Nivelrikon genetiikka

Osteoarthritis (OA) is a complex disease characterized by the destruction of the articular cartilage of the joints. The main symptoms are pain and disability, caused most probably by secondary synovitis. Secondary manifestations of OA are considered to be bone changes, osteophytes, subchondral sclerosis, and bone cysts. The suspected risk factors for OA include genetic predisposition, gender (greater in females), old age, obesity (also in non-weight-bearing joints), previous injury and various physical loading conditions. Prevalence of the disease varies between approximately 8 % and 60 %, dependent on the joint, but also largely on the age of study subjects, the population and OA definition. The disease affects the cartilage, bone, and synovium, but the etiology is still mainly unknown. Even the initiating events and tissue are unknown, but mechanical wear and tear is considered as the prime candidate for the root cause of the disease. The role of the genetic component in common skeletal diseases is well established but remains poorly understood. Heritability of hand and knee OA in women has been shown to range from 39 % to 65 %. Previous association studies have provided some evidence for genes affecting bone density, inflammation, composition and break down of the extracellular matrix. However, these results have been inconsistent. The objective of the present study was to identify predisposing genes for OA using single nucleotide polymorphism (SNP) markers. The study consisted of hand, knee and hip OA cases (n = 1466) and controls (n = 4475). A set of 25 candidate genes were studied in carefully selected case-control, family and twin settings. The objective of Study I was to pinpoint an OA-predisposing gene at the 2q11.2 region, which has previously been linked with hand OA using partially the same study sample (Leppävuori et al. 1999). In total 32 SNPs were genotyped in this region comprising 6 genes belonging to the interleukin 1 super-family. IL1R1 was associated with hand OA (p = 0.00091, with a significance threshold of p = 0.0021). The aim of Study II was to identify genetic variants in MMP8 and MMP9 genes that predispose to OA. Five different study cohorts including 1369 OA cases and 4445 controls were studied. Evidence for the role of MMP8 in knee OA was observed in one study sample (p = 0.0049, with a significance threshold of 0.0057) without statistically significant replication. The main association finding was found in the Finnish study sample for knee OA, while a similar tendency was observed in both the knee OA study sample of Spanish origin, and the hand OA sample of Finnish origin. The aim of Study III was to identify variants predisposing to hip OA from a preselected set of 25 biologically interesting candidate genes. Hips of the study subjects had been analyzed using magnetic resonance imaging (MRI). Variants in the COL9A2 and COL10A1 genes showed suggestive association (p = 0.0021 and p = 0.0015, with significance threshold of 0.00073). The change in the same codon of the COL9A2 has previously been shown to associate with a disc degeneration phenotype (Videman et al. 2009). In conclusion, the results of this thesis support the theory that inflammatory factors, cartilage breaking factors and originally poor quality of collagen associate with OA. Validation of all these results in larger study populations with more accurate genetic analysis are still needed for any further conclusions.Nivelrikko on monitekijäinen nivelruston rappeumasairaus. Sen pääasialliset oireet ovat kipu ja toiminnalliset nivelvaivat. Perintötekijät, naissukupuoli, ikä, lihavuus, aiemmat nivelvammat ja erilaiset fyysiset kuormitukset ovat nivelrikon riskitekijöitä. Taudin yleisyys vaihtelee 8 ja 60 %:n välillä riippuen tutkittavasta nivelestä, ikäryhmästä, väestöstä ja nivelrikon määritelmästä. Tauti vaikuttaa rustoon, luuhun ja nivelkalvoon, mutta taudin etiologia on vielä tuntematon. Jopa taudin alulle panevia tapahtumia tai varhaisia kudosmuutoksia ei vielä tunneta, mutta mekaanista kulutusta pidetään yhtenä tärkeimpänä tekijänä taudin synnyssä. Geneettisten tekijöiden merkitys tuki- ja liikuntaelinsairauksissa on yleisesti tunnustettu, mutta huonosti ymmärretty. Geneettiset tekijät selittävät käsi- ja polvinivelrikosta 39 - 65 %. Aiemmat assosiaatiotutkimukset ovat osoittaneet luun tiheyteen, tulehdukseen, ruston koostumukseen ja hajotukseen liittyvien geenien vaikuttavan nivelrikkoon, mutta useat tulokset ovat edelleen ristiriitaisia. Tämän väitöskirjatyön tavoitteena oli tunnistaa nivelrikolle altistavia geenejä. Tutkimus koostui käden, polven ja lonkan nivelrikkoa sairastavista henkilöistä (n = 1466) sekä näiden verrokkihenkilöistä (n = 4475). Yhteensä 25 ennalta valittua ehdokasgeeniä tutkittiin tarkoin valituissa tapaus-verrokki-, perhe- sekä kaksosasetelmissa. Ensimmäisen tutkimuksen tavoitteena oli osoittaa kromosomialueelta 2q11.2 nivelrikolle altistava geeni. Alueen oli aiemmassa suomalaistutkimuksessa havaittu kytkeytyvän käden nivelrikkoon aineistossa, joka oli osittain päällekkäinen tämän tutkimuksen aineiston kanssa (Leppävuori et al. 1999). Yhteensä 32 SNPiä (yhden emäksen polymorfioita) analysoitiin tältä kuusi interleukiiniperheen geeniä sisältävältä alueelta. IL1R1-geenin todettiin assosioituvan käden nivelrikkoon (p = 0.00091, kun merkitsevyysraja oli p = 0.0021). Toisessa tutkimuksessa syvennyttiin matriksi metalloproteinaasi 8 (MMP8) ja matriksi metalloproteinaasi 9 (MMP9) -geeneihin polven nivelrikossa. Tutkimuksessa käytettiin viittä eri tutkimusaineistoa, jotka sisälsivät 1369 nivelrikkoa sairastavaa and 4445 tervettä verrokkia. Näiden avulla löydettiin assosiaatio MMP8-geeniin (p = 0.0049, kun merkitsevyysraja oli 0.0057), mutta löydös ei toistunut muissa aineistoissa tilastollisesti merkittävällä tasolla. Päälöydös tehtiin suomalaisessa polven nivelrikkoaineistossa, mutta myös suomalainen käden nivelrikkoaineisto ja espanjalainen polven nivelrikkoaineisto näyttivät samansuuntaista tulosta. Kolmannen osatyön tavoitteena oli tutkia nivelrikolle altistavia variantteja 25:stä biologisen merkityksensä vuoksi ennalta valitusta ehdokasgeenistä. Tutkimushenkilöiden lonkkanivelet oli analysoitu magneettisella resonanssikuvantamisella (MRI). Kaksi varianttia, geeneissä kollageeni 9 alfa 2 (COL9A2) sekä kollageeni 10 alfa 1 (COL10A1), näyttivät altistavan lonkan nivelrikolle (p = 0.0021 and p = 0.0015, kun merkitsevyysraja oli 0.00073). Tulos ei ollut tilastollisesti merkitsevä. Saman kodonin muutoksen COL9A2-geenissä on aiemmin todettu altistavan selän välilevyrappeumalle (Videman et al. 2009). Yhteenvetona voidaan todeta, että tämän väitöskirjatyön tulokset tukevat aiempaa teoriaa siitä, että tulehdukselliset ja rustoa hajottavat tekijät sekä jo alun alkaen huonolaatuinen kollageeni altistavat nivelrikolle. Nämä tulokset on kuitenkin validoitava laajemmissa aineistoissa ja geneettisiä analyysejä on tarkennettava varmempien johtopäätösten tekemiseksi

Association of Human FOS Promoter Variants with the Occurrence of Knee-Osteoarthritis in a Case Control Association Study

Our aim was to analyse (i) the presence of single nucleotide polymorphisms (SNPs) in the JUN and FOS core promoters in patients with rheumatoid arthritis (RA), knee-osteoarthritis (OA), and normal controls (NC); (ii) their functional influence on JUN/FOS transcription levels; and (iii) their associations with the occurrence of RA or knee-OA. JUN and FOS promoter SNPs were identified in an initial screening population using the Non-Isotopic RNase Cleavage Assay (NIRCA); their functional influence was analysed using reporter gene assays. Genotyping was done in RA (n = 298), knee-OA (n = 277), and NC (n = 484) samples. For replication, significant associations were validated in a Finnish cohort (OA: n = 72, NC: n = 548). Initially, two SNPs were detected in the JUN promoter and two additional SNPs in the FOS promoter in perfect linkage disequilibrium (LD). JUN promoter SNP rs4647009 caused significant downregulation of reporter gene expression, whereas reporter gene expression was significantly upregulated in the presence of the FOS promoter SNPs. The homozygous genotype of FOS promoter SNPs showed an association with the susceptibility for knee-OA (odds ratio (OR) 2.12, 95% confidence interval (CI) 1.2–3.7, p = 0.0086). This association was successfully replicated in the Finnish Health 2000 study cohort (allelic OR 1.72, 95% CI 1.2–2.5, p = 0.006). FOS Promoter variants may represent relevant susceptibility markers for knee-OA

Association of Human FOS Promoter Variants with the Occurrence of Knee-Osteoarthritis in a Case Control Association Study

Our aim was to analyse (i) the presence of single nucleotide polymorphisms (SNPs) in the JUN and FOS core promoters in patients with rheumatoid arthritis (RA), knee-osteoarthritis (OA), and normal controls (NC); (ii) their functional influence on JUN/FOS transcription levels; and (iii) their associations with the occurrence of RA or knee-OA. JUN and FOS promoter SNPs were identified in an initial screening population using the Non-Isotopic RNase Cleavage Assay (NIRCA); their functional influence was analysed using reporter gene assays. Genotyping was done in RA (n = 298), knee-OA (n = 277), and NC (n = 484) samples. For replication, significant associations were validated in a Finnish cohort (OA: n = 72, NC: n = 548). Initially, two SNPs were detected in the JUN promoter and two additional SNPs in the FOS promoter in perfect linkage disequilibrium (LD). JUN promoter SNP rs4647009 caused significant downregulation of reporter gene expression, whereas reporter gene expression was significantly upregulated in the presence of the FOS promoter SNPs. The homozygous genotype of FOS promoter SNPs showed an association with the susceptibility for knee-OA (odds ratio (OR) 2.12, 95% confidence interval (CI) 1.2-3.7, p = 0.0086). This association was successfully replicated in the Finnish Health 2000 study cohort (allelic OR 1.72, 95% CI 1.2-2.5, p = 0.006). FOS Promoter variants may represent relevant susceptibility markers for knee-OA.Peer reviewe

Allelic variants of IL1R1 gene associate with severe hand osteoarthritis

BACKGROUND: In search for genes predisposing to osteoarthritis (OA), several genome wide scans have provided evidence for linkage on 2q. In this study we targeted a 470 kb region on 2q11.2 presenting the locus with most evidence for linkage to severe OA of distal interphalangeal joints (DIP) in our genome wide scan families. METHODS: We genotyped 32 single nucleotide polymorphisms (SNPs) in this 470 kb region comprising six genes belonging to the interleukin 1 superfamily and monitored for association with individual SNPs and SNP haplotypes among severe familial hand OA cases (material extended from our previous linkage study; n = 134), unrelated end-stage bilateral primary knee OA cases (n = 113), and population based controls (n = 436). RESULTS: Four SNPs in the IL1R1 gene, mapping to a 125 kb LD block, provided evidence for association with hand OA in family-based and case-control analysis, the strongest association being with SNP rs2287047 (p-value = 0.0009). CONCLUSIONS: This study demonstrates an association between severe hand OA and IL1R1 gene. This gene represents a highly relevant biological candidate since it encodes protein that is a known modulator of inflammatory processes associated with joint destruction and resides within a locus providing consistent evidence for linkage to hand OA. As the observed association did not fully explain the linkage obtained in the previous study, it is plausible that also other variants in this genome region predispose to hand OA.Peer reviewe

Association of Human FOS Promoter Variants with the Occurrence of Knee-Osteoarthritis in a Case Control Association Study

Our aim was to analyse (i) the presence of single nucleotide polymorphisms (SNPs) in the JUN and FOS core promoters in patients with rheumatoid arthritis (RA), knee-osteoarthritis (OA), and normal controls (NC); (ii) their functional influence on JUN/FOS transcription levels; and (iii) their associations with the occurrence of RA or knee-OA. JUN and FOS promoter SNPs were identified in an initial screening population using the Non-Isotopic RNase Cleavage Assay (NIRCA); their functional influence was analysed using reporter gene assays. Genotyping was done in RA (n = 298), knee-OA (n = 277), and NC (n = 484) samples. For replication, significant associations were validated in a Finnish cohort (OA: n = 72, NC: n = 548). Initially, two SNPs were detected in the JUN promoter and two additional SNPs in the FOS promoter in perfect linkage disequilibrium (LD). JUN promoter SNP rs4647009 caused significant downregulation of reporter gene expression, whereas reporter gene expression was significantly upregulated in the presence of the FOS promoter SNPs. The homozygous genotype of FOS promoter SNPs showed an association with the susceptibility for knee-OA (odds ratio (OR) 2.12, 95% confidence interval (CI) 1.2–3.7, p = 0.0086). This association was successfully replicated in the Finnish Health 2000 study cohort (allelic OR 1.72, 95% CI 1.2–2.5, p = 0.006). FOS Promoter variants may represent relevant susceptibility markers for knee-OA

Association of Human FOS Promoter Variants with the Occurrence of Knee-Osteoarthritis in a Case Control Association Study

Our aim was to analyse (i) the presence of single nucleotide polymorphisms (SNPs) in the JUN and FOS core promoters in patients with rheumatoid arthritis (RA), knee-osteoarthritis (OA), and normal controls (NC); (ii) their functional influence on JUN/FOS transcription levels; and (iii) their associations with the occurrence of RA or knee-OA. JUN and FOS promoter SNPs were identified in an initial screening population using the Non-Isotopic RNase Cleavage Assay (NIRCA); their functional influence was analysed using reporter gene assays. Genotyping was done in RA (n = 298), knee-OA (n = 277), and NC (n = 484) samples. For replication, significant associations were validated in a Finnish cohort (OA: n = 72, NC: n = 548). Initially, two SNPs were detected in the JUN promoter and two additional SNPs in the FOS promoter in perfect linkage disequilibrium (LD). JUN promoter SNP rs4647009 caused significant downregulation of reporter gene expression, whereas reporter gene expression was significantly upregulated in the presence of the FOS promoter SNPs. The homozygous genotype of FOS promoter SNPs showed an association with the susceptibility for knee-OA (odds ratio (OR) 2.12, 95% confidence interval (CI) 1.2–3.7, p = 0.0086). This association was successfully replicated in the Finnish Health 2000 study cohort (allelic OR 1.72, 95% CI 1.2–2.5, p = 0.006). FOS Promoter variants may represent relevant susceptibility markers for knee-OA

Association of Human FOS Promoter Variants with the Occurrence of Knee-Osteoarthritis in a Case Control Association Study

Our aim was to analyse (i) the presence of single nucleotide polymorphisms (SNPs) in the JUN and FOS core promoters in patients with rheumatoid arthritis (RA), knee-osteoarthritis (OA), and normal controls (NC); (ii) their functional influence on JUN/FOS transcription levels; and (iii) their associations with the occurrence of RA or knee-OA. JUN and FOS promoter SNPs were identified in an initial screening population using the Non-Isotopic RNase Cleavage Assay (NIRCA); their functional influence was analysed using reporter gene assays. Genotyping was done in RA (n = 298), knee-OA (n = 277), and NC (n = 484) samples. For replication, significant associations were validated in a Finnish cohort (OA: n = 72, NC: n = 548). Initially, two SNPs were detected in the JUN promoter and two additional SNPs in the FOS promoter in perfect linkage disequilibrium (LD). JUN promoter SNP rs4647009 caused significant downregulation of reporter gene expression, whereas reporter gene expression was significantly upregulated in the presence of the FOS promoter SNPs. The homozygous genotype of FOS promoter SNPs showed an association with the susceptibility for knee-OA (odds ratio (OR) 2.12, 95% confidence interval (CI) 1.2–3.7, p = 0.0086). This association was successfully replicated in the Finnish Health 2000 study cohort (allelic OR 1.72, 95% CI 1.2–2.5, p = 0.006). FOS Promoter variants may represent relevant susceptibility markers for knee-OA

Allelic variants of <it>IL1R1 </it>gene associate with severe hand osteoarthritis

Abstract Background In search for genes predisposing to osteoarthritis (OA), several genome wide scans have provided evidence for linkage on 2q. In this study we targeted a 470 kb region on 2q11.2 presenting the locus with most evidence for linkage to severe OA of distal interphalangeal joints (DIP) in our genome wide scan families. Methods We genotyped 32 single nucleotide polymorphisms (SNPs) in this 470 kb region comprising six genes belonging to the interleukin 1 superfamily and monitored for association with individual SNPs and SNP haplotypes among severe familial hand OA cases (material extended from our previous linkage study; n = 134), unrelated end-stage bilateral primary knee OA cases (n = 113), and population based controls (n = 436). Results Four SNPs in the IL1R1 gene, mapping to a 125 kb LD block, provided evidence for association with hand OA in family-based and case-control analysis, the strongest association being with SNP rs2287047 (p-value = 0.0009). Conclusions This study demonstrates an association between severe hand OA and IL1R1 gene. This gene represents a highly relevant biological candidate since it encodes protein that is a known modulator of inflammatory processes associated with joint destruction and resides within a locus providing consistent evidence for linkage to hand OA. As the observed association did not fully explain the linkage obtained in the previous study, it is plausible that also other variants in this genome region predispose to hand OA.</p