An InDel in Phospholipase-C-B-1 Is Linked with Euthyroid Multinodular Goiter
Background: Euthyroid multinodular goiter (MNG) is common, but little is known about the genetic variations conferring predisposition. Previously, a family with MNG of adolescent onset was reported in which some family members developed papillary thyroid carcinomas (PTC). Methods: Genome-wide linkag...
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| Veröffentlicht in: | Thyroid (New York, N.Y.) N.Y.), 2018-07, Vol.28 (7), p.891-901 |
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| creator | Bakhsh, Ameen D. Ladas, Ioannis Hamshere, Marian L. Bullock, Martyn Kirov, George Zhang, Lei Taylor, Peter N. Gregory, John W. Scott-Coombes, David Völzke, Henry Teumer, Alexander Mantripragada, Kiran Williams, E. Dillwyn Clifton-Bligh, Roderick J. Williams, Nigel M. Ludgate, Marian E. |
| description | Background:
Euthyroid multinodular goiter (MNG) is common, but little is known about the genetic variations conferring predisposition. Previously, a family with MNG of adolescent onset was reported in which some family members developed papillary thyroid carcinomas (PTC).
Methods:
Genome-wide linkage analysis and next-generation sequencing were conducted to identify genetic variants that may confer disease predisposition. A multipoint nonparametric LOD score of 3.01 was obtained, covering 19 cM on chromosome 20p. Haplotype analysis reduced the region of interest to 10 cM.
Results:
Analysis of copy number variation identified an intronic InDel (∼1000 bp) in the
PLCB1
gene in all eight affected family members and carriers (an unaffected person who has inherited the genetic trait). This InDel is present in approximately 1% of “healthy” Caucasians. Next-generation sequencing of the region identified no additional disease-associated variant, suggesting a possible role of the InDel. Since
PLCB1
contributes to thyrocyte growth regulation, the InDel was investigated in relevant Caucasian cohorts. It was detected in 0/70 PTC but 4/81 unrelated subjects with MNG (three females; age at thyroidectomy 27–59 years; no family history of MNG/PTC). The InDel frequency is significantly higher in MNG subjects compared to controls (χ
2
= 5.076;
p
= 0.024.
PLCB1
transcript levels were significantly higher in thyroids with the InDel than without (
p
|
| doi_str_mv | 10.1089/thy.2017.0312 |
| format | Article |
| fullrecord | <record><control><sourceid>pubmed_cross</sourceid><recordid>TN_cdi_crossref_primary_10_1089_thy_2017_0312</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>29897006</sourcerecordid><originalsourceid>FETCH-LOGICAL-c376t-55ef33d7c9efa7ce4d8e5719e0b6852756a87e93c5cdc7e35e55be2954d15f813</originalsourceid><addsrcrecordid>eNqFkLFOwzAQhi0EolAYWZFfwMWOe3E8llJKpSAYYI6S-KIYUieyE6G-PYkKrEz36_Tpv9NHyI3gC8ETfdfXh0XEhVpwKaITciEAFNNcqdMxc-BMRRDPyGUIH5yLOFHynMwinWjFeXxB0pWjO_eADbWOvtZt6Oq2sV0ekK3ZPRN0F2hq3Sca-mX7mm6G8aBvraHPQ9Nb15qhyT3dtrZHf0XOqrwJeP0z5-T9cfO2fmLpy3a3XqWslCruGQBWUhpVaqxyVeLSJAhKaORFnECkIM4ThVqWUJpSoQQEKDDSsDQCqkTIOWHH3tK3IXisss7bfe4PmeDZZCUbn8wmK9lkZeRvj3w3FHs0f_SvhhGQR2Ba5841Fgv0_T-130SCblw</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>An InDel in Phospholipase-C-B-1 Is Linked with Euthyroid Multinodular Goiter</title><source>MEDLINE</source><source>Alma/SFX Local Collection</source><creator>Bakhsh, Ameen D. ; Ladas, Ioannis ; Hamshere, Marian L. ; Bullock, Martyn ; Kirov, George ; Zhang, Lei ; Taylor, Peter N. ; Gregory, John W. ; Scott-Coombes, David ; Völzke, Henry ; Teumer, Alexander ; Mantripragada, Kiran ; Williams, E. Dillwyn ; Clifton-Bligh, Roderick J. ; Williams, Nigel M. ; Ludgate, Marian E.</creator><creatorcontrib>Bakhsh, Ameen D. ; Ladas, Ioannis ; Hamshere, Marian L. ; Bullock, Martyn ; Kirov, George ; Zhang, Lei ; Taylor, Peter N. ; Gregory, John W. ; Scott-Coombes, David ; Völzke, Henry ; Teumer, Alexander ; Mantripragada, Kiran ; Williams, E. Dillwyn ; Clifton-Bligh, Roderick J. ; Williams, Nigel M. ; Ludgate, Marian E.</creatorcontrib><description>Background:
Euthyroid multinodular goiter (MNG) is common, but little is known about the genetic variations conferring predisposition. Previously, a family with MNG of adolescent onset was reported in which some family members developed papillary thyroid carcinomas (PTC).
Methods:
Genome-wide linkage analysis and next-generation sequencing were conducted to identify genetic variants that may confer disease predisposition. A multipoint nonparametric LOD score of 3.01 was obtained, covering 19 cM on chromosome 20p. Haplotype analysis reduced the region of interest to 10 cM.
Results:
Analysis of copy number variation identified an intronic InDel (∼1000 bp) in the
PLCB1
gene in all eight affected family members and carriers (an unaffected person who has inherited the genetic trait). This InDel is present in approximately 1% of “healthy” Caucasians. Next-generation sequencing of the region identified no additional disease-associated variant, suggesting a possible role of the InDel. Since
PLCB1
contributes to thyrocyte growth regulation, the InDel was investigated in relevant Caucasian cohorts. It was detected in 0/70 PTC but 4/81 unrelated subjects with MNG (three females; age at thyroidectomy 27–59 years; no family history of MNG/PTC). The InDel frequency is significantly higher in MNG subjects compared to controls (χ
2
= 5.076;
p
= 0.024.
PLCB1
transcript levels were significantly higher in thyroids with the InDel than without (
p
< 0.02).
Conclusions:
The intronic
PLCB1
InDel is the first variant found in familial multiple papilloid adenomata-type MNG and in a subset of patients with sporadic MNG. It may function through overexpression, and increased PLC activity has been reported in thyroid neoplasms. The potential role of the deletion as a biomarker to identify MNG patients more likely to progress to PTC merits exploration.</description><identifier>ISSN: 1050-7256</identifier><identifier>EISSN: 1557-9077</identifier><identifier>DOI: 10.1089/thy.2017.0312</identifier><identifier>PMID: 29897006</identifier><language>eng</language><publisher>United States: Mary Ann Liebert, Inc</publisher><subject>Adult ; DNA Copy Number Variations ; Female ; Genetic Linkage ; Genetic Predisposition to Disease ; Goiter, Nodular - genetics ; Goiter, Nodular - pathology ; Haplotypes ; Humans ; Introns - genetics ; Male ; Middle Aged ; Pedigree ; Phospholipase C beta - genetics ; Thyroid Cancer and Nodules ; Thyroid Gland - pathology ; Thyroidectomy</subject><ispartof>Thyroid (New York, N.Y.), 2018-07, Vol.28 (7), p.891-901</ispartof><rights>2018, Mary Ann Liebert, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c376t-55ef33d7c9efa7ce4d8e5719e0b6852756a87e93c5cdc7e35e55be2954d15f813</citedby><cites>FETCH-LOGICAL-c376t-55ef33d7c9efa7ce4d8e5719e0b6852756a87e93c5cdc7e35e55be2954d15f813</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29897006$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bakhsh, Ameen D.</creatorcontrib><creatorcontrib>Ladas, Ioannis</creatorcontrib><creatorcontrib>Hamshere, Marian L.</creatorcontrib><creatorcontrib>Bullock, Martyn</creatorcontrib><creatorcontrib>Kirov, George</creatorcontrib><creatorcontrib>Zhang, Lei</creatorcontrib><creatorcontrib>Taylor, Peter N.</creatorcontrib><creatorcontrib>Gregory, John W.</creatorcontrib><creatorcontrib>Scott-Coombes, David</creatorcontrib><creatorcontrib>Völzke, Henry</creatorcontrib><creatorcontrib>Teumer, Alexander</creatorcontrib><creatorcontrib>Mantripragada, Kiran</creatorcontrib><creatorcontrib>Williams, E. Dillwyn</creatorcontrib><creatorcontrib>Clifton-Bligh, Roderick J.</creatorcontrib><creatorcontrib>Williams, Nigel M.</creatorcontrib><creatorcontrib>Ludgate, Marian E.</creatorcontrib><title>An InDel in Phospholipase-C-B-1 Is Linked with Euthyroid Multinodular Goiter</title><title>Thyroid (New York, N.Y.)</title><addtitle>Thyroid</addtitle><description>Background:
Euthyroid multinodular goiter (MNG) is common, but little is known about the genetic variations conferring predisposition. Previously, a family with MNG of adolescent onset was reported in which some family members developed papillary thyroid carcinomas (PTC).
Methods:
Genome-wide linkage analysis and next-generation sequencing were conducted to identify genetic variants that may confer disease predisposition. A multipoint nonparametric LOD score of 3.01 was obtained, covering 19 cM on chromosome 20p. Haplotype analysis reduced the region of interest to 10 cM.
Results:
Analysis of copy number variation identified an intronic InDel (∼1000 bp) in the
PLCB1
gene in all eight affected family members and carriers (an unaffected person who has inherited the genetic trait). This InDel is present in approximately 1% of “healthy” Caucasians. Next-generation sequencing of the region identified no additional disease-associated variant, suggesting a possible role of the InDel. Since
PLCB1
contributes to thyrocyte growth regulation, the InDel was investigated in relevant Caucasian cohorts. It was detected in 0/70 PTC but 4/81 unrelated subjects with MNG (three females; age at thyroidectomy 27–59 years; no family history of MNG/PTC). The InDel frequency is significantly higher in MNG subjects compared to controls (χ
2
= 5.076;
p
= 0.024.
PLCB1
transcript levels were significantly higher in thyroids with the InDel than without (
p
< 0.02).
Conclusions:
The intronic
PLCB1
InDel is the first variant found in familial multiple papilloid adenomata-type MNG and in a subset of patients with sporadic MNG. It may function through overexpression, and increased PLC activity has been reported in thyroid neoplasms. The potential role of the deletion as a biomarker to identify MNG patients more likely to progress to PTC merits exploration.</description><subject>Adult</subject><subject>DNA Copy Number Variations</subject><subject>Female</subject><subject>Genetic Linkage</subject><subject>Genetic Predisposition to Disease</subject><subject>Goiter, Nodular - genetics</subject><subject>Goiter, Nodular - pathology</subject><subject>Haplotypes</subject><subject>Humans</subject><subject>Introns - genetics</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Pedigree</subject><subject>Phospholipase C beta - genetics</subject><subject>Thyroid Cancer and Nodules</subject><subject>Thyroid Gland - pathology</subject><subject>Thyroidectomy</subject><issn>1050-7256</issn><issn>1557-9077</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkLFOwzAQhi0EolAYWZFfwMWOe3E8llJKpSAYYI6S-KIYUieyE6G-PYkKrEz36_Tpv9NHyI3gC8ETfdfXh0XEhVpwKaITciEAFNNcqdMxc-BMRRDPyGUIH5yLOFHynMwinWjFeXxB0pWjO_eADbWOvtZt6Oq2sV0ekK3ZPRN0F2hq3Sca-mX7mm6G8aBvraHPQ9Nb15qhyT3dtrZHf0XOqrwJeP0z5-T9cfO2fmLpy3a3XqWslCruGQBWUhpVaqxyVeLSJAhKaORFnECkIM4ThVqWUJpSoQQEKDDSsDQCqkTIOWHH3tK3IXisss7bfe4PmeDZZCUbn8wmK9lkZeRvj3w3FHs0f_SvhhGQR2Ba5841Fgv0_T-130SCblw</recordid><startdate>20180701</startdate><enddate>20180701</enddate><creator>Bakhsh, Ameen D.</creator><creator>Ladas, Ioannis</creator><creator>Hamshere, Marian L.</creator><creator>Bullock, Martyn</creator><creator>Kirov, George</creator><creator>Zhang, Lei</creator><creator>Taylor, Peter N.</creator><creator>Gregory, John W.</creator><creator>Scott-Coombes, David</creator><creator>Völzke, Henry</creator><creator>Teumer, Alexander</creator><creator>Mantripragada, Kiran</creator><creator>Williams, E. Dillwyn</creator><creator>Clifton-Bligh, Roderick J.</creator><creator>Williams, Nigel M.</creator><creator>Ludgate, Marian E.</creator><general>Mary Ann Liebert, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20180701</creationdate><title>An InDel in Phospholipase-C-B-1 Is Linked with Euthyroid Multinodular Goiter</title><author>Bakhsh, Ameen D. ; Ladas, Ioannis ; Hamshere, Marian L. ; Bullock, Martyn ; Kirov, George ; Zhang, Lei ; Taylor, Peter N. ; Gregory, John W. ; Scott-Coombes, David ; Völzke, Henry ; Teumer, Alexander ; Mantripragada, Kiran ; Williams, E. Dillwyn ; Clifton-Bligh, Roderick J. ; Williams, Nigel M. ; Ludgate, Marian E.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c376t-55ef33d7c9efa7ce4d8e5719e0b6852756a87e93c5cdc7e35e55be2954d15f813</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adult</topic><topic>DNA Copy Number Variations</topic><topic>Female</topic><topic>Genetic Linkage</topic><topic>Genetic Predisposition to Disease</topic><topic>Goiter, Nodular - genetics</topic><topic>Goiter, Nodular - pathology</topic><topic>Haplotypes</topic><topic>Humans</topic><topic>Introns - genetics</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Pedigree</topic><topic>Phospholipase C beta - genetics</topic><topic>Thyroid Cancer and Nodules</topic><topic>Thyroid Gland - pathology</topic><topic>Thyroidectomy</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bakhsh, Ameen D.</creatorcontrib><creatorcontrib>Ladas, Ioannis</creatorcontrib><creatorcontrib>Hamshere, Marian L.</creatorcontrib><creatorcontrib>Bullock, Martyn</creatorcontrib><creatorcontrib>Kirov, George</creatorcontrib><creatorcontrib>Zhang, Lei</creatorcontrib><creatorcontrib>Taylor, Peter N.</creatorcontrib><creatorcontrib>Gregory, John W.</creatorcontrib><creatorcontrib>Scott-Coombes, David</creatorcontrib><creatorcontrib>Völzke, Henry</creatorcontrib><creatorcontrib>Teumer, Alexander</creatorcontrib><creatorcontrib>Mantripragada, Kiran</creatorcontrib><creatorcontrib>Williams, E. Dillwyn</creatorcontrib><creatorcontrib>Clifton-Bligh, Roderick J.</creatorcontrib><creatorcontrib>Williams, Nigel M.</creatorcontrib><creatorcontrib>Ludgate, Marian E.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Thyroid (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bakhsh, Ameen D.</au><au>Ladas, Ioannis</au><au>Hamshere, Marian L.</au><au>Bullock, Martyn</au><au>Kirov, George</au><au>Zhang, Lei</au><au>Taylor, Peter N.</au><au>Gregory, John W.</au><au>Scott-Coombes, David</au><au>Völzke, Henry</au><au>Teumer, Alexander</au><au>Mantripragada, Kiran</au><au>Williams, E. Dillwyn</au><au>Clifton-Bligh, Roderick J.</au><au>Williams, Nigel M.</au><au>Ludgate, Marian E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>An InDel in Phospholipase-C-B-1 Is Linked with Euthyroid Multinodular Goiter</atitle><jtitle>Thyroid (New York, N.Y.)</jtitle><addtitle>Thyroid</addtitle><date>2018-07-01</date><risdate>2018</risdate><volume>28</volume><issue>7</issue><spage>891</spage><epage>901</epage><pages>891-901</pages><issn>1050-7256</issn><eissn>1557-9077</eissn><abstract>Background:
Euthyroid multinodular goiter (MNG) is common, but little is known about the genetic variations conferring predisposition. Previously, a family with MNG of adolescent onset was reported in which some family members developed papillary thyroid carcinomas (PTC).
Methods:
Genome-wide linkage analysis and next-generation sequencing were conducted to identify genetic variants that may confer disease predisposition. A multipoint nonparametric LOD score of 3.01 was obtained, covering 19 cM on chromosome 20p. Haplotype analysis reduced the region of interest to 10 cM.
Results:
Analysis of copy number variation identified an intronic InDel (∼1000 bp) in the
PLCB1
gene in all eight affected family members and carriers (an unaffected person who has inherited the genetic trait). This InDel is present in approximately 1% of “healthy” Caucasians. Next-generation sequencing of the region identified no additional disease-associated variant, suggesting a possible role of the InDel. Since
PLCB1
contributes to thyrocyte growth regulation, the InDel was investigated in relevant Caucasian cohorts. It was detected in 0/70 PTC but 4/81 unrelated subjects with MNG (three females; age at thyroidectomy 27–59 years; no family history of MNG/PTC). The InDel frequency is significantly higher in MNG subjects compared to controls (χ
2
= 5.076;
p
= 0.024.
PLCB1
transcript levels were significantly higher in thyroids with the InDel than without (
p
< 0.02).
Conclusions:
The intronic
PLCB1
InDel is the first variant found in familial multiple papilloid adenomata-type MNG and in a subset of patients with sporadic MNG. It may function through overexpression, and increased PLC activity has been reported in thyroid neoplasms. The potential role of the deletion as a biomarker to identify MNG patients more likely to progress to PTC merits exploration.</abstract><cop>United States</cop><pub>Mary Ann Liebert, Inc</pub><pmid>29897006</pmid><doi>10.1089/thy.2017.0312</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1050-7256 |
| ispartof | Thyroid (New York, N.Y.), 2018-07, Vol.28 (7), p.891-901 |
| issn | 1050-7256 1557-9077 |
| language | eng |
| recordid | cdi_crossref_primary_10_1089_thy_2017_0312 |
| source | MEDLINE; Alma/SFX Local Collection |
| subjects | Adult DNA Copy Number Variations Female Genetic Linkage Genetic Predisposition to Disease Goiter, Nodular - genetics Goiter, Nodular - pathology Haplotypes Humans Introns - genetics Male Middle Aged Pedigree Phospholipase C beta - genetics Thyroid Cancer and Nodules Thyroid Gland - pathology Thyroidectomy |
| title | An InDel in Phospholipase-C-B-1 Is Linked with Euthyroid Multinodular Goiter |
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