Post Genome-Wide Association Studies of Novel Genes Associated with Type 2 Diabetes Show Gene-Gene Interaction and High Predictive Value

被引：120

作者：

Cauchi, Stephane ^{[1
]}

Meyre, David ^{[1
]}

Durand, Emmanuelle ^{[1
]}

Proenca, Christine ^{[1
]}

Marre, Michel ^{[2
,3
,4
]}

Hadjadj, Samy ^{[5
]}

Choquet, Helene ^{[1
]}

De Graeve, Franck ^{[1
]}

Gaget, Stefan ^{[1
]}

Allegaert, Frederic ^{[1
]}

Delplanque, Jerome ^{[1
]}

Permutt, Marshall Alan ^{[6
]}

Wasson, Jon ^{[6
]}

Blech, Ilana ^{[7
]}

Charpentier, Guillaume ^{[8
]}

Balkau, Beverley ^{[9
,10
]}

Vergnaud, Anne-Claire ^{[11
]}

Czernichow, Sebastien ^{[11
,12
]}

Patsch, Wolfgang ^{[13
]}

Chikri, Mohamed ^{[14
]}

Glaser, Benjamin ^{[7
]}

Sladek, Robert ^{[15
,16
,17
]}

Froguel, Philippe ^{[1
,18
]}

机构：

[1] Inst Pasteur, Inst Biol, CNRS 8090, F-59019 Lille, France

[2] INSERM U695, Paris, France

[3] Rene Diderot Paris 7 Univ, Paris, France

[4] Bichat Claude Bernard Hosp, Dept Endocrinol Diabetol & Nutrit, Paris, France

[5] UFR Med Pharm, Univ Poitiers, INSERM U927, CIC INSERM 0801,CHU Poitiers, Poitiers, France

[6] Washington Univ, Sch Med, St Louis, MO USA

[7] Hadassah Hebrew Univ, Med Ctr, Dept Internal Med, Endocrinol & Metabolism Serv, Jerusalem, Israel

[8] Corbeil Essonnes Hosp, Endocrinol Diabetol Unit, Corbeil Essonnes, France

[9] INSERM U780 IFR69, Villejuif, France

[10] Univ Paris Sud, Paris, France

[11] PARIS 13 CRNH IdF, CNAM, U1125 INRA, UMR U557 INSERM, Bobigny, France

[12] Assistance Publ Hop Paris AP HP, Dept Sante Publ, Hop Avicenne, Bobigny, France

[13] Paracelsus Med Univ, Landeskrankenhaus Salzburg, Dept Lab Med, Salzburg, Austria

[14] Route Sidi Harazem, Pharm Fez, Fac Med, Lab Biochem, Fes, Morocco

[15] McGill Univ, Fac Med, Dept Human Genet, Montreal, PQ, Canada

[16] McGill Univ, Fac Med, Dept Med, Montreal, PQ, Canada

[17] McGill Univ, Fac Med, Dept Pediat, Montreal, PQ, Canada

[18] Imperial Coll London, Hammersmith Hosp, Genom Med, London, England

来源：

PLOS ONE | 2008年 / 3卷 / 05期

基金：

英国医学研究理事会;

关键词：

D O I：

10.1371/journal.pone.0002031

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Background: Recently, several Genome Wide Association (GWA) studies in populations of European descent have identified and validated novel single nucleotide polymorphisms (SNPs), highly associated with type 2 diabetes (T2D). Our aims were to validate these markers in other European and non-European populations, then to assess their combined effect in a large French study comparing T2D and normal glucose tolerant (NGT) individuals. Methodology/Principal Findings: In the same French population analyzed in our previous GWA study (3,295 T2D and 3,595 NGT), strong associations with T2D were found for CDKAL1 (ORrs7756992 = 1.30[1.19-1.42], P = 2.3 x 10(-9)), CDKN2A/2B (ORrs10811661 = 0.74[0.66-0.82], P = 3.5 x 10(-8)) and more modestly for IGFBP2 (ORrs1470579 = 1.17[1.07-1.27], P = 0.0003) SNPs. These results were replicated in both Israeli Ashkenazi (577 T2D and 552 NGT) and Austrian (504 T2D and 753 NGT) populations (except for CDKAL1) but not in the Moroccan population (521 T2D and 423 NGT). In the overall group of French subjects (4,232 T2D and 4,595 NGT), IGFBP2 and CXCR4 synergistically interacted with (LOC38776, SLC30A8, HHEX) and (NGN3, CDKN2A/2B), respectively, encoding for proteins presumably regulating pancreatic endocrine cell development and function. The T2D risk increased strongly when risk alleles, including the previously discovered T2D-associated TCF7L2 rs7903146 SNP, were combined (8.68-fold for the 14% of French individuals carrying 18 to 30 risk alleles with an allelic OR of 1.24). With an area under the ROC curve of 0.86, only 15 novel loci were necessary to discriminate French individuals susceptible to develop T2D. Conclusions/Significance: In addition to TCF7L2, SLC30A8 and HHEX, initially identified by the French GWA scan, CDKAL1, IGFBP2 and CDKN2A/2B strongly associate with T2D in French individuals, and mostly in populations of Central European descent but not in Moroccan subjects. Genes expressed in the pancreas interact together and their combined effect dramatically increases the risk for T2D, opening avenues for the development of genetic prediction tests.

引用

页数：11

共 33 条

[1]

[Anonymous], DIABETES

[2] TCF7L2 is reproducibly associated with type 2 diabetes in various ethnic groups: a global meta-analysis [J].

Cauchi, Stephane ;

El Achhab, Younes ;

Choquet, Helene ;

Dina, Christian ;

Krempler, Franz ;

Weitgasser, Raimund ;

Nejjari, Chakib ;

Patsch, Wolfgang ;

Chikri, Mohamed ;

Meyre, David ;

Froguel, Philippe .

JOURNAL OF MOLECULAR MEDICINE-JMM, 2007, 85 (07) :777-782

[3] ZnT-8, a pancreatic beta-cell-specific zinc transporter [J].

Chimienti, F ;

Favier, A ;

Seve, M .

BIOMETALS, 2005, 18 (04) :313-317

[4] In vivo expression and functional characterization of the zinc transporter ZnT8 in glucose-induced insulin secretion [J].

Chimienti, Fabrice ;

Devergnas, Severine ;

Pattou, Francois ;

Schuit, Frans ;

Garcia-Cuenca, Rachel ;

Vandewalle, Brigitte ;

Kerr-Conte, Julie ;

Van Lommel, Leentje ;

Grunwald, Didier ;

Favier, Alain ;

Seve, Michel .

JOURNAL OF CELL SCIENCE, 2006, 119 (20) :4199-4206

[5] A common polymorphism in the promoter of UCP2 is associated with decreased risk of obesity in middle-aged humans [J].

Esterbauer, H ;

Schneitler, C ;

Oberkofler, H ;

Ebenbichler, C ;

Paulweber, B ;

Sandhofer, F ;

Ladurner, G ;

Hell, E ;

Strosberg, AD ;

Patsch, JR ;

Krempler, F ;

Patsch, W .

NATURE GENETICS, 2001, 28 (02) :178-183

[6]

FLOREZ JC, 2007, DIABETES

[7] Genome-wide association studies provide new insights into type 2 diabetes aetiology [J].

Frayling, Timothy M. .

NATURE REVIEWS GENETICS, 2007, 8 (09) :657-662

[8] Polymorphisms in the IDE-KIF11-HHEX gene locus are reproducibly associated with type 2 diabetes in a Japanese population [J].

Furukawa, Yasushi ;

Shimada, Takeshi ;

Furuta, Hiroto ;

Matsuno, Shohei ;

Kusuyama, Akiko ;

Doi, Asako ;

Nishi, Masahiro ;

Sasaki, Hideyuki ;

Sanke, Tokio ;

Nanjo, Kishio .

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2008, 93 (01) :310-314

[9]

GRARUP N, 2007, DIABETES

[10]

HADJADJ S, PROGNOSTIC VAL UNPUB

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