Overweight condition and waist circumference and a candidate gene within the 12q24 locus.

0.17 MB·English

by  Gragnoli, Claudia

GragnoliCardiovascularDiabetology2013,12:2 CARDIO
http://www.cardiab.com/content/12/1/2 VASCULAR
DIABETOLOGY
ORIGINAL INVESTIGATION Open Access
Overweight condition and waist circumference
and a candidate gene within the 12q24 locus
Claudia Gragnoli1,2,3
Abstract
Aims: Obesity and obesity-associated phenotypesare linked to the chromosome12q24 locus, the non-insulin-
dependent-diabetes 2(NIDDM2) locus. The gene of proteasome modulator 9 (PSMD9) lies inthe NIDDM2 region
and is linked to type 2 diabetes (T2D), microvascular and macrovascular complications ofT2D.
We aimed atstudying whether thePSMD9 T2D risk single nucleotide polymorphisms (SNPs) IVS3+nt460, IVS3+nt437,
and 197G are linked to obesity, overweight status and waist circumference inItalian T2D families.
Methods and results: We screened 200 Italians T2D siblings/families for PSMD9 variants. Using Merlin software, we
performed non-parametric linkage analysis to testfor linkage withobesityand overweight condition and variance
component analysis to test for linkage with waist circumference inour T2D siblings/families dataset.
Our study shows thatthePSMD9 SNPs IVS3+nt460, IVS3+nt437, and 197G are inlinkage with overweight condition
and waist circumference inItalians. The statistical power tests performed via simulations on real data confirm that
theresultsare not due to random chance.
Conclusions: In summary, the linkage strategy using a homogeneous family/subject dataset can identify a gene
contributing to a complex trait. PMSD9may be atleast one of the genes responsible for thelinkage to obesityand
obesity-associated phenotypesatthe locus 12q24 inother populations.
Keywords: PSMD9, SNP,Linkage, 12q24, Overweight, Waist
Introduction transcription of the ligand-dependent retinoid-target genes
SeveralgroupsreportedlinkagewithintheNIDDM2(non- (www.millipore.com/pathways/pathviewer.do?pathwayId=76).
insulin-dependent diabetes mellitus) locus at chromosome Since PSMD9 is a coactivator of insulin gene transcription
12q24 to T2D, obesity, central fat mass and waist circum- [9],andinpancreaticoverexpressionoftransgenicmicecause
ference [1-8]. Within the 12q24 locus lies the gene of diabetes[11],PSMD9variantsmaycontributetoT2Daswell
proteasome modulator 9 (PSMD9), a transcriptional regu- astoobesity,overweightstatusandvisceralobesity.
lator of the insulin gene, highly expressed in pancreaticis- We reported that PSMD9 may rarely cause T2D by
lets [9]. PSMD9 is a ubiquitous protein of eukaryotic cells unique mutations [12] and that is linked to T2D [13],
and part of the 26S proteasome complex, contributing to maturity-onset diabetes of the young 3 (MODY3) [14],
intracellularproteinsdegradationintoantigenicpeptidesin T2D-microvascular[15-18]andT2D-macrovascularcom-
the immuneresponse to antigenpresentationbyMHC class plications [19], hypercholesterolemia [20], hypertension
Icells(www.genecards.org/cgi-bin/carddisp.pl?gene=PSMD9). [21],carpaltunnelsyndrome[22],anddepression[23].Of
PSMD9 may play a role in inflammation as part of the note, the 12q24 locus is not only linked to T2D [24],
autoimmune process [10]. Further, PSMD9 regulates the macrovascular[25,26] and microvasculardisease[27],but
also to dyslipidemia [28], hypertension, obesity, [2], body
Correspondence:[email protected] massindexandC-reactiveproteinjointly[29],cat-specific
1LaboratoryofMolecularGeneticsofComplexandMonogenicDisorders, IgEandtotalIgEinasthma[30],andmostinterestinglyto
DepartmentofMedicineandCellular&MolecularPhysiologyand
bipolar disorder [31] and depression [32]. Also a recent
Biostatistics,M.S.HersheyMedicalCenter,PennStateUniversityCollegeof
Medicine,Hershey,PA,USA studyhasreportedthatadeletionatthelocus12q24.33is
2CenterforBiotechnologyandDepartmentofBiology,TempleUniversity’s significantly correlated with height, suggesting that this
CollegeofScience&Technology,Philadelphia,PA,USA
Fulllistofauthorinformationisavailableattheendofthearticle
©2013Gragnoli;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative
CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and
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locusisimportantindeterminingheightandmaycontrib- Linkageanalysis
utetoheightvariationinhumanpopulations[33]. We tested in the 200 Italians families for linkage of the
The aim of the present study is to identify whether PSMD9 SNPswith maximum lifetimeobesity, maximum
PSMD9 IVS3+nt460, IVS3+nt437, and 197G single nu- lifetimeoverweightconditionandwaist circumference.
cleotide polymorphisms (SNPs) may be linked to max- The non-parametric linkage analysis for the qualitative
imum lifetime obesity, maximum lifetime overweight phenotypes and the variance component analysis for the
status and visceral obesity measured by waist circumfer- quantitativetraitwereperformedbyusingMerlinsoftware
enceinanItalian familydataset. [49], calculating the allelic frequency from the total 200
genotyped families. Merlin analyzed all the informative
Methods families within this dataset. All results are reported as
Ethicsstatement LODscorescalculatedbyMerlin.
The subjects were all recruited from center Italy follow-
ing the Helsinki declaration guidelines. Subjects gave Simulations
written informed consent and the Penn State College of For each test performed, to exclude the presence of any
MedicineEthical Committeeapprovedthestudy. results due to random chance, we calculated how many
times similar P-values were expected by chance in 1,000
Families replicates of simulations by using the gene dropping
We recruited 200 Italian T2D affected siblings and fam- method: this analysis replaces real data with simulated
ilies. We excluded all families with identical twins and data, while maintaining the pedigree structure, allele fre-
confirmed that at least three generations were Italian. quencies and recombination fraction. These datasets are
Italians are a homogeneous population living in a penin- generated underthenull hypothesisofnolinkage.
sula and they are suitable for genetic studies due to lack
of genetic admixture. This family dataset has helped Results
studying and identifying T2D and MODYgenes contrib- The results (LOD score, P-value and empirical P-value)
utingtodisease[34-48]. of the non-parametric linkage analysis performed for the
qualitative phenotypes overweight status and obesity are
Clinicalphenotyping showninTable1.
We characterized the Italian families for maximum life- The results of the variance component analysis per-
timebodymassindex[BMI=weightinKg/(heightinm)2], formed for the quantitative trait waist circumference in
indicating as overweight those with maximum lifetime cm with the LOD score, P-value, empirical P-value, trait
BMI ≥25 and as obese those with maximum lifetime heritability and trait heritability attributable to the SNPs
BMI ≥30. We measured also the waist circumference in under study arereportedinTable2.
cm. BMI and waist circumference during pregnancy in
females were not considered. Phenotypes are described Discussion
as unknown if diagnosis is unclear because data are Our analyses show that the PSMD9 IVS3+nt460, IVS3
lacking. In our 200 Italian families, data are less than +nt437, and 197G SNPs are in linkage with maximum
100%foreachphenotype. lifetime overweight and with waist circumference, repre-
senting visceral obesity. Further, there is a trend towards
Sequencing linkage with obesity. The reduced number of families
Via PCR, we amplified with specific primers in the af- meeting the criteria for obesity may have reduced the
fected and unaffected family members the IVS3 PSMD9 powertodetect linkage.
region containing the +nt460 A/G and +nt437 C/T SNPs The 12q24.2 chromosome bears the NIDDM2 locus,
and the exon 5 coding region containing the E197G A/G the MODY3 gene HNF-1α, cause of T2D and MODY3,
SNP. We directly sequenced the PCR products, status respectively. We previously reported that unique rare
post-purification via EXOSAP-IT on an automated ABI PSMD9 mutations contribute to T2D and that the IVS3
3730Sequencer. +nt460, IVS3+nt437, and 197G SNPs are linked to T2D
Table1Non-parametriclinkageanalysisofphenotypesofthe200ItalianfamiliesbyMerlinsoftware
Phenotype Prevalence Families Lodscore P-value EmpiricalP-value
Overweight 85.20% 112 1.22 0.009 0.004
Obesity 47.50% 42 0.62 0.050 0.053
Prevalence=phenotypeprevalenceamongthefamilysubjectsstudied;Families=familiesnumberanalyzed;Lodscore=derivedfromthenon-parametric
linkageanalysisbyMerlin;EmpiricalP-value=derivedfrom1000replicatesbyusingthegenedroppingmethod;Overweight=presenceofBMI≥25;
Obesity=presenceofBMI≥30.
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Table2Variancecomponentlinkageanalysisofthewaistcircumferenceincmofthe200ItalianfamiliesbyMerlin
software
Quantitativetrait Families Traitheritability Genetraitheritability Lodscore P-value EmpiricalP-value
Waistincm 108 50.66% 49.17% 0.93 0.020 0.023
Families=familiesnumberanalyzed;Lodscore=derivedfromthequantitativetraitanalysisbyMerlin;EmpiricalP-value=derivedfrom1000replicatesbyusing
thegenedroppingmethod;TraitHeritability=HeritabilityofthequantitativetraitcalculatedbyMerlin;TraitHeritabilityattributabletothePSMD9SNPs.
and MODY3 in our Italian dataset [12,13,14]. Of note, immune response (www.genecards.org/cgi-bin/carddisp.
PSMD9 linkage to micro- and macro-vascular disease of pl?gene=PSMD9). PSMD9 may playan inflammatoryrole
T2D [15-19], hypercolesterolemia [20], hypertension [21] inautoimmunity[10]withpleiotropiceffects.Ofnote,the
and depression [23] suggest a potential role in mediating finding that 12q24.33 deletion affects height [33] could
an inflammatory response, which could explain the pres- representanoutcomeoftheinheritanceoffactorspredis-
enceoflinkagetotheobesity-associatedphenotypes. posing to pre-disease states and thus affecting adult final
Our results demonstrating the presence of linkage to growth. In fact, height is inversely associated with cardio-
overweight condition as well as to waist circumference vascular disease [50] and cardiovascular risk factors, such
are encouraging as the same locus is in linkage in other as insulin resistance [51]. Thus, the 12q24 locus could
populations with obesity, central fat mass and waist bear the gene or genes contributing to waist circumfer-
circumference [1,2,8]. The data should be replicable in ence,insulin resistance, cardiovasculardisease, depression
other ethnic groups and are of high interest to the and height determination. Itwould beof interest tostudy
groups who revealed linkage in the same locus, which the roleofPSMD9 in asthma and IgE-mediated disorders
maybeexplainedbythePSMD9variants. aswellasinfinaladultheight.
In addition, we again provethe strengthand validity of
Competinginterest
the linkage approach in identifying genes in complex
Theauthorhasnotconflictofinteresttodeclare.
disorders. In fact, family-based linkage studies are safer
in their statistical nature compared to association stud- Acknowledgments
SpecialthanksgototheMolecularBiologystaffofBiosBiotechMulti-
ies. Also, we consider that the use of microsatellites as
DiagnosticHealthCenter(Rome,Italy),whichhasprovidedtechnicalaswell
markers in the past may have negatively affected the re- asfinancialsupportforthisstudy.
sults of the linkage, especially in polygenic diseases and
Funding
with the use of affected siblings, as these markers may
ThisworkwassupportedbyPennStateCollegeofMedicine.
undergo duplications and mutations in vivo. In fact, pre-
viously we could not identify linkage withT2D at 12q24 Authordetails
1LaboratoryofMolecularGeneticsofComplexandMonogenicDisorders,
using multiple highly informative and polymorphic
DepartmentofMedicineandCellular&MolecularPhysiologyand
microsatellites within the same family dataset (data not Biostatistics,M.S.HersheyMedicalCenter,PennStateUniversityCollegeof
shown) in which the linkage was identified using SNPs Medicine,Hershey,PA,USA.2CenterforBiotechnologyandDepartmentof
Biology,TempleUniversity’sCollegeofScience&Technology,Philadelphia,
[13].Hence,SNP-basedlinkagestudiesaremorereliable.
PA,USA.3MolecularBiologyLaboratory,BiosBiotechMulti-DiagnosticHealth
Also, the family dataset should be ethnically Center,Rome,Italy.
homogenoustoallow resultstoberevealed.
PSMD9 should be screened in other populations for Received:19December2012Accepted:28December2012
Published:3January2013
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doi:10.1186/1475-2840-12-2
Citethisarticleas:Gragnoli:Overweightconditionandwaist
circumferenceandacandidategenewithinthe12q24locus.
CardiovascularDiabetology201312:2.
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