Identification and Replication of a Novel Obesity Locus on Chromosome 1q24 in Isolated Populations of Cilento

Ciullo, Marina; Nutile, Teresa; Dalmasso, Cyril; Sorice, Rossella; Bellenguez, Céline; Colonna, Vincenza; Persico, M. Graziella; Bourgain, Catherine

doi:10.2337/db07-0970

Cited by 17 publications

(12 citation statements)

References 43 publications

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“…The consistent effect observed with both plasma lipid and lipoprotein traits suggests that INSIG2 may play a The genetic variant of INSIG2 that was recently implicated in obesity through a genome-wide association study performed in the Framingham Heart Study 1 has been inconsistently replicated by other research groups. [3][4][5][6][7][8][9][10][11][12][13][14] In the present study, using 32 SNPs, we show that a dense map of the INSIG2 locus, including the previously reported SNP, rs7566605, did not yield a significant association with BMI. The lack of reproducibility of rs7566605 with obesity seen in our study could be due to several reasons, including insufficient power, heterogeneity of ascertainment, and/or unknown gene-gene or gene-environment interactions.…”

Section: Discussioncontrasting

confidence: 54%

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Fine Mapping of the Insulin-Induced Gene 2 Identifies a Variant Associated With LDL Cholesterol and Total Apolipoprotein B Levels

Bailey

Paré

et al. 2010

Circ Cardiovasc Genet

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Background-In a whole-genome scan, a single nucleotide polymorphism (SNP) (rs7566605) upstream of the insulin-induced gene 2 (INSIG2) was shown to influence body mass index and obesity in the Framingham Heart Study, with replication of these results in an additional 4 of 5 studies. However, other studies could not replicate the association. Because INSIG2 plays an important role in cholesterol biosynthesis, we hypothesized that human INSIG2 variants might play a role in the regulation of plasma lipid and lipoprotein levels. Methods and Results-We selected tagging SNPs spanning Ͼ100 kb of INSIG2 locus and sequenced 18 434 base pairs to discover novel SNPs. Thirty-two SNPs were genotyped in 645 individuals from the Quebec Family Study. Two SNPs (rs10490626 and rs12464355) were associated with plasma low-density lipoprotein cholesterol (LDL-C) (PϽ0.0015) and total apolipoprotein B (apoB) levels (PϽ0.014), whereas no association was found between any SNP and body mass index. We replicated the finding of rs10490626 for both LDL-C and total apoB in additional study samples, including 758 individuals from Saguenay-Lac St. Jean, Quebec (Pϭ0.040 for LDL-C, Pϭ0.044 for apoB), 3247 Europeans (Pϭ0.028 for LDL-C, Pϭ0.030 for apoB), and 1695 South Asians (Pϭ0.0036 for LDL-C, Pϭ0.034 for apoB) from the INTERHEART study (for LDL-C, the combined 2-sided Pϭ6.2ϫ10 Ϫ5 and for total apoB, Pϭ0.0011). Furthermore, we identified a variant in the human sorbin and SH 3 -domain-containing-1 gene that was associated with INSIG2 mRNA levels, and this SNP was shown to act in combination with rs10490626 to affect LDL-C (Pϭ0.022) in the Quebec Family Study and in INTERHEART South Asians (Pϭ0.019) and Europeans (Pϭ0.052). A n association between a single nucleotide polymorphism (SNP) (rs7566605) in the insulin-induced gene 2 (IN-SIG2) and body mass index (BMI) was discovered in a genome-wide scan of 86 604 SNPs in 923 individuals from the Framingham Heart Study. 1 The association was replicated in an additional 4 of 5 independent study samples composed of western Europeans and blacks. 1 A follow-up study reproduced this result in 5 of 9 samples. 2 However, subsequent studies performed by other groups could not replicate the association. [3][4][5][6][7][8][9][10][11][12][13][14] A recent meta-analysis suggested that different study designs might have contributed to these heterogeneous results. 15 Conclusion-These Clinical Perspective on p 461Although the physiologic role of INSIG2 in obesity is unclear, there is strong evidence suggesting that the gene plays a key role in both fatty acid and cholesterol biosynthesis. Double-knockout mice containing germline disruption of Received October 30, 2009; accepted August 20, 2010 20 A limitation of previous gene association studies involving INSIG2 is that they have all focused on a single SNP (ie, rs7566605) and/or on 1 trait (obesity or BMI). The inconsistency of the association with obesity among studies could be due to differential linkage disequilibrium (LD) with a causal SNP or differential corre...

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Section: Discussioncontrasting

confidence: 54%

“…2 However, subsequent studies performed by other groups could not replicate the association. [3][4][5][6][7][8][9][10][11][12][13][14] A recent meta-analysis suggested that different study designs might have contributed to these heterogeneous results. 15 …”

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confidence: 99%

Fine Mapping of the Insulin-Induced Gene 2 Identifies a Variant Associated With LDL Cholesterol and Total Apolipoprotein B Levels

Bailey

Paré

et al. 2010

Circ Cardiovasc Genet

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“…In particular, a recent linkage analysis of quantitative traits in the less inbred isolated populations of Cilento was based on this procedure. Interestingly, this led to the detection and replication of a new locus for BMI on chromosome 1q24 [Ciullo et al, 2008]. Other usages, including implementing simulation-based linkage statistics on larger sub-pedigrees, might also be interesting to consider.…”

Section: Discussionmentioning

confidence: 99%

A multiple splitting approach to linkage analysis in large pedigrees identifies a linkage to asthma on chromosome 12

Bellenguez

Ober

Bourgain

2008

Genetic Epidemiology

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Large genealogies are potentially very informative for linkage analysis. However, the software available for exact nonparametric multipoint linkage analysis is limited with respect to the complexity of the families it can handle. A solution is to split the large pedigrees into sub-families meeting complexity constraints. Different methods have been proposed to “best” split large genealogies. Here, we propose a new procedure in which linkage is performed on several carefully chosen sub-pedigree sets from the genealogy instead of using just a single sub-pedigree set. Our multiple splitting procedure capitalizes on the sensitivity of linkage results to family structure and has been designed to control computational feasibility and global type I error. We describe and apply this procedure to the extreme case of the highly complex Hutterite pedigree and use it to perform a genome-wide linkage analysis on asthma. The detection of a genome-wide significant linkage for asthma on chromosome 12q21 illustrates the potential of this multiple splitting approach.

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“…PRDX6 is an antioxidant enzyme with calcium-independent phospholipase A2 activity ( 42 ). PRDX6 was identifi ed in a recent study as a possible candidate gene underlying a novel obesity locus on chromosome 1q24 in an isolated population of Cilento, Italy ( 43 ). Recently, a study of 21,000 individuals identifi ed PRDX6 associated with body mass index (BMI) as an indicator of obesity ( 44 ).…”

Section: Canonical Pathway Analysismentioning

confidence: 99%

Integrating expression profiling and whole-genome association for dissection of fat traits in a porcine model

Ponsuksili

Muráni

Brand

et al. 2011

Journal of Lipid Research

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This article is available online at http://www.jlr.org lated to body composition, leanness, and obesity. Traits related to fatness are important not only as economic factors in pork production but also because of their association with serious diseases in humans ( 1, 2 ). Pigs share many similarities with humans in physiology and genomes and, therefore, provide a good model to study the genetic determination of complex traits ( 3 ). The study of a porcine model is benefi cial because a number of fatness traits (e.g., "fat area") can be determined quantitatively with great accuracy and reproducibility post mortem, and RNA samples are available for transcriptomic approaches. In humans, indices for obesity are obtained intra vitam (i.e., body mass index or body fat percentage are estimated based on statistical models of measures of near-infrared interactance, body average density measurement, bioelectrical impedance analysis, or anthropometric methods) ( 4 ).Functional genomics provides an insight into the molecular processes underlying phenotypic differences. The analysis of trait-correlated expression levels reveals genes belonging to pathways or networks relevant for the control of quantitative traits. However, holistic expression profi ling does not often discriminate differential expression of the genes as either an effect or a cause of variation.Genome-wide association studies (GWAS) in large natural populations of unrelated individuals have resulted in the association of many genes with complex traits (http:// www. genome.gov/gwastudies). Unfortunately, for a conAbstract Traits related to fatness, important as economic factors in pork production, are associated with serious diseases in humans. Genetical genomics is a useful approach for studying the effects of genetic variation at the molecular level in biological systems. Here we applied a whole-genome association analysis to hepatic gene expression traits, focusing on transcripts with expression levels that correlated with fatness traits in a porcine model. A total of 150 crossbred pigs [Pietrain×(German Large White × German Landrace)] were studied for transcript levels in the liver. The 24K Affymetrix expression microarrays and 60K Illumina single nucleotide polymorphism (SNP) chips were used for genotyping. A total of 663 genes, whose expression signifi cantly correlated with the trait "fat area," were analyzed for enrichment of functional annotation groups as defi ned in the Ingenuity Pathways Knowledge Base (IPKB). Genes involved in metabolism of various macromolecules and nutrients as well as functions related to dynamic cellular processes correlated with fatness traits. Regions affecting the transcription levels of these genes were mapped and revealed 4,727 expression quantitative trait loci (eQTL) at P < 10 The metabolic activities of the liver are essential for providing fuel to the peripheral organs. Most components absorbed by the intestine pass through the liver, which enables it to regulate the levels of many metabolites in the blood. Storage, ...

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Identification and Replication of a Novel Obesity Locus on Chromosome 1q24 in Isolated Populations of Cilento

Cited by 17 publications

References 43 publications

Fine Mapping of the Insulin-Induced Gene 2 Identifies a Variant Associated With LDL Cholesterol and Total Apolipoprotein B Levels

Fine Mapping of the Insulin-Induced Gene 2 Identifies a Variant Associated With LDL Cholesterol and Total Apolipoprotein B Levels

A multiple splitting approach to linkage analysis in large pedigrees identifies a linkage to asthma on chromosome 12

Integrating expression profiling and whole-genome association for dissection of fat traits in a porcine model

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