AustralieFrV1, Main, Exploration, bibRecord, 006668

Tests for Genetic Interactions in Type 1 Diabetes: Linkage and Stratification Analyses of 4,422 Affected Sib-Pairs

Identifieur interne : 006668 ( Main/Exploration ); précédent : 006667; suivant : 006669

Tests for Genetic Interactions in Type 1 Diabetes: Linkage and Stratification Analyses of 4,422 Affected Sib-Pairs

Auteurs : Grant Morahan [Australie] ; Munish Mehta [Australie] ; Ian James [Australie] ; Wei-Min Chen [États-Unis] ; Beena Akolkar [États-Unis] ; Henry A. Erlich [États-Unis] ; Joan E. Hilner [États-Unis] ; Cecile Julier [France] ; J Rn Nerup [Danemark] ; Concepcion Nierras [États-Unis] ; Flemming Pociot [Danemark] ; John A. Todd [Royaume-Uni] ; Stephen S. Rich [États-Unis]

Source :

Diabetes : (New York, NY) [ 0012-1797 ] ; 2011.

RBID : Pascal:11-0204485

Descripteurs français

Pascal (Inist)
- Génétique, Interaction, Liaison génétique, Diabète de type 1.
Wicri :
- topic : Génétique.

English descriptors

KwdEn :
- Genetic linkage, Genetics, Interaction, Type 1 diabetes.

Abstract

OBJECTIVE-Interactions between genetic and environmental factors lead to immune dysregulation causing type 1 diabetes and other autoimmune disorders. Recently, many common genetic variants have been associated with type 1 diabetes risk, but each has modest individual effects. Familial clustering of type 1 diabetes has not been explained fully and could arise from many factors, including undetected genetic variation and gene interactions. RESEARCH DESIGN AND METHODS-To address this issue, the Type 1 Diabetes Genetics Consortium recruited 3,892 families, including 4,422 affected sib-pairs. After genotyping 6,090 markers, linkage analyses of these families were performed, using a novel method and taking into account factors such as genotype at known susceptibility loci. RESULTS-Evidence for linkage was robust at the HLA and INS loci, with logarithm of odds (LOD) scores of 398.6 and 5.5, respectively. There was suggestive support for five other loci. Stratification by other risk factors (including HLA and age at diagnosis) identified one convincing region on chromosome 6q14 showing linkage in male subjects (corrected LOD = 4.49; replication P = 0.0002), a locus on chromosome 19q in HLA identical siblings (replication P = 0.006), and four other suggestive loci. CONCLUSIONS-This is the largest linkage study reported for any disease. Our data indicate there are no major type 1 diabetes subtypes definable by linkage analyses; susceptibility is caused by actions of HLA and an apparently random selection from a large number of modest-effect loci; and apart from HLA and INS, there is no important susceptibility factor discoverable by linkage methods.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3046821

Affiliations:

Le document en format XML

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<front><div type="abstract" xml:lang="en">OBJECTIVE-Interactions between genetic and environmental factors lead to immune dysregulation causing type 1 diabetes and other autoimmune disorders. Recently, many common genetic variants have been associated with type 1 diabetes risk, but each has modest individual effects. Familial clustering of type 1 diabetes has not been explained fully and could arise from many factors, including undetected genetic variation and gene interactions. RESEARCH DESIGN AND METHODS-To address this issue, the Type 1 Diabetes Genetics Consortium recruited 3,892 families, including 4,422 affected sib-pairs. After genotyping 6,090 markers, linkage analyses of these families were performed, using a novel method and taking into account factors such as genotype at known susceptibility loci. RESULTS-Evidence for linkage was robust at the HLA and INS loci, with logarithm of odds (LOD) scores of 398.6 and 5.5, respectively. There was suggestive support for five other loci. Stratification by other risk factors (including HLA and age at diagnosis) identified one convincing region on chromosome 6q14 showing linkage in male subjects (corrected LOD = 4.49; replication P = 0.0002), a locus on chromosome 19q in HLA identical siblings (replication P = 0.006), and four other suggestive loci. CONCLUSIONS-This is the largest linkage study reported for any disease. Our data indicate there are no major type 1 diabetes subtypes definable by linkage analyses; susceptibility is caused by actions of HLA and an apparently random selection from a large number of modest-effect loci; and apart from HLA and INS, there is no important susceptibility factor discoverable by linkage methods.</div>
</front>
</TEI>
<affiliations><list><country><li>Australie</li>
<li>Danemark</li>
<li>France</li>
<li>Royaume-Uni</li>
<li>États-Unis</li>
</country>
<region><li>Alabama</li>
<li>Angleterre</li>
<li>Angleterre de l'Est</li>
<li>Californie</li>
<li>Maryland</li>
<li>Virginie</li>
<li>État de New York</li>
<li>Île-de-France</li>
</region>
<settlement><li>Cambridge</li>
<li>Paris</li>
</settlement>
<orgName><li>Université de Cambridge</li>
</orgName>
</list>
<tree><country name="Australie"><noRegion><name sortKey="Morahan, Grant" sort="Morahan, Grant" uniqKey="Morahan G" first="Grant" last="Morahan">Grant Morahan</name>
</noRegion>
<name sortKey="James, Ian" sort="James, Ian" uniqKey="James I" first="Ian" last="James">Ian James</name>
<name sortKey="Mehta, Munish" sort="Mehta, Munish" uniqKey="Mehta M" first="Munish" last="Mehta">Munish Mehta</name>
<name sortKey="Mehta, Munish" sort="Mehta, Munish" uniqKey="Mehta M" first="Munish" last="Mehta">Munish Mehta</name>
<name sortKey="Morahan, Grant" sort="Morahan, Grant" uniqKey="Morahan G" first="Grant" last="Morahan">Grant Morahan</name>
</country>
<country name="États-Unis"><region name="Virginie"><name sortKey="Chen, Wei Min" sort="Chen, Wei Min" uniqKey="Chen W" first="Wei-Min" last="Chen">Wei-Min Chen</name>
</region>
<name sortKey="Akolkar, Beena" sort="Akolkar, Beena" uniqKey="Akolkar B" first="Beena" last="Akolkar">Beena Akolkar</name>
<name sortKey="Erlich, Henry A" sort="Erlich, Henry A" uniqKey="Erlich H" first="Henry A." last="Erlich">Henry A. Erlich</name>
<name sortKey="Hilner, Joan E" sort="Hilner, Joan E" uniqKey="Hilner J" first="Joan E." last="Hilner">Joan E. Hilner</name>
<name sortKey="Nierras, Concepcion" sort="Nierras, Concepcion" uniqKey="Nierras C" first="Concepcion" last="Nierras">Concepcion Nierras</name>
<name sortKey="Rich, Stephen S" sort="Rich, Stephen S" uniqKey="Rich S" first="Stephen S." last="Rich">Stephen S. Rich</name>
</country>
<country name="France"><region name="Île-de-France"><name sortKey="Julier, Cecile" sort="Julier, Cecile" uniqKey="Julier C" first="Cecile" last="Julier">Cecile Julier</name>
</region>
<name sortKey="Julier, Cecile" sort="Julier, Cecile" uniqKey="Julier C" first="Cecile" last="Julier">Cecile Julier</name>
</country>
<country name="Danemark"><noRegion><name sortKey="Nerup, J Rn" sort="Nerup, J Rn" uniqKey="Nerup J" first="J Rn" last="Nerup">J Rn Nerup</name>
</noRegion>
<name sortKey="Pociot, Flemming" sort="Pociot, Flemming" uniqKey="Pociot F" first="Flemming" last="Pociot">Flemming Pociot</name>
</country>
<country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Todd, John A" sort="Todd, John A" uniqKey="Todd J" first="John A." last="Todd">John A. Todd</name>
</region>
</country>
</tree>
</affiliations>
</record>

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Tests for Genetic Interactions in Type 1 Diabetes: Linkage and Stratification Analyses of 4,422 Affected Sib-Pairs

Tests for Genetic Interactions in Type 1 Diabetes: Linkage and Stratification Analyses of 4,422 Affected Sib-Pairs

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