Reproducible genetic associations between candidate genes and clinical knee osteoarthritis in men and women

Valdes, Ana M.; Oene, Mark Van; Hart, Deborah; Surdulescu, Gabriela L.; Loughlin, John; Doherty, Michael; Spector, Tim D.

doi:10.1002/art.21621

Cited by 157 publications

(122 citation statements)

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“…These include age, sex, genetics, ethnicity, behavioral influences, obesity and occupation 17. A genetic contribution to OA has been suggested in several epidemiologic and other studies 31819. The genetics of OA are complex and not completely understood.…”

Section: Discussionmentioning

confidence: 99%

Prevalence of the Pro12Ala missense mutation in the PPARG2 gene in Kuwaiti patients with primary knee osteoarthritis

Al-Jarallah

Shehab

Haider

2011

Annals of Saudi Medicine

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BACKGROUND AND OBJECTIVES:Peroxisome proliferator–activated receptors (PPARs) play an important role in a number of cellular and metabolic functions. This study was carried out to determine the prevalence of a missense mutation (Pro12Ala) in the PPARG2 gene in Kuwaiti Arab patients with primary knee osteoarthritis (OA) and healthy controls with the aim of identifying a possible association.DESIGN AND SETTING:A prospective cross-sectional study carried out at three major teaching hospitals (referral centers) in the country over a one-year period.PATIENTS AND METHODS:The prevalence of PPARG2 gene Pro12Ala missense mutation was determined in 104 Kuwaiti Arab patients with primary knee OA and 111 ethnically matched healthy controls. The prevalence of this Pro12Ala missense mutation was also determined in clinical subgroups of OA patients divided on the basis of age at onset, function and radiologic grading.RESULTSThe Pro-Pro genotype of the PPARG2 gene Pro12Ala missense mutation was detected in 95/104 (91.3%) cases compared to 111/111 (100%) in the control subjects. The heterozygous Pro-Ala genotype was detected in 9/104 (8.7%) of the OA patients, while it was not detected in any of the controls. The Ala-Ala genotype was not detected in any of the OA patients or the controls. No significant differences were detected in the PPARG2 gene Pro12Ala genotypes in the subgroups of patients classified on the basis of age at onset, functional assessment using Lequesne’s functional index, and radiological grading using Kellgren-Lawrence (K-L) grading.CONCLUSIONSThis study found no significant association between the PPARG2 gene Pro12Ala missense mutation and knee OA. However, the presence of the Pro-Pro genotype of the PPARG2 gene mutation has a protective effect against development of OA.

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Section: Discussionmentioning

confidence: 99%

Prevalence of the Pro12Ala missense mutation in the PPARG2 gene in Kuwaiti patients with primary knee osteoarthritis

Al-Jarallah

Shehab

Haider

2011

Annals of Saudi Medicine

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“…In cartilage, BMP-2 has both anabolic and catabolic effects by stimulating expression of ECM proteins, such as collagen type II, and matrix degrading enzymes, such as MMPs (Blaney Davidson et al 2007; van der Kraan et al 2010). Single-nucleotide polymorphisms (SNPs) in BMP2 were found in OA patients but their functional relevance is unknown (Valdes et al 2004(Valdes et al , 2006. The expression levels of BMP7 decline with increasing age and with progression of OA (Chubinskaya et al 2002), and the expression domains of GDF5 and GDF6 expand in adult human OA articular cartilage (Erlacher et al 1998).…”

Section: Dysregulation Of Tgf-b or Bmp Signaling In Catabolic Bone DImentioning

confidence: 99%

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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The transforming growth factor b (TGF-b) family of signaling molecules, which includes TGF-bs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-b family members play different roles in these tissues, and their activities are often balanced with those of other TGF-b family members and by interactions with other signaling pathways. Perturbations in TGF-b family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-b family of signaling mediators and the extracellular matrix in connective tissues.T he transforming growth factor b (TGF-b) family of cytokines comprises the three TGF-b proteins (TGF-b1, TGF-b2, and TGFb3) and related growth and differentiation factors such as activins, inhibins, bone morphogenic proteins (BMPs), and growth and differentiation factors (GDFs). These molecules play critical roles both in normal development and in several pathological conditions, including inflammation, fibrosis, and cancer (reviewed in Li and Flavell 2006;Gordon and Blobe 2008;Ikushima and Miyazono 2010). This review focuses on the role of these proteins in development and homeostasis of the skeleton and other connective tissues (summarized in Fig. 1) and on the diseases that ensue when these pathways are altered. Aberrant signaling in these pathways has been associated with common connective 6 These authors contributed equally to this work.

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“…Three possible reasons accounting for the inconsistency of results are the different ethnicities of the subjects investigated, the sites of OA that were chosen, and the sex of the patients and controls. We recently reported that genetic associations with knee OA are strongly influenced by sex (32). In the current study, we assessed genetic variants in the above-mentioned 5 genes in an ethnically homogeneous cohort of patients with knee OA, analyzing men and women separately.…”

mentioning

confidence: 96%

Sex and ethnic differences in the association of ASPN, CALM1, COL2A1, COMP, and FRZB with genetic susceptibility to osteoarthritis of the knee

Valdes

Loughlin

Oene

et al. 2007

Arthritis & Rheumatism

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Objective. To assess whether the association of genetic polymorphisms with osteoarthritis (OA) in other populations could be replicated in a large, multicenter, mixed-sex, case-control study of clinical knee OA.Methods. Genetic polymorphisms in OA candidate genes were genotyped in 298 men and 305 women, ages 50-86 years, all of whom had a diagnosis of knee OA as assessed clinically and radiographically, and in 300 male and 299 female control subjects matched for age and ethnicity. Allele and haplotype frequencies for 5 genes (ASPN, CALM1, COL2A1, COMP, and FRZB) previously tested for association with hip and/or knee OA in other populations were compared between patients and control subjects, analyzing men and women separately.Results. The same FRZB 2-marker single-nucleotide polymorphism (SNP) haplotype associated with hip OA in other populations of Caucasian women was shown to increase the risk of knee OA among the women (but not the men) in the current study (odds ratio [OR] 2.87, P < 0.04). The CALM1 SNP, which affects the risk of hip OA in Japanese individuals, was not shown to be associated with susceptibility to OA in men or women. COL2A1 haplotypes were demonstrated to be associated with a decreased risk of knee OA in men (OR 0.68, P < 0.005) but not in women. COMP haplotypes that were associated with susceptibility to knee OA were different in men and women (P < 0.014 and P < 0.032, respectively). A meta-analysis of these data and those from previously published reports indicated a strong association between the FRZB G324 allele (P < 0.0003) and suggested that an ASPN allele is protective against the risk of knee OA in Caucasians (P < 0.02).Conclusion. Our results indicate that genetic polymorphisms affecting knee OA vary between populations (Japanese versus Caucasian) and sexes and indicate a role for ASPN, COMP, FRZB, and COL2A1 in Caucasians.

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Reproducible genetic associations between candidate genes and clinical knee osteoarthritis in men and women

Cited by 157 publications

References 15 publications

Prevalence of the Pro12Ala missense mutation in the PPARG2 gene in Kuwaiti patients with primary knee osteoarthritis

Prevalence of the Pro12Ala missense mutation in the PPARG2 gene in Kuwaiti patients with primary knee osteoarthritis

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

Sex and ethnic differences in the association of ASPN, CALM1, COL2A1, COMP, and FRZB with genetic susceptibility to osteoarthritis of the knee

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