linda Berglind,
Jaana Panelius, Taina Hasan,
Heikki Julkunen,
Mauro D'Amato,
Ulpu Saarialho-Kere,
Juha Kere
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ABSTRACT: Several candidate genes have been implicated in susceptibility for systemic lupus erythematosus (SLE), a complex autoimmune disease. The proposed genes include members of the type I interferon (IFN) pathway and genes involved in immunological defense functions. Our aim was to systematically replicate 6 such genes, TYK2, IRF5, CTLA4, PDCD1, FCGR2A, and NOD2.
Single-nucleotide polymorphisms in TYK2, IRF5, CTLA4, PDCD1, FCGR2A, and NOD2 were genotyped in 277 SLE patients and 356 healthy controls from Finland, giving a power of 42%-70% for different genes at published allele frequencies.
Significant association was seen for rs2304256 (p = 0.0001) and rs12720270 (p = 0.0031) in TYK2 and rs10954213 (p = 0.0043) in IRF5 in our samples, but not for the other genes. We found evidence for genetic interaction (p = 0.014) between rs2304256 in TYK2 and rs10954213 in IRF5, both members of the type I IFN pathway, strengthening the role of the type I IFN pathway in the pathogenesis of SLE.
The IFN pathway genes IRF5 and TYK2 may act epistatically in increasing risk for SLE, but our lack of replication does not exclude effects of the other genes studied.
The Journal of Rheumatology 07/2009; 36(8):1631-8. · 3.69 Impact Factor
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Anna Hellquist,
Marco Zucchelli,
Cecilia M Lindgren,
Ulpu Saarialho-Kere,
Tiina M Järvinen,
Sari Koskenmies,
Heikki Julkunen,
Päivi Onkamo,
Tiina Skoog,
Jaana Panelius, [......],
Leonid Padyukov,
Ghazaleh Assadi,
Linda Berglind,
Ville-Veikko Mäkelä,
Katja Kivinen,
Andrew Wong,
Deborah S Cunningham Graham,
Timothy J Vyse,
Mauro D'Amato,
Juha Kere
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ABSTRACT: Systemic lupus erythematosus (SLE) is a complex autoimmune disorder with multiple susceptibility genes. We have previously reported suggestive linkage to the chromosomal region 14q21-q23 in Finnish SLE families.
Genetic fine mapping of this region in the same family material, together with a large collection of parent affected trios from UK and two independent case-control cohorts from Finland and Sweden, indicated that a novel uncharacterized gene, MAMDC1 (MAM domain containing glycosylphosphatidylinositol anchor 2, also known as MDGA2, MIM 611128), represents a putative susceptibility gene for SLE. In a combined analysis of the whole dataset, significant evidence of association was detected for the MAMDC1 intronic single nucleotide polymorphisms (SNP) rs961616 (P -value = 0.001, Odds Ratio (OR) = 1.292, 95% CI 1.103-1.513) and rs2297926 (P -value = 0.003, OR = 1.349, 95% CI 1.109-1.640). By Northern blot, real-time PCR (qRT-PCR) and immunohistochemical (IHC) analyses, we show that MAMDC1 is expressed in several tissues and cell types, and that the corresponding mRNA is up-regulated by the pro-inflammatory cytokines tumour necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) in THP-1 monocytes. Based on its homology to known proteins with similar structure, MAMDC1 appears to be a novel member of the adhesion molecules of the immunoglobulin superfamily (IgCAM), which is involved in cell adhesion, migration, and recruitment to inflammatory sites. Remarkably, some IgCAMs have been shown to interact with ITGAM, the product of another SLE susceptibility gene recently discovered in two independent genome wide association (GWA) scans.
Further studies focused on MAMDC1 and other molecules involved in these pathways might thus provide new insight into the pathogenesis of SLE.
PLoS ONE 01/2009; 4(12):e8037. · 4.09 Impact Factor
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Duodecim; lääketieteellinen aikakauskirja 02/2007; 123(17):2125-8.
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Duodecim; lääketieteellinen aikakauskirja 02/2005; 121(12):1327-9.
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ABSTRACT: Photodamage is characterized by degradation of collagen and accumulation of abnormal elastin in the superficial dermis and several matrix metalloproteinases have previously been implicated in this process. Using immunohistochemistry and in situ hybridization, we have studied the localization of two elastolytic matrix metalloproteinases, matrilysin (matrix metalloproteinase-7) and human macrophage metalloelastase (matrix metalloproteinase-12) in solar damage. Human macrophage metalloelastase protein was detected in the superficial dermis in areas of elastotic material. Matrix metalloproteinase-7 was seen in the mid-dermis in regions with less damaged elastic fibers and morphologically better preserved collagen as well as in a band-like pattern below basal keratinocytes in eight of 18 solar elastosis. In samples taken from healthy volunteers 3 d after repeated ultraviolet A or ultraviolet B photoprovocation, occasional immunopositive cells for human macrophage metalloelastase (stromal) or matrix metalloproteinase-7 (sweat gland epithelium) were detected. In samples taken 1 d after ultraviolet B exposure, however, basal keratinocytes were matrix metalloproteinase-7 immunopositive, explaining the linear immunostaining below basal keratinocytes noted particularly in ultraviolet B treated 3 d specimens. Upregulation of metalloelastase was also demonstrated in the skin of hairless mice after repeated ultraviolet exposure. In normal skin, no staining for human macrophage metalloelastase or matrix metalloproteinase-7 was observed in association with elastin. The amount of immunoreactivity for the substrates of matrix metalloproteinase-7, versican, and tenascin, was clearly increased in solar elastosis and photoprovocated skin; versican but not tenascin was detected in the same areas as matrix metalloproteinase-7. Our results suggest that both matrix metalloproteinase-7 and -12 may contribute to remodeling of elastotic areas in sun-damaged skin.Keywords: elastin, keratosis, tenascin, versican
Journal of Investigative Dermatology 09/1999; 113(4):664-672. · 6.31 Impact Factor
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Lasse Kanerva,
Tapio Rantanen,
Kristiina Aalto-Korte,
Tuula Estlander,
Matti Hannuksela,
Rauno J. Harvima, Taina Hasan,
Maija Horsmanheimo,
Riita Jolanki,
Kirsti Kalimo,
Arto Lahti,
Kaija Lammintausta,
Antti Lauerma,
Aila Niinim[auml ]ki,
Kristiina Turjanmaa,
Anna-Maija Vuorela
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ABSTRACT: Background: Dental products contain many allergens, and may cause problems both for patients undergoing dental treatment and for dental personnel because of occupational exposure. Individual patch test clinics may not study sufficient numbers of patients to collect reliable data on uncommon allergens. Objective: To collect information on dental allergens based on a multicenter study. Materials and Methods: The Finnish Contact Dermatitis Group tested more than 4,000 patients (for most allergens, 2,300 to 2,600 patients) with dental screening series. Conventional patch testing was performed. The total number and percentage of irritant (scored as irritant [IR] or doubtful [?]) and allergic (scored as +, ++, or +++) patch test reactions, respectively, were calculated, as well as the highest and lowest percentage of allergic patch test reactions recorded by the different patch test clinics. A reaction index (RI) was calculated, giving information on the irritancy of the patch test substances. Results: The most frequent allergic patch test reactions were caused by nickel (14.6%), ammoniated mercury (13%), mercury (10.3%), gold (7.7%), benzoic acid (4.3%), palladium (4.2%) and cobalt (4.1%). 2-hydroxyethyl methacrylate (2.8%) provoked most of the reactions caused by (meth)acrylates. Menthol, peppermint oil, ammonium tetrachloroplatinate, and amalgam alloying metals provoked no (neither allergic nor irritant) patch test reactions. Conclusion: Patch testing with allergens in the dental screening series, including (meth)acrylates and mercury, needs to be performed to detect contact allergy to dental products.
American Journal of Contact Dermatitis.
