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Background: Several single-nucleotide variants (SNVs) in collagen genes have been reported as predisposing factors for anterior cruciate ligament (ACL) tears. However, the evidence is conflicting and does not support a clear association between genetic variants and risk of ACL ruptures., Purpose: To assess the association of previously identified candidate SNVs in genes encoding for collagen and the risk of ACL injury in a population of elite female athletes from high-risk team sports., Study Design: Cohort study; Level of evidence, 2., Methods: A total of 851 female Norwegian and Finnish elite athletes from team sports were included from 2007 to 2011. ACL injuries acquired before inclusion in the cohort were registered by interview. The participants were followed prospectively through 2015 to record new complete ACL injuries. Six selected SNVs were genotyped ( COL1A1: rs1800012, rs1107946; COL3A1: rs1800255; COL5A1: rs12722, rs13946; COL12A1: rs970547)., Results: No associations were found between ACL rupture and the SNVs tested., Conclusion: The study does not support a role of the 6 selected SNVs in genes encoding for collagen proteins as risk factors for ACL injury., Clinical Relevance: Genetic profiling to identify athletes at high risk for ACL rupture is not yet feasible.

Study Design: Cross-sectional., Objectives: To evaluate the interaction between the COL9A3 gene polymorphism and persistent obesity in relation to lumbar disc degeneration., Summary of Background Data: Obesity has been suggested to be a risk factor for disc degeneration. There is some indication for an association between collagen IX genes and lumbar disc disease characterized by sciatica. However, the interaction between those factors in their influences on the risk of disc degeneration has not been studied., Methods: Blood samples from 135 middle-aged men who had undergone magnetic resonance imaging (MRI) of the lumbar spine were analyzed for the presence of an arginine to tryptophan change in the COL9A3 gene (Trp3 allele). The men represented three occupations: 41 were machine drivers, 42 were carpenters, and 52 were office workers. The discs L2/L3-L5/S1 were evaluated on MRI, using decreased signal intensity of the nucleus pulposus, posterior disc bulges, and decreased disc height as signs of disc degeneration. Based on self-reports on body height and weight currently and at the age of 25 years, obesity history was classified as no obesity, persistent obesity, and other. Rothman's synergy index was used as a measure of interaction between two factors., Results: The Trp3 allele and persistent obesity acted synergistically to increase the risk of dark nucleus pulposus, posterior disc bulge, and decreased disc height at L4/L5; of multilevel posterior disc bulges; and of decreased disc height. From 45% to 71% of disc degeneration among persistently obese individuals with the Trp3 allele could be attributed to the synergism of these two factors., Conclusion: The effect of obesity on lumbar disc degeneration seems to be modified by the collagen IX gene polymorphism, so that people who carry the Trp3 allele are at increased risk if they are persistently obese.

Context: Lumbar disk disease (LDD) is one of the most common musculoskeletal diseases, with a prevalence of about 5%. A tryptophan (Trp) allele (Trp2) was recently discovered in the COL9A2 gene that is associated with dominantly inherited LDD but is only present in about 4% of Finnish patients with LDD., Objective: To determine if other collagen IX gene sequence variations play a role in the pathogenesis of LDD., Design and Setting: Case-control study conducted from February 1997 to May 1998 at university hospitals in Finland., Participants: A total of 171 individuals with LDD (evaluated clinically and by magnetic resonance imaging or computed tomography) and 321 controls without LDD (186 healthy individuals, 83 patients with primary osteoarthritis, 31 with rheumatoid arthritis, and 21 with chondrodysplasias)., Main Outcome Measures: Frequencies of sequence variations covering the entire coding sequences and exon boundaries of the collagen IX genes, COL9A1, COL9A2, and COL9A3, which code for the alpha1, alpha2, and alpha3 chains of the protein, detected by conformation-sensitive gel electrophoresis and confirmed by sequencing, compared between individuals with and without LDD., Results: Mutation analysis of all 3 collagen IX genes resulted in identification of an Arg103-->Trp (arginine-->tryptophan) substitution in the alpha3 chain (Trp3 allele). The frequency of the Trp3 allele was 12.2% in LDD cases, excluding 7 individuals who were carriers of the previously identified Gln326-->Trp (glutamine-->tryptophan) substitution in the alpha2 chain (Trp2 allele), and was 4.7% among controls. The difference in the frequency was statistically significant (P =.000013). Presence of at least 1 Trp3 allele increases risk of LDD about 3-fold., Conclusion: This study led to the identification of a novel common genetic risk factor for LDD, confirming that genetic risk factors likely play a significant role in LDD.

Alport syndrome (AS) is a hereditary kidney disorder, mainly caused by mutations in the X-chromosomal gene (COL4A5) encoding the type IV collagen a5 chain. In this study, detection of COL4A5 mutations was performed in 17 Finnish Alport syndrome families. Regions around the 51 previously known exons, as well as the two recently characterized exons 41A and 41B in COL4A5, were PCR-amplified from the patient DNA. Direct sequencing of the amplified products was performed and mutations were found in 12 families. None of the mutations involved exons 41A or 41B. Three of the mutations were potential splicing mutations, two of which were studied at the mRNA level. Seven of the mutations were single base substitutions, and two were deletions. In five families, no mutations were found., (Copyright 2000 Wiley-Liss, Inc.)

Purpose: To describe the incidence and type of ocular findings of 34 patients with Alport syndrome and to analyze the association of gene defect in COL4A5 gene to ocular abnormalities found., Methods: A nationwide search of Alport syndrome patients was performed in Finland, and patients were invited to take part in a thorough ophthalmologic investigation., Results: A total of 34 Alport syndrome patients from 14 different pedigrees were examined, and ocular abnormalities were found in 32% of them. The visual acuities were normal except in 4 of the 34 patients. Six individuals had retinal flecks and 4 men had anterior lenticonus. In 57% of the pedigrees the defect in COL4A5 gene was known., Conclusion: Ocular abnormalities were rare in childhood and increased with age. There was no correlation between the type of mutation and the type of ocular changes. In addition, the penetrance of the ocular findings varied considerably within most families.

Generalized atrophic benign epidermolysis bullosa (GABEB) is a nonlethal variant of junctional epidermolysis bullosa (JEB). Previous findings have suggested that type XVII collagen is the candidate gene for mutations in this disease. We now have cloned the entire human type XVII collagen gene (COL17A1) and have elucidated its intron-exon organization. The gene comprises 56 distinct exons, which span approximately 52 kb of the genome, on the long arm of chromosome 10. It encodes a polypeptide, the alpha1(XVII) chain, consisting of an intracellular globular domain, a transmembrane segment, and an extracellular domain that contains 15 separate collagenous subdomains, the largest consisting of 242 amino acids. We also have developed a strategy to identify mutations in COL17A1 by use of PCR amplification of genomic DNA, using primers placed on the flanking introns. The PCR products are scanned for sequence variants by heteroduplex analysis using conformation-sensitive gel electrophoresis and then are subjected to direct automated sequencing. We have identified several intragenic polymorphisms in COL17A1, as well as mutations, in both alleles, in two Finnish families with GABEB. The probands in both families showed negative immunofluorescence staining with an anti-type XVII collagen antibody. In one family, the proband was homozygous for a 5-bp deletion, 2944del5, which resulted in frameshift and a premature termination codon of translation. The proband in the other family was a compound heterozygote, with one allele containing the 2944del5 mutation and the other containing a nonsense mutation, Q1023X. These results expand the mutation database in different variants of JEB, and they attest to the functional importance of type XVII collagen as a transmembrane component of the hemidesmosomes at the dermal/epidermal junction.

The congenital nephrotic syndrome of the Finnish type (CNF) is an autosomal recessive disease characterized by massive proteinuria already at birth. The gene locus defective in CNF was searched for using polymorphic markers of candidate genes coding for components of the basement membrane (BM). The linkage analyses in 17 Finnish CNF families demonstrated exclusion of obligatory recombination events between the disease and eight genes coding for BM components. The genes coding for the alpha 1(IV), alpha 2(IV), alpha 3(IV) and alpha 4(IV) chain of type IV collagen, the B1e, B2e and B2t chains of laminin, as well as the BM heparan sulfate proteoglycan core protein were all excluded in this Finnish family material. Since the defect is not in any of the genes coding for major components of BM, the identification of the gene defect will most probably reveal a new gene important for the development and function of the glomerular basement membrane.

The pro alpha 2(I) collagen gene has been screened for Bgl II restriction fragment length polymorphisms (RFLPs) in the Finnish population which has a long background of genetic isolation. As genetically isolated populations tend to demonstrate deviations in the degree of heterozygosity, the RFLP markers described in more heterogeneous populations can not be utilized as such in the former. This proved to be the case with Bgl II polymorphism within the pro alpha 2(I) collagen gene, the gene involved in different disorders of connective tissue. This report describes the presence of three new RFLP-loci and the absence of one RFLP-locus, which had been earlier reported from a population with a genetic background remote from the population studied here.

Restriction fragment length polymorphism (RFLP) of the cartilage-specific type II collagen gene has been studied in the Finnish population. Two high-frequency alleles, also reported in other populations, were detected. The HindIII allele had a frequency of 0.33, and that detected with PvuII a frequency of 0.46. Both of these frequencies resembled the ones reported for other populations. Also one BamHI allele, not earlier reported, was found at a low frequency. Two other previously reported polymorphisms for BamHI and EcoRI were not detected in the Finnish population. The RFLPs showed a fair agreement with the Hardy-Weinberg equilibrium. A linkage disequilibrium was found between PvuII and HindIII markers. The alpha 1(II) collagen gene seems to be more conserved in populations of various origins than the alpha 2(I) collagen gene. These polymorphic collagen markers would be useful in linkage studies of various inherited cartilage disorders.