Genetic Susceptibility to Common Musculoskeletal Diseases

Project Leader: Docent Minna Männikkö, Ph.D.
Institute of Health Sciences, Faculty of Medicine and Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, University of Oulu


Background and Significance

Osteoarthritis (OA) is the most common degenerative disease worldwide. It is characterized by progressive degradation of articular cartilage that leads to joint space narrowing, subchondral sclerosis, osteophyte and cyst formation, and eventually loss of joint function. In Finland the Health 2000 national survey indicated a prevalence of 6.1% in men and 8.0% in women for clinically diagnosed knee OA. Certain forms of OA have long been known to have a genetic component. Recent studies have confirmed these findings and indicated a significant role for genetic factors in primary OA. Degeneration of the lumbar spine has a prevalence of about 5% in the Finnish population. Early epidemiological studies suggested that low back syndromes are mainly caused by environmental and anthropometric factors such as occupational load, back injuries, height and obesity. However, considerable familial predisposition to early onset sciatica and disc herniation has been shown, and more recent epidemiological studies indicate that disc degeneration may be explained primarily by genetic influences.

Osteoporosis (OP) in adults can be regarded as a complex disease with high social and economic costs and its diagnosis is focused on the assessment of bone mineral density (BMD). Every year over 7500 hip fractures occur in Finland, resulting in an annual cost of 45 million euros. There are numerous risk factors described in OP, the most significant being low bone mass, age and being female. In general, risk factor scores show poor specificity and sensitivity as regards the prediction of OP and fracture risk, and some risk factors vary significantly with age. Twin studies indicate that genetic factors account for up to 80% of peak bone mass. Studies of candidate genes for OP have been focused on cytokines, growth factors that regulate bone turnover, genes that encode components of bone matrix, and genes encoding receptors for calciotropic hormones. The common form of OP is considered to be multifactorial, arising from the interaction of common polymorphic alleles with multiple environmental factors.

In addition to studies of genetic susceptibility to common musculoskeletal diseases, we participate in the molecular diagnostics of Stickler (OMIM 108300, 604841, 184840) and Marshall (OMIM 154780) syndromes as part of the European Skeletal Dysplasia Network ( These are clinically overlapping dominantly inherited disorders characterised by midfacial hypoplasia, high-degree myopia and a sensorineural hearing deficit. Stickler syndrome is classified into three subtypes based on ocular phenotype, and molecular linkage and mutations are found in at least three genes (COL2A1, COL11A1 and COL11A2). In the area of common disorders affecting hearing, we are interested in genetic susceptibility to Ménière’s disease (MD), an inner ear condition with vertigo, tinnitus and sensorineural hearing loss.

Recent Progress

There is strong evidence that inflammatory mediators perpetuate disease progression in OA. In our previous candidate gene studies we have observed that a certain interleukin 6 (IL-6) promoter haplotype is associated with the severity of the symptoms in hand and lumbar spine OA (Kämäräinen et al. 2008; Karppinen et al. 2008a; Karppinen et al. 2008b). We have also observed that genetic variations in the interleukin-1 (IL-1) cluster and the matrix metalloproteinase-3 (MMP-3) gene together associate significantly with type II modic changes and specific bone marrow lesions visible in magnetic resonance imaging (MRI), and are strongly related to lower back pain (Karppinen et al. 2008b). Degeneration of the lumbar spine is a common condition that progresses with aging, but it has also been shown to be already frequent among young adults. We observed in a subpopulation of the NFBC1986 that the IL6 promoter variants also increased the risk of spinal degeneration (Kelempisioti et al. 2011). We have also investigated the role of environmental factors, low back pain history and sciatica symptoms in this subpopulation and showed that sciatica symptoms were already common in young adulthood (Karjalainen et al. 2013).

In a collaborative study we identified the gene for carbohydrate sulphotransferase 3 (CHST3), an enzyme that catalyzes proteoglycan sulphation, to be a susceptibility gene as regards lumbar disc degeneration (Song et al. 2013). The initial finding came through linkage studies in Southern Chinese families, and further association analyses in a multi-ethnic population of 32,642 subjects indicated a variant that lies within a potential microRNA-513a-5p binding site. Functional studies showed that interaction of the susceptibility allele with the microRNA was enhanced, and that CHST3 mRNA was significantly reduced in the intervertebral disc cells of human subjects carrying this allele (Song et al. 2013).

Ménière’s disease is an inner ear condition with vertigo, tinnitus and sensorineural hearing loss. Only a handful of systematic studies exist on the familial form of the disease (FMD), and therefore more detailed information about FMD and its prevalence is needed in order to provide the patients with accurate information about the heredity of MD, to provide genetic counselling to patients affected with FMD, and to design future genetic studies. In recent years we have studied the prevalence of FMD in Northern Finland, including all the patients treated at Oulu University Hospital and Kainuu Central Hospital during the years 2005–2010 (n=640). We confirmed a family history of the disease in 9.3% of the patients, but 32.7% of them reported Ménière-like symptoms in their families (Hietikko et al. 2013). Multiple candidate genes have been presented for MD, but to date no positive replications have been reported. Our review on the candidate genes reported so far showed that current understanding of the genetic factors contributing to the development of MD is very limited, and no association with these genes was seen in the Finnish MD patients (Hietikko et al. 2012). Given that the aetiology of the disease is not known, novel genetic approaches, especially in cases of FMD, may bring knowledge of the pathways involved in the disease mechanisms.

Future Goals

Our main goal is to identify metabolic pathways defective in musculoskeletal diseases, by using genetic approaches. Although genome-wide association studies (GWASs) have revealed several interesting predisposing candidate genes for OA, they all indicate relatively low individual risk. These studies are also complicated by clinical and genetic heterogeneity and the contribution of numerous rare alleles that are not identified in GWASs. We will apply next-generation sequencing techniques to identify rare variants with high genetic impact on these common musculoskeletal diseases, using well defined phenotypes in both population and family cohorts. We will use a combination of in silico, in vitro and in cellulo methodologies to demonstrate causality of the genetic variants on the disease state and to study the underlying molecular mechanisms.

Publications 2014-

Eskola P, Männikkö M, Samartzis D, Karppinen J. Genome-wide association studies of lumbar disc degeneration -are we there yet? Spine J 14:479-482, 2014.

Hietikko E, Sorri M, Männikkö M, Kotimäki J. Higher prevalence of autoimmune diseases and longer spells of vertigo in patients affected with familial Meniere's disease -a clinical comparison of familial and sporadic Meniere's disease. Am J Audiol. 23:232-7, 2014.

Research Group Members

Project Leader:
Minna Männikkö, Ph.D., Docent (University of Oulu)

Senior and Post-doctoral Investigators:
Pasi Eskola, M.D., Ph.D., (University of Oulu)
Elina Hietikko, M.D., Ph.D. (Biocenter Oulu and University of Oulu)

Ph.D. Students:
Anthi Kelempisioti, M.Sc. (Biocenter Oulu and University of Oulu)
Minna Kraatari, Med.Cand. (University of Oulu)
Marika Löija, M.D. (Biocenter Oulu and University of Oulu)
Eeva Nevala, M.Sc. (University of Oulu)
Sini Skarp, M.Sc. (Biocenter Oulu and University of Oulu)
Mari Taipale, M.Sc. (Biocenter Oulu Doctoral Programme)
Maiju Welling, Med.Cand. (University of Oulu)

Laboratory Technicians, 2 (University of Oulu)

Main source of salary in brackets.

Last updated: 23.3.2016