Linkage disequilibrium between polymorphisms in the human TNFRSF1B gene and their association with bone mass in perimenopausal women
Osteoporosis is a multifactorial disease with a strong genetic component characterized by reduced bone density and increased fracture risk. A candidate locus for regulation of hip bone mineral density (BMD) has been identified on chromosome 1p36 by linkage analysis. One of the positional and functio...
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| Veröffentlicht in: | Human molecular genetics 2002-09, Vol.11 (19), p.2289-2295 |
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| creator | Albagha, Omar M.E. Tasker, Paul N. McGuigan, Fiona E.A. Reid, David M. Ralston, Stuart H |
| description | Osteoporosis is a multifactorial disease with a strong genetic component characterized by reduced bone density and increased fracture risk. A candidate locus for regulation of hip bone mineral density (BMD) has been identified on chromosome 1p36 by linkage analysis. One of the positional and functional candidate genes located within this region is the tumour necrosis factor receptor superfamily member 1B (TNFRSF1B). In order to investigate whether allelic variation in TNFRSF1B contributes to regulation of bone mass, we studied several polymorphisms of this gene in a population based cohort study of 1240 perimenopausal women from the UK. We studied a T676G change in exon 6 (196: Met–Arg) and three SNPs (G593A, T598G, and T620C) in the 3′UTR of the gene. The 3′UTR SNPs were in strong linkage disequilibrium (LD) with each other (P |
| doi_str_mv | 10.1093/hmg/11.19.2289 |
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A candidate locus for regulation of hip bone mineral density (BMD) has been identified on chromosome 1p36 by linkage analysis. One of the positional and functional candidate genes located within this region is the tumour necrosis factor receptor superfamily member 1B (TNFRSF1B). In order to investigate whether allelic variation in TNFRSF1B contributes to regulation of bone mass, we studied several polymorphisms of this gene in a population based cohort study of 1240 perimenopausal women from the UK. We studied a T676G change in exon 6 (196: Met–Arg) and three SNPs (G593A, T598G, and T620C) in the 3′UTR of the gene. The 3′UTR SNPs were in strong linkage disequilibrium (LD) with each other (P<0.00001), and the exon 6 SNP was in LD with G593A and T598G (P<0.00001). We found no association between T676G alleles and BMD at the spine or hip. However, haplotype analysis showed that subjects homozygous for the A593–T598–C620 haplotype (n=85) had femoral neck BMD values 5.7% lower than those who did not carry the haplotype (n=1155; P<0.00008) and this remained significant after correcting for confounding factors and multiple testing (P<0.0009). Regression analysis showed that the ATC haplotype accounted for 1.2% of the population variance in hip BMD and was the second strongest predictor after body weight. In summary, our work supports the view that allelic variation in the 3′UTR of TNFRSF1B gene contributes to the genetic regulation of bone mass, with effects that are specific for femoral neck BMD.</description><identifier>ISSN: 0964-6906</identifier><identifier>ISSN: 1460-2083</identifier><identifier>EISSN: 1460-2083</identifier><identifier>DOI: 10.1093/hmg/11.19.2289</identifier><identifier>PMID: 12217957</identifier><identifier>CODEN: HNGEE5</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>3' Untranslated Regions ; Biological and medical sciences ; Bone Density - genetics ; Bone Density - physiology ; Diseases of the osteoarticular system ; Female ; Femur Neck - physiology ; General aspects. Genetic counseling ; Haplotypes ; Humans ; Linkage Disequilibrium ; Medical genetics ; Medical sciences ; Middle Aged ; Osteoporosis. Osteomalacia. Paget disease ; Polymorphism, Genetic ; Receptors, Tumor Necrosis Factor - genetics ; Receptors, Tumor Necrosis Factor - physiology ; Receptors, Tumor Necrosis Factor, Type II</subject><ispartof>Human molecular genetics, 2002-09, Vol.11 (19), p.2289-2295</ispartof><rights>2002 INIST-CNRS</rights><rights>Copyright Oxford University Press(England) Jul 15, 2002</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c486t-73b0f0510bf4907cf9475a866fbc351f4c36eb5c1f3510f3b559f4e36a60eab43</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,27928,27929</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=13949644$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12217957$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Albagha, Omar M.E.</creatorcontrib><creatorcontrib>Tasker, Paul N.</creatorcontrib><creatorcontrib>McGuigan, Fiona E.A.</creatorcontrib><creatorcontrib>Reid, David M.</creatorcontrib><creatorcontrib>Ralston, Stuart H</creatorcontrib><title>Linkage disequilibrium between polymorphisms in the human TNFRSF1B gene and their association with bone mass in perimenopausal women</title><title>Human molecular genetics</title><addtitle>Hum. Mol. Genet</addtitle><description>Osteoporosis is a multifactorial disease with a strong genetic component characterized by reduced bone density and increased fracture risk. A candidate locus for regulation of hip bone mineral density (BMD) has been identified on chromosome 1p36 by linkage analysis. One of the positional and functional candidate genes located within this region is the tumour necrosis factor receptor superfamily member 1B (TNFRSF1B). In order to investigate whether allelic variation in TNFRSF1B contributes to regulation of bone mass, we studied several polymorphisms of this gene in a population based cohort study of 1240 perimenopausal women from the UK. We studied a T676G change in exon 6 (196: Met–Arg) and three SNPs (G593A, T598G, and T620C) in the 3′UTR of the gene. The 3′UTR SNPs were in strong linkage disequilibrium (LD) with each other (P<0.00001), and the exon 6 SNP was in LD with G593A and T598G (P<0.00001). We found no association between T676G alleles and BMD at the spine or hip. However, haplotype analysis showed that subjects homozygous for the A593–T598–C620 haplotype (n=85) had femoral neck BMD values 5.7% lower than those who did not carry the haplotype (n=1155; P<0.00008) and this remained significant after correcting for confounding factors and multiple testing (P<0.0009). Regression analysis showed that the ATC haplotype accounted for 1.2% of the population variance in hip BMD and was the second strongest predictor after body weight. In summary, our work supports the view that allelic variation in the 3′UTR of TNFRSF1B gene contributes to the genetic regulation of bone mass, with effects that are specific for femoral neck BMD.</description><subject>3' Untranslated Regions</subject><subject>Biological and medical sciences</subject><subject>Bone Density - genetics</subject><subject>Bone Density - physiology</subject><subject>Diseases of the osteoarticular system</subject><subject>Female</subject><subject>Femur Neck - physiology</subject><subject>General aspects. Genetic counseling</subject><subject>Haplotypes</subject><subject>Humans</subject><subject>Linkage Disequilibrium</subject><subject>Medical genetics</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Osteoporosis. Osteomalacia. Paget disease</subject><subject>Polymorphism, Genetic</subject><subject>Receptors, Tumor Necrosis Factor - genetics</subject><subject>Receptors, Tumor Necrosis Factor - physiology</subject><subject>Receptors, Tumor Necrosis Factor, Type II</subject><issn>0964-6906</issn><issn>1460-2083</issn><issn>1460-2083</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUFr3DAQhU1paTZprz0WUUhu3mgsWVodm9BtCqaFZgslFyF7pbUSW3Ikm23u_eGV2aWBXnoaZt43D2Zelr0DvAQsyGXb7y4BliCWRbESL7IFUIbzAq_Iy2yBBaM5E5idZKcx3mMMjBL-OjuBogAuSr7IflfWPaidRlsb9eNkO1sHO_Wo1uNea4cG3z31PgytjX1E1qGx1aideuXQ5uv6--0artBOO42U286aDUjF6BurRusd2tuxRbVPep_G8_6gg-2184OaourQ3qfmTfbKqC7qt8d6lv1Yf9pc3-TVt89frj9WeUNXbMw5qbHBJeDaUIF5YwTlpVoxZuqGlGBoQ5iuywZM6rAhdVkKQzVhimGtakrOsouD7xD846TjKHsbG911ymk_RckLzAsg8F8QVgyXHEgCP_wD3vspuHSELCA5YaAiQcsD1AQfY9BGDukHKjxJwHJOUaYUJYAEIecU08L7o-tU93r7jB9jS8D5EVCxUZ0JyjU2PnNE0BT9fHB-4Gwc9a-_ugoPknHCS3nz807eldXthldXEpM_U8W1iA</recordid><startdate>20020915</startdate><enddate>20020915</enddate><creator>Albagha, Omar M.E.</creator><creator>Tasker, Paul N.</creator><creator>McGuigan, Fiona E.A.</creator><creator>Reid, David M.</creator><creator>Ralston, Stuart H</creator><general>Oxford University Press</general><general>Oxford Publishing Limited (England)</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20020915</creationdate><title>Linkage disequilibrium between polymorphisms in the human TNFRSF1B gene and their association with bone mass in perimenopausal women</title><author>Albagha, Omar M.E. ; Tasker, Paul N. ; McGuigan, Fiona E.A. ; Reid, David M. ; Ralston, Stuart H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c486t-73b0f0510bf4907cf9475a866fbc351f4c36eb5c1f3510f3b559f4e36a60eab43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>3' Untranslated Regions</topic><topic>Biological and medical sciences</topic><topic>Bone Density - genetics</topic><topic>Bone Density - physiology</topic><topic>Diseases of the osteoarticular system</topic><topic>Female</topic><topic>Femur Neck - physiology</topic><topic>General aspects. Genetic counseling</topic><topic>Haplotypes</topic><topic>Humans</topic><topic>Linkage Disequilibrium</topic><topic>Medical genetics</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Osteoporosis. Osteomalacia. Paget disease</topic><topic>Polymorphism, Genetic</topic><topic>Receptors, Tumor Necrosis Factor - genetics</topic><topic>Receptors, Tumor Necrosis Factor - physiology</topic><topic>Receptors, Tumor Necrosis Factor, Type II</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Albagha, Omar M.E.</creatorcontrib><creatorcontrib>Tasker, Paul N.</creatorcontrib><creatorcontrib>McGuigan, Fiona E.A.</creatorcontrib><creatorcontrib>Reid, David M.</creatorcontrib><creatorcontrib>Ralston, Stuart H</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Human molecular genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Albagha, Omar M.E.</au><au>Tasker, Paul N.</au><au>McGuigan, Fiona E.A.</au><au>Reid, David M.</au><au>Ralston, Stuart H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Linkage disequilibrium between polymorphisms in the human TNFRSF1B gene and their association with bone mass in perimenopausal women</atitle><jtitle>Human molecular genetics</jtitle><addtitle>Hum. Mol. Genet</addtitle><date>2002-09-15</date><risdate>2002</risdate><volume>11</volume><issue>19</issue><spage>2289</spage><epage>2295</epage><pages>2289-2295</pages><issn>0964-6906</issn><issn>1460-2083</issn><eissn>1460-2083</eissn><coden>HNGEE5</coden><abstract>Osteoporosis is a multifactorial disease with a strong genetic component characterized by reduced bone density and increased fracture risk. A candidate locus for regulation of hip bone mineral density (BMD) has been identified on chromosome 1p36 by linkage analysis. One of the positional and functional candidate genes located within this region is the tumour necrosis factor receptor superfamily member 1B (TNFRSF1B). In order to investigate whether allelic variation in TNFRSF1B contributes to regulation of bone mass, we studied several polymorphisms of this gene in a population based cohort study of 1240 perimenopausal women from the UK. We studied a T676G change in exon 6 (196: Met–Arg) and three SNPs (G593A, T598G, and T620C) in the 3′UTR of the gene. The 3′UTR SNPs were in strong linkage disequilibrium (LD) with each other (P<0.00001), and the exon 6 SNP was in LD with G593A and T598G (P<0.00001). We found no association between T676G alleles and BMD at the spine or hip. However, haplotype analysis showed that subjects homozygous for the A593–T598–C620 haplotype (n=85) had femoral neck BMD values 5.7% lower than those who did not carry the haplotype (n=1155; P<0.00008) and this remained significant after correcting for confounding factors and multiple testing (P<0.0009). Regression analysis showed that the ATC haplotype accounted for 1.2% of the population variance in hip BMD and was the second strongest predictor after body weight. In summary, our work supports the view that allelic variation in the 3′UTR of TNFRSF1B gene contributes to the genetic regulation of bone mass, with effects that are specific for femoral neck BMD.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>12217957</pmid><doi>10.1093/hmg/11.19.2289</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 3' Untranslated Regions Biological and medical sciences Bone Density - genetics Bone Density - physiology Diseases of the osteoarticular system Female Femur Neck - physiology General aspects. Genetic counseling Haplotypes Humans Linkage Disequilibrium Medical genetics Medical sciences Middle Aged Osteoporosis. Osteomalacia. Paget disease Polymorphism, Genetic Receptors, Tumor Necrosis Factor - genetics Receptors, Tumor Necrosis Factor - physiology Receptors, Tumor Necrosis Factor, Type II |
| title | Linkage disequilibrium between polymorphisms in the human TNFRSF1B gene and their association with bone mass in perimenopausal women |
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