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The A1330V polymorphism of the low-density lipoprotein receptor-related protein 5 gene (LRP5) associates with low peak bone mass in young healthy men.

https://arctichealth.org/en/permalink/ahliterature165637
Source
Bone. 2007 Apr;40(4):1006-12
Publication Type
Article
Date
Apr-2007
Author
Anne Saarinen
Ville-Valtteri Välimäki
Matti J Välimäki
Eliisa Löyttyniemi
Kirsi Auro
Piia Uusen
Mairi Kuris
Anna-Elina Lehesjoki
Outi Mäkitie
Author Affiliation
Folkhälsan Institute of Genetics and Department of Medical Genetics, University of Helsinki, Helsinki, Finland.
Source
Bone. 2007 Apr;40(4):1006-12
Date
Apr-2007
Language
English
Publication Type
Article
Keywords
Adolescent
Adult
Alleles
Bone Density - genetics
Calcifediol - blood
Finland
Fractures, Bone - etiology - genetics
Gene Frequency
Humans
LDL-Receptor Related Proteins - genetics
Low Density Lipoprotein Receptor-Related Protein-5
Male
Military Personnel
Osteoporosis - etiology - genetics
Parathyroid Hormone - blood
Polymorphism, Single Nucleotide
Risk factors
Abstract
Polymorphisms in the gene coding for low-density lipoprotein receptor-related protein 5 (LRP5) contribute to variation in bone mass in the general population. Whether this is due to influence on bone mass acquisition or on bone loss thereafter has not been established.
We studied the association of LRP5 polymorphisms with peak bone mass in young men. The study included 235 Finnish men, aged 18.3 to 20.6 years. Lifestyle factors and fracture history were recorded. Bone mineral content (BMC), density (BMD) and scan area were measured for the lumbar spine and proximal femur by dual energy X-ray absorptiometry (DXA). Blood and urine were collected for determination of bone turnover markers, serum 25-OHD and PTH. Genomic DNA was extracted from peripheral blood for genetic analysis of LRP5. Ten single nucleotide polymorphisms in LRP5 were analyzed and correlated with bone parameters.
Only the A1330V polymorphism of LRP5 significantly associated with bone parameters. In comparison with subjects with the AlaAla genotype (n=215), those with AlaVal genotype (n=20) had lower femoral neck BMC (P=0.029) and BMD (P=0.012), trochanter BMC (P=0.0067) and BMD (P=0.015), and total hip BMC (P=0.0044) and BMD (P=0.0089). Fracture history was similar for the genotypes.
The polymorphic valine variant at position 1330 of LRP5 was significantly associated with reduced BMC and BMD values in healthy young Finnish men. The results provide evidence for the crucial role of LRP5 in peak bone mass acquisition.
PubMed ID
17223614 View in PubMed
Less detail

Body composition and bone mineral density in children with premature adrenarche and the association of LRP5 gene polymorphisms with bone mineral density.

https://arctichealth.org/en/permalink/ahliterature148293
Source
J Clin Endocrinol Metab. 2009 Nov;94(11):4144-51
Publication Type
Article
Date
Nov-2009
Author
Pauliina Utriainen
Jarmo Jääskeläinen
Anne Saarinen
Esko Vanninen
Outi Mäkitie
Raimo Voutilainen
Author Affiliation
Departments of Pediatrics, University of Kuopio and Kuopio University Hospital, FI-70211 Kuopio, Finland. pauliina.utriainen@uku.fi
Source
J Clin Endocrinol Metab. 2009 Nov;94(11):4144-51
Date
Nov-2009
Language
English
Publication Type
Article
Keywords
Adrenarche - genetics
Body Composition
Bone Density - genetics
Child
Cross-Sectional Studies
Female
Femur Neck - anatomy & histology
Finland
Humans
LDL-Receptor Related Proteins - genetics
Low Density Lipoprotein Receptor-Related Protein-5
Male
Pituitary Gland - growth & development
Polymorphism, Genetic
Reference Values
Spine - anatomy & histology
Abstract
Precocious increase in adrenal androgen production is the hallmark of premature adrenarche (PA). Adrenal androgens have anabolic properties.
The objective of the study was to test whether body composition and bone mineral density (BMD) are altered in PA and study whether genetic variation in low-density lipoprotein receptor-related protein 5 (LRP5) affects BMD in PA.
This was a cross-sectional study.
The study was conducted at a university hospital.
The study included 126 prepubertal children (64 with PA, 10 boys; 62 non-PA controls, 10 boys). Femoral neck and lumbar spine areal and calculated volumetric BMD (dual energy X-ray absorptiometry), body composition (bioimpedance), serum 25-hydroxyvitamin D, and markers of bone turnover and calcium homeostasis were compared between the PA and control groups. Single-nucleotide polymorphisms of LRP5 were determined and associated with BMD.
Children with PA had higher femoral neck and lumbar spine BMD(areal) than the controls (Z-score 0.56 vs. -0.09, P
PubMed ID
19789208 View in PubMed
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Cerebroretinal microangiopathy with calcifications and cysts: characterization of the skeletal phenotype.

https://arctichealth.org/en/permalink/ahliterature134950
Source
Am J Med Genet A. 2011 Jun;155A(6):1322-8
Publication Type
Article
Date
Jun-2011
Author
Sanna Toiviainen-Salo
Tarja Linnankivi
Anne Saarinen
Mervi K Mäyränpää
Riitta Karikoski
Outi Mäkitie
Author Affiliation
Helsinki Medical Imaging Center, Helsinki University Hospital, Finland. sanna.toiviainen-salo@fimnet.fi
Source
Am J Med Genet A. 2011 Jun;155A(6):1322-8
Date
Jun-2011
Language
English
Publication Type
Article
Keywords
Bone Density
Bone Diseases, Metabolic - physiopathology
Bone and Bones - radiography
Calcinosis - pathology
Central Nervous System Cysts - pathology
DNA Mutational Analysis
Finland
Growth Disorders - physiopathology
Humans
LDL-Receptor Related Proteins - genetics
Leukoencephalopathies - pathology
Low Density Lipoprotein Receptor-Related Protein-5
Mutation - genetics
Phenotype
Retinal Vessels - abnormalities
Syndrome
Abstract
Cerebral cysts and calcifications with leukoencephalopathy and retinal vascular abnormalities are diagnostic hallmarks of cerebroretinal microangiopathy with calcifications and cysts (CRMCC). Previous studies have suggested that skeletal involvement is also common, but its characteristics remain unknown. This study aimed to assess the skeletal phenotype in CRMCC. All Finnish patients with features consistent with CRMCC and for whom radiographs were available were included. Clinical information pertinent to the skeletal phenotype was collected from hospital records, and all plain radiographs were reviewed for skeletal features. Bone mineral density (BMD) was measured by DXA. In one patient, bone biopsies were obtained for bone histology and histomorphometric analyses. The LRP5 gene was analyzed for mutations by direct sequencing. Our results show that the skeletal phenotype in CRMCC includes (1) compromised longitudinal growth pre- and postnatally, (2) generalized osteopenia or early onset low turnover osteoporosis with fragility fractures, and (3) metaphyseal abnormalities that may lead to limb deformities such as short femoral neck or genua valga. DXA measurements in three patients showed low BMD, and bone biopsies in the fourth patient with pathological fractures and impaired fracture healing showed low-turnover osteoporosis, with reduced osteoclast and osteoblast activity. Direct sequencing of all LRP5 coding exons and exon-intron boundaries in six patients with CRMCC revealed no putative mutations. We conclude that the CRMCC-associated bone disease is characterized by low BMD and pathological fractures with delayed healing, metaphyseal changes, and short stature pre- and postnatally. LRP5 is not a disease-causing gene in CRMCC.
PubMed ID
21523908 View in PubMed
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[Familial hypercholesterolemia in Russia: genetic and phenotypic characteristics].

https://arctichealth.org/en/permalink/ahliterature147970
Source
Ter Arkh. 2009;81(9):23-8
Publication Type
Article
Date
2009
Author
A N Meshkov
P P Malyshev
V V Kukharchuk
Source
Ter Arkh. 2009;81(9):23-8
Date
2009
Language
Russian
Publication Type
Article
Keywords
Adult
Apolipoproteins B - genetics
Cardiovascular Diseases - etiology
Cholesterol - blood
Female
Heterozygote
Humans
Hypercholesterolemia - complications - epidemiology - genetics - metabolism
Incidence
LDL-Receptor Related Proteins - genetics
Lipid Metabolism - genetics
Male
Middle Aged
Mutation - genetics
Pedigree
Polymorphism, Genetic
Russia - epidemiology
Abstract
To make qualitative and quantitative analyses of phenotypical characteristics and to study a spectrum and frequency of mutations in LDLR and APOB genes in patients with familial heterozygous hypercholesterolemia (FHHC).
Clinical symptoms of FHHC were studied in males and females. Mutations were detected with PCR, analysis of SSCP of all the exones of LDLR gene and a fragment of exone 26 of APOB gene with subsequent sequestration of DNA fragments with anomalous electrophoretic motility, analysis of restriction fragments length polymorphism.
LDLR gene mutations were detected in 50%, of APOB gene in 2.6% patients with FHHC, 70% of LDLR gene mutations have never been discovered before. Three known mutations were detected in the APOB gene: R3500Q (1.9% cases), H3543Y (0.55%), R3531C (0.15%). Incidence of coronary heart disease in untreated FHHC patients is 61.5%, of myocardial infarction--31%. Life span of both males and females with FHHC was subnormal, especially of men (median: 53 years in 95% CI, 49.2-56.8 years and 62 years in 95% CI 59.2-64.8 years, respectively). Incidence rate of basic clinical symptoms increased with age and significantly correlated with LDLP cholesterol.
Frequency and severity of clinical symptoms and complications in FHHC and in Russian population agree with those of the European countries. The same occurs with frequency and mutations of the APOB gene, while mutations of the LDLR gene in 70% cases are unique for Russian population and are not described in other countries. This makes impossible to use foreign test kits for FHHC diagnosis in Russia.
PubMed ID
19827648 View in PubMed
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Heterozygous mutations in the LDL receptor-related protein 5 (LRP5) gene are associated with primary osteoporosis in children.

https://arctichealth.org/en/permalink/ahliterature29774
Source
J Bone Miner Res. 2005 May;20(5):783-9
Publication Type
Article
Date
May-2005
Author
Heini Hartikka
Outi Mäkitie
Minna Männikkö
Andrea S Doria
Alan Daneman
William G Cole
Leena Ala-Kokko
Etienne B Sochett
Author Affiliation
Collagen Research Unit, Biocenter and Department of Medical Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland.
Source
J Bone Miner Res. 2005 May;20(5):783-9
Date
May-2005
Language
English
Publication Type
Article
Keywords
Adolescent
Child
Collagen - genetics
Collagen Type I - genetics
Female
Frameshift Mutation
Heterozygote
Humans
LDL-Receptor Related Proteins - genetics
Male
Models, Genetic
Mutation
Mutation, Missense
Osteogenesis Imperfecta - blood - genetics
Osteoporosis - genetics
Phenotype
RNA - metabolism
Research Support, Non-U.S. Gov't
Reverse Transcriptase Polymerase Chain Reaction
Variation (Genetics)
Abstract
Three of 20 patients with juvenile osteoporosis were found to have a heterozygous mutation in the LRP5 gene. No mutations were found in the type I collagen genes. Mutations in the other family members with similar bone phenotype confirmed that LRP5 has a role in both juvenile and adult osteoporosis. INTRODUCTION: The gene encoding the low-density lipoprotein receptor-related protein 5 (LRP5) gene has recently been shown to affect bone mass accrual during growth and to be involved in osteoporosis-pseudoglioma syndrome and a high bone mass phenotype. Mutations in the type I collagen genes (COL1A1 and COL1A2) are known to cause osteogenesis imperfecta, characterized by increased bone fragility. MATERIALS AND METHODS: Here we analyzed COL1A1, COL1A2, and LRP5 for mutations in 20 pediatric patients with primary osteoporosis characterized by low BMD, recurrent fractures, and absent extraskeletal manifestations. RESULTS AND CONCLUSIONS: No mutations were detected in the type I collagen genes, but two missense mutations (A29T and R1036Q) and one frameshift mutation (C913fs) were found in the LRP5 gene in three of the patients. The frameshift mutation was also seen in the proband's father and brother, who both were found to have significant osteoporosis. R1036Q was observed in the proband's mother and two brothers, who all had osteoporosis. These results indicate that heterozygous mutations in the LRP5 gene can cause osteoporosis in both children and adults.
PubMed ID
15824851 View in PubMed
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LRP5 coding polymorphisms influence the variation of peak bone mass in a normal population of French-Canadian women.

https://arctichealth.org/en/permalink/ahliterature165096
Source
Bone. 2007 May;40(5):1299-307
Publication Type
Article
Date
May-2007
Author
Sylvie Giroux
Latifa Elfassihi
Guy Cardinal
Nathalie Laflamme
François Rousseau
Author Affiliation
Unité de Recherche en Génétique Humaine et Moléculaire, Centre de Recherche de l'Hôpital St-François d'Assise du Centre Hospitalier Universitaire de Québec, Québec, Canada G1L 3L5.
Source
Bone. 2007 May;40(5):1299-307
Date
May-2007
Language
English
Publication Type
Article
Keywords
Adult
Aged
Aged, 80 and over
Bone Density - drug effects - genetics - physiology
Canada - ethnology
Female
France - ethnology
Haplotypes
Hormones - therapeutic use
Humans
LDL-Receptor Related Proteins - genetics
Low Density Lipoprotein Receptor-Related Protein-5
Menopause
Middle Aged
Polymorphism, Genetic - genetics
Abstract
Bone mineral density has a strong genetic component but it is also influenced by environmental factors making it a complex trait to study. LRP5 gene was previously shown to be involved in rare diseases affecting bone mass. Mutations associated with gain-of-function were described as well as loss-of-function mutations. Following this discovery, many frequent LRP5 polymorphisms were tested against the variation of BMD in the normal population.
Heel bone parameters (SOS, BUA) were measured by right calcaneal QUS in 5021 healthy French-Canadian women and for 2104 women, BMD evaluated by DXA at two sites was available (femoral neck (FN) and lumbar spine (LS)). Among women with QUS measures and those with DXA measures, 26.5% and 32.8% respectively were premenopausal, 9.2% and 10.7% were perimenopausal and 64.2% and 56.5% were postmenopausal. About a third of the peri- and postmenopausal women never received hormone therapy. Two single nucleotide coding polymorphisms (Val667Met and Ala1330Val) in LRP5 gene were genotyped by allele-specific PCR. All bone measures were tested individually for associations with each polymorphism by analysis of covariance with adjustment for non genetic risk factors. Furthermore, haplotype analysis was performed to take into account the strong linkage disequilibrium between the two polymorphisms.
The two LRP5 polymorphisms were found to be associated with all five bone measures (L2L4 and femoral neck DXA as well as heel SOS, BUA and stiffness index) in the whole sample. Premenopausal women drove the association as expected from the proposed role of LRP5 in peak bone mass. Our results suggest that the Val667Met polymorphism is the causative variant but this remains to be functionally proven.
PubMed ID
17307038 View in PubMed
Less detail

LRP5 in premature adrenarche and in metabolic characteristics of prepubertal children.

https://arctichealth.org/en/permalink/ahliterature155539
Source
Clin Endocrinol (Oxf). 2009 May;70(5):725-31
Publication Type
Article
Date
May-2009
Author
Saila Lappalainen
Anne Saarinen
Pauliina Utriainen
Raimo Voutilainen
Jarmo Jääskeläinen
Outi Mäkitie
Author Affiliation
Department of Paediatrics, Kuopio University and University Hospital, Kuopio, Finland. saila.lappalainen@uku.fi
Source
Clin Endocrinol (Oxf). 2009 May;70(5):725-31
Date
May-2009
Language
English
Publication Type
Article
Keywords
Adrenarche - genetics - metabolism
Alleles
Case-Control Studies
Child
Cross-Sectional Studies
Female
Finland
Gene Frequency
Genetic Predisposition to Disease
Genetic Variation
Genotype
Humans
LDL-Receptor Related Proteins - genetics
Lipids - blood
Low Density Lipoprotein Receptor-Related Protein-5
Male
Metabolic Syndrome X - etiology - genetics - metabolism
Phenotype
Polymorphism, Single Nucleotide
Signal Transduction
Wnt Proteins - metabolism
Abstract
Premature adrenarche (PA) is associated with unfavourable metabolic characteristics. We hypothesized that genetic variation in low density lipoprotein (LDL) receptor-related protein 5 (LRP5), which is involved in Wnt signalling in the adrenal cortex and in cholesterol metabolism, plays a role in the pathogenesis of PA.
We performed a cross-sectional association study in 73 Finnish children with PA and 97 age- and gender-matched healthy controls.
LRP5 genotypes were determined by direct sequencing. Single-marker associations with clinical-metabolic characteristics, including adrenocortical function, glucose tolerance and lipid profile, were examined with age and gender as covariates.
Nineteen single nucleotide polymorphisms (SNPs) in LRP5 were found in the 170 children. No significant differences in the genotype distributions were observed between the PA and control groups. SNPs A1330V and N740N were associated with higher serum dehydroepiandrosterone sulphate (DHEAS) levels in the control subjects (A/A vs. A/a; mean 0.8 vs. 1.4 micromol/l, P = 0.01). They were also associated with higher plasma levels of total (4.2 vs. 4.7 mmol/l, P = 0.02) and LDL cholesterol (2.4 vs. 2.9 mmol/l, P = 0.02) in the control group, as was SNP V1119V (P = 0.04 and P = 0.03, respectively). SNPs F549F and V1119V were associated with higher systolic blood pressure (P = 0.04 and P = 0.02, respectively). There were no differences in the parameters of glucose metabolism between the genotype groups.
Genetic variation in LRP5 did not predispose to PA but was associated with metabolic characteristics, especially lipid profile, in healthy prepubertal children.
PubMed ID
18721193 View in PubMed
Less detail

No association between hip geometry and four common polymorphisms associated with fracture: the Danish osteoporosis prevention study.

https://arctichealth.org/en/permalink/ahliterature89978
Source
Calcif Tissue Int. 2009 Apr;84(4):276-85
Publication Type
Article
Date
Apr-2009
Author
Nissen N.
Madsen J S
Bladbjerg E M
Beck Jensen J E
Jørgensen N R
Langdahl B.
Abrahamsen B.
Brixen K.
Author Affiliation
Department of Endocrinology, Odense University Hospital, University of Southern Denmark, Odense, 5000, Odense C, Denmark. hra@dadlnet.dk
Source
Calcif Tissue Int. 2009 Apr;84(4):276-85
Date
Apr-2009
Language
English
Publication Type
Article
Keywords
Adult
Anthropometry
Body Weights and Measures
Bone Density - genetics
Cross-Sectional Studies
Denmark - epidemiology
Female
Femoral Neck Fractures - epidemiology - etiology - genetics
Gene Frequency
Genetic Predisposition to Disease
Genotype
Hip - anatomy & histology
Hip Fractures - epidemiology - etiology - genetics
Humans
LDL-Receptor Related Proteins - genetics
Methylenetetrahydrofolate Reductase (NADPH2) - genetics
Middle Aged
Osteoporosis, Postmenopausal - complications
Polymorphism, Genetic
Receptors, Purinergic P2 - genetics
Risk assessment
Abstract
Both osteoporosis and hip geometry are independently associated with fracture risk. There is a significant genetic contribution to the risk of osteoporosis, and evidence provided by twin studies has suggested that hip geometry may also in part be genetically programmed. Polymorphisms in a number of genes, including those coding for methylene-tetrahydrofolate reductase (MTHFR c.677C > T), the purinergic P2X(7) receptor (Glu496Ala and Ile568Asn), and the low-density lipoprotein receptor-related protein 5 (LRP5 exon 9 [c.266A > G]), have been associated with an increased fracture incidence and/or reduced bone mineral density (BMD). The aim of the present study was to test whether these polymorphisms influence hip structural geometry in perimenopausal women. The four polymorphisms were genotyped in 800 healthy recently perimenopausal women never using hormone replacement therapy. BMD of the femoral neck was measured using a Hologic QDR-2000 densitometer and femoral neck axis length, neck width, neck shaft angle, and femoral head diameter were measured from the screen images. Genotype frequencies were compatible with Hardy-Weinberg equilibrium. No significant differences between homozygotes for the minor allele and carriers of the common allele regarding parameters of hip geometry were demonstrated. According to the anthropometric characteristics of the subjects, only body height in the MTHFR TT genotype group was significantly different from the combined CT/CC genotype group (P T, P2X(7) (Glu496Ala), P2X(7) (Ile568Asn), and LRP5 exon 9 (c.266A > G) polymorphisms.
PubMed ID
19225709 View in PubMed
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Sequence variation in SORL1 and dementia risk in Swedes.

https://arctichealth.org/en/permalink/ahliterature98953
Source
Neurogenetics. 2010 Feb;11(1):139-42
Publication Type
Article
Date
Feb-2010
Author
Chandra A Reynolds
Mun-Gwan Hong
Ulrika K Eriksson
Kaj Blennow
Boo Johansson
Bo Malmberg
Stig Berg
Margaret Gatz
Nancy L Pedersen
Anna M Bennet
Jonathan A Prince
Author Affiliation
Department of Psychology, University of California at Riverside, Riverside, CA 92521, USA.
Source
Neurogenetics. 2010 Feb;11(1):139-42
Date
Feb-2010
Language
English
Publication Type
Article
Keywords
Alzheimer Disease - ethnology - genetics
Dementia - genetics
Genetic markers
Genetic Predisposition to Disease
Genetic Variation
Haplotypes
Humans
LDL-Receptor Related Proteins - genetics
Linkage Disequilibrium
Membrane Transport Proteins - genetics
Models, Genetic
Quantitative Trait Loci
Risk
Sweden
Abstract
The gene encoding the neuronal sortilin-related receptor SORL1 has been claimed to be associated with Alzheimer's disease (AD) by independent groups and across various human populations. We evaluated six genetic markers in SORL1 in a sample of 1,558 Swedish dementia cases (including 1,270 AD cases) and 2,179 controls. For both single-marker-based and haplotype-based analyses, we found no strong support for SORL1 as a dementia or AD risk-modifying gene in our sample in isolation nor did we observe association with AD/dementia-related traits, including cerebrospinal fluid beta-amyloid(1-42), tau levels, or age at onset. However, meta-analyses of markers in this study together with previously published studies on SORL1 encompassing in excess of 13,000 individuals does suggest significant association with AD (best odds ratio = 1.097; 95% confidence interval = 1.038-1.158, p = 0.001). All six markers were significant in meta-analyses and it is notable that they occur in two distinct linkage disequilibrium blocks. These data are consistent with either allelic heterogeneity or the existence of as yet untested functional variants and these will be important considerations in further attempts to evaluate the importance of sequence variation in SORL1 with AD risk.
PubMed ID
19653016 View in PubMed
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9 records – page 1 of 1.