Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes

被引：298

作者：

Strawbridge, Rona J. ^{[2
]}

Dupuis, Josee ^{[3
,4
]}

Prokopenko, Inga ^{[5
,6
]}

Barker, Adam ^{[7
]}

Ahlqvist, Emma ^{[8
]}

Rybin, Denis ^{[9
]}

Petrie, John R. ^{[10
]}

Travers, Mary E. ^{[5
]}

Bouatia-Naji, Nabila ^{[11
,12
]}

Dimas, Antigone S. ^{[6
,13
]}

Nica, Alexandra ^{[13
]}

Wheeler, Eleanor ^{[14
]}

Chen, Han ^{[3
]}

Voight, Benjamin F. ^{[1
,15
,16
]}

Taneera, Jalal ^{[8
]}

Kanoni, Stavroula ^{[17
]}

Peden, John F. ^{[6
,18
]}

Turrini, Fabiola ^{[8
,19
]}

Gustafsson, Stefan ^{[20
]}

Zabena, Carina ^{[21
,22
]}

Almgren, Peter ^{[8
]}

Barker, David J. P. ^{[23
]}

Barnes, Daniel ^{[7
]}

Dennison, Elaine M. ^{[24
]}

Eriksson, Johan G. ^{[25
,26
,27
,28
]}

Eriksson, Per ^{[2
]}

Eury, Elodie ^{[11
,12
]}

Folkersen, Lasse ^{[29
]}

Fox, Caroline S. ^{[4
,30
]}

Frayling, Timothy M. ^{[31
]}

Goel, Anuj ^{[6
,18
]}

Gu, Harvest F. ^{[32
]}

Horikoshi, Momoko ^{[5
,6
]}

Isomaa, Bo ^{[27
,33
]}

Jackson, Anne U. ^{[34
]}

Jameson, Karen A. ^{[24
]}

Kajantie, Eero ^{[25
,35
]}

Kerr-Conte, Julie ^{[11
,36
]}

Kuulasmaa, Teemu ^{[37
,38
]}

Kuusisto, Johanna ^{[37
,38
]}

Loos, Ruth J. F. ^{[7
]}

Luan, Jian'an ^{[7
]}

Makrilakis, Konstantinos ^{[39
]}

Manning, Alisa K. ^{[3
]}

Teresa Martinez-Larrad, Maria ^{[21
,22
]}

Narisu, Narisu ^{[40
]}

Mannila, Maria Nastase ^{[2
]}

Ohrvik, John ^{[2
]}

Osmond, Clive ^{[24
]}

Pascoe, Laura ^{[41
]}

机构：

[1] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA

[2] Karolinska Inst, Karolinska Univ Hosp Solna, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden

[3] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[4] NHLBI, Framingham Heart Study, Framingham, MA USA

[5] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England

[6] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[7] Addenbrookes Hosp, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England

[8] Lund Univ, Dept Clin Sci Diabet & Endocrinol, Univ Hosp & Malmo, Malmo, Sweden

[9] Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA

[10] Univ Glasgow, BHF Cardiovasc Res Ctr, Glasgow, Lanark, Scotland

[11] Univ Lille Nord France, Lille, France

[12] Inst Pasteur, CNRS UMR 8199, Lille, France

[13] Univ Geneva, Sch Med, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland

[14] Wellcome Trust Sanger Inst, Metab Dis Grp, Hinxton, England

[15] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[16] Massachusetts Gen Hosp, Diabet Unit, Diabet Res Ctr, Boston, MA 02114 USA

[17] Harokopio Univ, Dept Dietet Nutr, Athens, Greece

[18] Univ Oxford, Dept Cardiovasc Med, Oxford, England

[19] Univ Verona, Dept Med, I-37100 Verona, Italy

[20] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

[21] CIBER Diabet & Enfermedades Metab Asociadas CIBER, Madrid, Spain

[22] Hosp Clin San Carlos, Fdn Invest Biomed, Madrid, Spain

[23] Oregon Hlth & Sci Univ, Heart Res Ctr, Portland, OR 97201 USA

[24] Univ Southampton, Southampton Gen Hosp, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England

[25] Natl Inst Hlth & Welf, Helsinki, Finland

[26] Helsinki Univ Cent Hosp, Unit Gen Practice, Helsinki, Finland

[27] Folkhalsan Res Ctr, Helsinki, Finland

[28] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland

[29] Karolinska Inst, Dept Med Solna, Expt Cardiovasc Res Unit, Stockholm, Sweden

[30] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA

[31] Univ Exeter, Peninsula Med Sch, Inst Biomed & Clin Sci, Exeter, Devon, England

[32] Karolinska Inst, Endocrinol & Diabet Unit, Dept Mol Med & Surg, Stockholm, Sweden

[33] Malmska Municipal Hlth Care Ctr & Hosp, Pietarsaari, Finland

[34] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[35] Helsinki Univ Cent Hosp, Hosp Children & Adolescents, Helsinki, Finland

[36] INSERM, UMR 859, F-59045 Lille, France

[37] Univ Kuopio, Dept Med, SF-70210 Kuopio, Finland

[38] Kuopio Univ Hosp, SF-70210 Kuopio, Finland

[39] Univ Athens, Sch Med, Laiko Gen Hosp, Dept Propaedeut Med 1, GR-11527 Athens, Greece

[40] Natl Human Genome Res Inst, NIH, Bethesda, MD USA

[41] Newcastle Univ, Inst Cell & Mol Biosci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[42] Uppsala Univ, Sci Life Lab, Dept Med Sci, Uppsala, Sweden

[43] Helsinki Univ Cent Hosp, Dept Med, Helsinki, Finland

[44] Univ Helsinki, Res Program Mol Med, Helsinki, Finland

[45] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[46] Uppsala Univ, Dept Publ Hlth & Caring Sci, Uppsala, Sweden

[47] Univ Oxford, John Radcliffe Hosp, Dept Cardiovasc Med, Oxford OX3 9DU, England

[48] Univ Oxford, Clin Trial Serv Unit, Oxford, England

[49] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England

[50] Ctr Noncommunicable Dis Pakistan, Karachi, Pakistan

来源：

DIABETES | 2011年 / 60卷 / 10期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

CORONARY HEART-DISEASE; BETA-CELL FUNCTION; SUSCEPTIBILITY LOCI; GLUCOSE-HOMEOSTASIS; INSULIN SENSITIVITY; POPULATION; TCF7L2; RISK; OBESITY; METAANALYSIS;

D O I：

10.2337/db11-0415

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

OBJECTIVE-Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired beta-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS-We have conducted a meta-analysis of genome-wide association tests of similar to 2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS-Nine SNPs at eight loci were associated with proinsulin levels (P < 5 x 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC3OA8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 x 10(-4)), improved beta-cell function (P = 1.1 x 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 x 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS-We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis. Diabetes 60:2624-2634, 2011

引用

页码：2624 / 2634

页数：11

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