Promoter and 3'-untranslated-region haplotypes in the vitamin d receptor gene predispose to osteoporotic fracture: the rotterdam study.

Abstract:

:Polymorphisms of the vitamin D receptor gene (VDR) have been shown to be associated with several complex diseases, including osteoporosis, but the mechanisms are unknown and study results have been inconsistent. We therefore determined sequence variation across the major relevant parts of VDR, including construction of linkage disequilibrium blocks and identification of haplotype alleles. We analyzed 15 haplotype-tagging SNPs in relation to 937 clinical fractures recorded in 6,148 elderly whites over a follow-up period of 7.4 years. Haplotype alleles of the 5' 1a/1e, 1b promoter region and of the 3' untranslated region (UTR) were strongly associated with increased fracture risk. For the 16% of subjects who had risk genotypes at both regions, their risk increased 48% for clinical fractures (P = .0002), independent of age, sex, height, weight, and bone mineral density. The population-attributable risk varied between 1% and 12% for each block and was 4% for the combined VDR risk genotypes. Functional analysis of the variants demonstrated 53% lower expression of a reporter construct with the 1e/1a promoter risk haplotype (P = 5 x 10(-7)) in two cell lines and 15% lower mRNA level of VDR expression constructs carrying 3'-UTR risk haplotype 1 in five cell lines (P = 2 x 10(-6)). In a further analysis, we showed 30% increased mRNA decay in an osteoblast cell line for the construct carrying the 3'-UTR risk haplotype (P = .02). This comprehensive candidate-gene analysis demonstrates that the risk allele of multiple VDR polymorphisms results in lower VDR mRNA levels. This could impact the vitamin D signaling efficiency and might contribute to the increased fracture risk we observed for these risk haplotype alleles.

journal_name

Am J Hum Genet

authors

Fang Y,van Meurs JB,d'Alesio A,Jhamai M,Zhao H,Rivadeneira F,Hofman A,van Leeuwen JP,Jehan F,Pols HA,Uitterlinden AG

doi

10.1086/497438

subject

Has Abstract

pub_date

2005-11-01 00:00:00

pages

807-23

issue

5

eissn

0002-9297

issn

1537-6605

pii

S0002-9297(07)63362-X

journal_volume

77

pub_type

杂志文章
  • Analysis of deoxyribonucleic acid replication in human X chromosomes by fluorescence microscopy.

    abstract::The genetically inactive, late-replicating human female X chromosome can be effectively distinguished from its more active, earlier-replicating homologue, when cells are grown according to the appropriate BrdU-33258 Hoechst protocol. Results obtained from a fluorescence analysis of DNA replication in X chromosomes are...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Willard HF,Latt SA

    更新日期:1976-05-01 00:00:00

  • Huntington disease phenocopy is a familial prion disease.

    abstract::Huntington disease (HD) is a common autosomal dominant neurodegenerative disease with early adult-onset motor abnormalities and dementia. Many studies of HD show that huntingtin (CAG)n repeat-expansion length is a sensitive and specific marker for HD. However, there are a significant number of examples of HD in the ab...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/324414

    authors: Moore RC,Xiang F,Monaghan J,Han D,Zhang Z,Edström L,Anvret M,Prusiner SB

    更新日期:2001-12-01 00:00:00

  • Linkage of otopalatodigital syndrome type 2 (OPD2) to distal Xq28: evidence for allelism with OPD1.

    abstract::Otopalatodigital syndrome type 1 (OPD1) is an X-linked semidominant condition characterized by malformations of the skeleton, auditory apparatus, and palate. Previous studies have established linkage to a 16-cM region of Xq27-q28. A proposed allelic variant of OPD1, termed "OPD2," is associated with a more severe, fre...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/321280

    authors: Robertson SP,Walsh S,Oldridge M,Gunn T,Becroft D,Wilkie AO

    更新日期:2001-07-01 00:00:00

  • Age trends in human chiasma frequencies and recombination fractions. I. Chiasma frequencies.

    abstract::Chiasma frequency data on 183 males were subjected to an analysis of covariance. There appeared to be little or no linear trend in chiasma frequency with age. This conclusion was supported by a detailed analysis of chiasma frequencies for each autosome from 21 males. There were, however, significant differences among ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Lange K,Page BM,Elston RC

    更新日期:1975-05-01 00:00:00

  • Homozygous Mutations in WEE2 Cause Fertilization Failure and Female Infertility.

    abstract::Fertilization is a fundamental process of development and is a prerequisite for successful human reproduction. In mice, although several receptor proteins have been shown to play important roles in the process of fertilization, only three genes have been shown to cause fertilization failure and infertility when delete...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2018.02.015

    authors: Sang Q,Li B,Kuang Y,Wang X,Zhang Z,Chen B,Wu L,Lyu Q,Fu Y,Yan Z,Mao X,Xu Y,Mu J,Li Q,Jin L,He L,Wang L

    更新日期:2018-04-05 00:00:00

  • Effect of reproductive compensation and the desire to have male offspring on the incidence of a sex-linked lethal disease.

    abstract::The effects of reproductive compensation on an X-linked recessive lethal are examined. Complete compensation without regard to the sex of the offspring increases the incidence of female carriers by a factor of 1.5, and of affected males by 1.33. However, if families reproduce until they have a healthy male offspring, ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Templeton AR,Yokoyama S

    更新日期:1980-07-01 00:00:00

  • Testing for genetic linkage in families by a variance-components approach in the presence of genomic imprinting.

    abstract::Some genes that affect development and behavior in mammals are known to be imprinted; and > or = 1% of all mammalian genes are imprinted. Hence, incorporating an imprinting parameter into linkage analysis may increase the power to detect linkage for these traits. Here we propose theoretical justifications for a recent...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/338931

    authors: Shete S,Amos CI

    更新日期:2002-03-01 00:00:00

  • Arysulfatase A modulation with pH in multiple sulfatase deficiency disorder fibroblasts.

    abstract::It has been observed that multiple sulfatase deficiency disorder (MSDD) fibroblasts contained from profoundly deficient to near normal amounts of arylsulfatase (ARS) A depending on the medium in which they were cultured. Our present findings show that the major factor determining the enzyme level is the pH of the medi...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Fluharty AL,Stevens RL,de la Flor SD,Shapiro LJ,Kihara H

    更新日期:1979-09-01 00:00:00

  • Linkage disequilibrium mapping of the gene for Margarita Island ectodermal dysplasia (ED4) to 11q23.

    abstract::Margarita Island ectodermal dysplasia (ED4) is an autosomal recessive disorder characterized by unusual facies, dental anomalies, hypotrichosis, palmoplantar hyperkeratosis and onychodysplasia, syndactyly, and cleft lip/cleft palate. We have used an affected-only DNA-pooling strategy to carry out linkage disequilibriu...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/302072

    authors: Suzuki K,Bustos T,Spritz RA

    更新日期:1998-10-01 00:00:00

  • Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci.

    abstract::Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ~50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analy...

    journal_title:American journal of human genetics

    pub_type: 杂志文章,meta分析

    doi:10.1016/j.ajhg.2013.12.016

    authors: Tragante V,Barnes MR,Ganesh SK,Lanktree MB,Guo W,Franceschini N,Smith EN,Johnson T,Holmes MV,Padmanabhan S,Karczewski KJ,Almoguera B,Barnard J,Baumert J,Chang YP,Elbers CC,Farrall M,Fischer ME,Gaunt TR,Gho JM,Gieg

    更新日期:2014-03-06 00:00:00

  • Multicentric origin of hemochromatosis gene (HFE) mutations.

    abstract::Genetic hemochromatosis (GH) is believed to be a disease restricted to those of European ancestry. In northwestern Europe, >80% of GH patients are homozygous for one mutation, the substitution of tyrosine for cysteine at position 282 (C282Y) in the unprocessed protein. In a proportion of GH patients, two mutations are...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/302318

    authors: Rochette J,Pointon JJ,Fisher CA,Perera G,Arambepola M,Arichchi DS,De Silva S,Vandwalle JL,Monti JP,Old JM,Merryweather-Clarke AT,Weatherall DJ,Robson KJ

    更新日期:1999-04-01 00:00:00

  • Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis.

    abstract::Acrodysostosis is a rare autosomal-dominant condition characterized by facial dysostosis, severe brachydactyly with cone-shaped epiphyses, and short stature. Moderate intellectual disability and resistance to multiple hormones might also be present. Recently, a recurrent mutation (c.1102C>T [p.Arg368*]) in PRKAR1A has...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2012.03.003

    authors: Michot C,Le Goff C,Goldenberg A,Abhyankar A,Klein C,Kinning E,Guerrot AM,Flahaut P,Duncombe A,Baujat G,Lyonnet S,Thalassinos C,Nitschke P,Casanova JL,Le Merrer M,Munnich A,Cormier-Daire V

    更新日期:2012-04-06 00:00:00

  • A comparison of phasing algorithms for trios and unrelated individuals.

    abstract::Knowledge of haplotype phase is valuable for many analysis methods in the study of disease, population, and evolutionary genetics. Considerable research effort has been devoted to the development of statistical and computational methods that infer haplotype phase from genotype data. Although a substantial number of su...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/500808

    authors: Marchini J,Cutler D,Patterson N,Stephens M,Eskin E,Halperin E,Lin S,Qin ZS,Munro HM,Abecasis GR,Donnelly P,International HapMap Consortium.

    更新日期:2006-03-01 00:00:00

  • Sex-dependent mechanisms for expansions and contractions of the CAG repeat on affected Huntington disease chromosomes.

    abstract::A total of 254 affected parent-child pairs with Huntington disease (HD) and 440 parent-child pairs with CAG size in the normal range were assessed to determine the nature and frequency of intergenerational CAG changes in the HD gene. Intergenerational CAG changes are extremely rare (3/440 [0.68%]) on normal chromosome...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Kremer B,Almqvist E,Theilmann J,Spence N,Telenius H,Goldberg YP,Hayden MR

    更新日期:1995-08-01 00:00:00

  • Linkage analysis of human leukocyte antigen (HLA) markers in familial psoriasis: strong disequilibrium effects provide evidence for a major determinant in the HLA-B/-C region.

    abstract::Although psoriasis is strongly associated with certain human leukocyte antigens (HLAs), evidence for linkage to HLA markers has been limited. The objectives of this study were (1) to provide more definitive evidence for linkage of psoriasis to HLA markers in multiplex families; (2) to compare the major HLA risk allele...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/301899

    authors: Jenisch S,Henseler T,Nair RP,Guo SW,Westphal E,Stuart P,Krönke M,Voorhees JJ,Christophers E,Elder JT

    更新日期:1998-07-01 00:00:00

  • Management of Secondary Genomic Findings.

    abstract::Secondary genomic findings are increasingly being returned to individuals as opportunistic screening results. A secondary finding offers the chance to identify and mitigate disease that may otherwise be unrecognized in an individual. As a form of screening, secondary findings must be considered differently from sequen...

    journal_title:American journal of human genetics

    pub_type: 杂志文章,评审

    doi:10.1016/j.ajhg.2020.05.002

    authors: Katz AE,Nussbaum RL,Solomon BD,Rehm HL,Williams MS,Biesecker LG

    更新日期:2020-07-02 00:00:00

  • Significant linkage on chromosome 10p in families with bulimia nervosa.

    abstract::Bulimia nervosa (BN) is strongly familial, and additive genetic effects appear to contribute substantially to the observed familiality. In turn, behavioral components of BN, such as self-induced vomiting, are reliably measured and heritable. To identify regions of the genome harboring genetic variants conferring susce...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/345801

    authors: Bulik CM,Devlin B,Bacanu SA,Thornton L,Klump KL,Fichter MM,Halmi KA,Kaplan AS,Strober M,Woodside DB,Bergen AW,Ganjei JK,Crow S,Mitchell J,Rotondo A,Mauri M,Cassano G,Keel P,Berrettini WH,Kaye WH

    更新日期:2003-01-01 00:00:00

  • The interleukin 1 gene cluster contains a major susceptibility locus for ankylosing spondylitis.

    abstract::Ankylosing spondylitis (AS) is a common and highly heritable inflammatory arthropathy. Although the gene HLA-B27 is almost essential for the inheritance of the condition, it alone is not sufficient to explain the pattern of familial recurrence of the disease. We have previously demonstrated suggestive linkage of AS to...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/424695

    authors: Timms AE,Crane AM,Sims AM,Cordell HJ,Bradbury LA,Abbott A,Coyne MR,Beynon O,Herzberg I,Duff GW,Calin A,Cardon LR,Wordsworth BP,Brown MA

    更新日期:2004-10-01 00:00:00

  • TMEM199 Deficiency Is a Disorder of Golgi Homeostasis Characterized by Elevated Aminotransferases, Alkaline Phosphatase, and Cholesterol and Abnormal Glycosylation.

    abstract::Congenital disorders of glycosylation (CDGs) form a genetically and clinically heterogeneous group of diseases with aberrant protein glycosylation as a hallmark. A subgroup of CDGs can be attributed to disturbed Golgi homeostasis. However, identification of pathogenic variants is seriously complicated by the large num...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2015.12.011

    authors: Jansen JC,Timal S,van Scherpenzeel M,Michelakakis H,Vicogne D,Ashikov A,Moraitou M,Hoischen A,Huijben K,Steenbergen G,van den Boogert MA,Porta F,Calvo PL,Mavrikou M,Cenacchi G,van den Bogaart G,Salomon J,Holleboom AG,

    更新日期:2016-02-04 00:00:00

  • Contrasting evolutionary histories among tightly linked HLA loci.

    abstract::Genes comprising the major histocompatibility complex (MHC) play a central role in governing the immune response of vertebrates. A great deal of information has been revealed on the molecular biology and physiology of these loci, but three features-the high polymorphism, tight linkage among the loci, and the nonrandom...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Klitz W,Thomson G,Baur MP

    更新日期:1986-09-01 00:00:00

  • Genetic counseling in rare syndromes: a resampling method for determining an approximate confidence interval for gene location with linkage data from a single pedigree.

    abstract::Multipoint linkage analysis is a powerful method for mapping a rare disease gene on the human gene map despite limited genotype and pedigree data. However, there is no standard procedure for determining a confidence interval for gene location by using multipoint linkage analysis. A genetic counselor needs to know the ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Suthers GK,Wilson SR

    更新日期:1990-07-01 00:00:00

  • Polymporphism of human C-band heterochromatin. II. Family studies with suggestive evidence for somatic crossing over.

    abstract::An analysis of the inherited pattern of C-band heterochromatin has been made in five pedigrees containing a total of 33 offspring that were available for analysis. The majority of variants were found to be inherited; however, at least seven of the 99 variants were not present in either parent, and an additional seven ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Craig-Holmes AP,Moore FB,Shaw MW

    更新日期:1975-03-01 00:00:00

  • Escobar syndrome is a prenatal myasthenia caused by disruption of the acetylcholine receptor fetal gamma subunit.

    abstract::Escobar syndrome is a form of arthrogryposis multiplex congenita and features joint contractures, pterygia, and respiratory distress. Similar findings occur in newborns exposed to nicotinergic acetylcholine receptor (AChR) antibodies from myasthenic mothers. We performed linkage studies in families with Escobar syndro...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/506257

    authors: Hoffmann K,Muller JS,Stricker S,Megarbane A,Rajab A,Lindner TH,Cohen M,Chouery E,Adaimy L,Ghanem I,Delague V,Boltshauser E,Talim B,Horvath R,Robinson PN,Lochmüller H,Hübner C,Mundlos S

    更新日期:2006-08-01 00:00:00

  • Genetics of acheiropodia (the handless and footless families of Brazil). VI. Formal genetic analysis.

    abstract::A genetic analysis is presented of data from 22 Brazilian sibships with cases of acheiropodia (the handless and footless families of Brazil). Segregation analysis performed using a 16K CDC 3100 computer showed a segregation frequency of .245 +/- .040, which is close to the expected value of .25. No sporadic cases wer...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Freire-Maia A,Freire-Maia N,Morton NE,Azevêdo ES,Quelce-Salgado A

    更新日期:1975-07-01 00:00:00

  • Juvenile hemochromatosis locus maps to chromosome 1q.

    abstract::Juvenile hemochromatosis (JH) is an autosomal recessive disorder that leads to severe iron loading in the 2d to 3d decade of life. Affected members in families with JH do not show linkage to chromosome 6p and do not have mutations in the HFE gene that lead to the common hereditary hemochromatosis. In this study we per...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/302379

    authors: Roetto A,Totaro A,Cazzola M,Cicilano M,Bosio S,D'Ascola G,Carella M,Zelante L,Kelly AL,Cox TM,Gasparini P,Camaschella C

    更新日期:1999-05-01 00:00:00

  • An autosomal locus predisposing to multiple deletions of mtDNA on chromosome 3p.

    abstract::Autosomal dominant progressive external ophthalmoplegia (adPEO) is a disorder characterized by ptosis, progressive weakness of the external eye muscles, and general muscle weakness. The patients have multiple deletions of mtDNA on Southern blots or in PCR analysis of muscle DNA and a mild deficiency of one or more res...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Kaukonen JA,Amati P,Suomalainen A,Rötig A,Piscaglia MG,Salvi F,Weissenbach J,Fratta G,Comi G,Peltonen L,Zeviani M

    更新日期:1996-04-01 00:00:00

  • Allele-specific replication of 15q11-q13 loci: a diagnostic test for detection of uniparental disomy.

    abstract::Allele-specific replication differences have been observed in imprinted chromosomal regions. We have exploited this characteristic of an imprinted region by using FISH at D15S9 and SNRPN (small nuclear ribonucleo protein N) on interphase nuclei to distinguish between Angelman and Prader-Willi syndrome patient samples ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: White LM,Rogan PK,Nicholls RD,Wu BL,Korf B,Knoll JH

    更新日期:1996-08-01 00:00:00

  • Parental trisomy 21 mosaicism.

    abstract::A family with three children with trisomy 21 in which the mother is a phenotypically normal, trisomy 21/normal mosaic was studied. Chromosome 21 fluorescent heteromorphisms were used to document that two of the three number 21's in two of the Down syndrome offspring were of maternal origin. Five cytogenetic surveys in...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Harris DJ,Begleiter ML,Chamberlin J,Hankins L,Magenis RE

    更新日期:1982-01-01 00:00:00

  • Interpretation of association signals and identification of causal variants from genome-wide association studies.

    abstract::GWAS have been successful in identifying disease susceptibility loci, but it remains a challenge to pinpoint the causal variants in subsequent fine-mapping studies. A conventional fine-mapping effort starts by sequencing dozens of randomly selected samples at susceptibility loci to discover candidate variants, which a...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2010.04.003

    authors: Wang K,Dickson SP,Stolle CA,Krantz ID,Goldstein DB,Hakonarson H

    更新日期:2010-05-14 00:00:00

  • Genomewide linkage analysis identifies polymorphism in the human interferon-gamma receptor affecting Helicobacter pylori infection.

    abstract::Helicobacter pylori is considered the most prevalent infectious agent among humans, and it causes gastric inflammation, gastroduodenal ulcers, and a risk of gastric cancer. We performed a genomewide linkage analysis among Senegalese siblings phenotyped for H. pylori-reactive serum immunoglobulin G. A multipoint LOD sc...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/367714

    authors: Thye T,Burchard GD,Nilius M,Müller-Myhsok B,Horstmann RD

    更新日期:2003-02-01 00:00:00