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 Genetjournal_title
American journal of human geneticsauthors
Fang Y,van Meurs JB,d'Alesio A,Jhamai M,Zhao H,Rivadeneira F,Hofman A,van Leeuwen JP,Jehan F,Pols HA,Uitterlinden AGdoi
10.1086/497438subject
Has Abstractpub_date
2005-11-01 00:00:00pages
807-23issue
5eissn
0002-9297issn
1537-6605pii
S0002-9297(07)63362-Xjournal_volume
77pub_type
杂志文章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:
更新日期:1976-05-01 00:00:00
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
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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
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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:
更新日期:1975-05-01 00:00:00
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
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doi:10.1016/j.ajhg.2018.02.015
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journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1980-07-01 00:00:00
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
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doi:10.1086/338931
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journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1979-09-01 00:00:00
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
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journal_title:American journal of human genetics
pub_type: 杂志文章,meta分析
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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
更新日期:1999-04-01 00:00:00
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
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doi:10.1016/j.ajhg.2012.03.003
更新日期:2012-04-06 00:00:00
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
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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:
更新日期:1995-08-01 00:00:00
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journal_title:American journal of human genetics
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doi:10.1086/301899
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journal_title:American journal of human genetics
pub_type: 杂志文章,评审
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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
更新日期:2003-01-01 00:00:00
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
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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
更新日期:2016-02-04 00:00:00
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
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更新日期:1986-09-01 00:00:00
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journal_title:American journal of human genetics
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更新日期:1990-07-01 00:00:00
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journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1975-03-01 00:00:00
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journal_title:American journal of human genetics
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journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1975-07-01 00:00:00
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
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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:
更新日期:1996-04-01 00:00:00
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:
更新日期:1996-08-01 00:00:00
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:
更新日期:1982-01-01 00:00:00
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
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