publication . Article . Other literature type . 2012

Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases

Andrew Hattersley;
Open Access English
  • Published: 01 May 2012 Journal: PLOS GENETICS (issn: 1553-7404, Copyright policy)
  • Publisher: PUBLIC LIBRARY SCIENCE
Abstract
Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m2) compared to obese cases (BMI≥30 Kg/m2). We performed two case-control genome-wide studies using two accepted cut-offs for defining individuals as overweight or obese. We used 2,112 lean type 2 diabetes cases (BMI<25 kg/m2) or 4,123 obese cases (BMI≥30 kg/m2), and 54,412 un-stratified controls. Replication was performed in 2,881 lean cases or 8,702 obese cases, and 18,957 un-stratified con...
Subjects
free text keywords: Laminin, Obesity, Polymorphism, Single Nucleotide, High Mobility Group Proteins, Humans, Aged, Body Mass Index, Genome-Wide Association Study, Asian Continental Ancestry Group, Alleles, Risk Factors, European Continental Ancestry Group, Diabetes Mellitus, Type 2, Case-Control Studies, Middle Aged, Genetic Predisposition to Disease, Male, Female, /dk/atira/pure/subjectarea/asjc/1100/1105, Ecology, Evolution, Behavior and Systematics, /dk/atira/pure/subjectarea/asjc/1300/1311, Genetics, /dk/atira/pure/subjectarea/asjc/1300/1312, Molecular Biology, /dk/atira/pure/subjectarea/asjc/2700/2716, Genetics(clinical), /dk/atira/pure/subjectarea/asjc/1300/1306, Cancer Research, Endocrinology and Diabetes, QH426-470, Research Article, Biology, Heredity, Complex Traits, Phenotypes, Human Genetics, Genome-Wide Association Studies, Medicine, Endocrinology, Diabetic Endocrinology, Diabetes Mellitus Type 2, Epidemiology, Genetic Epidemiology, Molecular Epidemiology, Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, GENOME-WIDE ASSOCIATION, SUSCEPTIBILITY LOCI, EXPRESSION, CELLS, DIFFERENTIATION, INSULIN, DISEASE, GLUCOSE, MOUSE, PROTEIN, MAGIC, DIAGRAM Consortium, GIANT Consortium, Developmental Biology, 0604 Genetics, Aged, Alleles, Asian Continental Ancestry Group, Body Mass Index, Case-Control Studies, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, High Mobility Group Proteins, Humans, Laminin, Male, Middle Aged, Obesity, Polymorphism, Single Nucleotide, Risk Factors
Funded by
NIH| Targeted Genetic Analysis of T2D and Quantitative Traits
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 2R01DK072193-10
  • Funding stream: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
,
NIH| A Whole Genome Admixture Scan For Prostate Cancer Genes
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 3R01CA063464-09S1
  • Funding stream: NATIONAL CANCER INSTITUTE
,
NIH| Study of Addiction: Genetics and Environment
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1U01HG004422-01
  • Funding stream: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
,
NIH| Genome-Wide Association Studies
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1Z01CP010200-01
  • Funding stream: NATIONAL CANCER INSTITUTE
,
NIH| Dental Caries: Whole Genome Association and Gene x Environment Studies
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 3U01DE018903-02S1
  • Funding stream: NATIONAL INSTITUTE OF DENTAL &CRANIOFACIAL RESEARCH
45 references, page 1 of 3

Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, et al. (2010) Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 42: 579-589.

Dupuis J, Langenberg C, Prokopenko I, Saxena R, Soranzo N, et al. (2010) New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 42: 105-116.

Qi L, Cornelis MC, Kraft P, Stanya KJ, Linda Kao WH, et al. (2010) Genetic variants at 2q24 are associated with susceptibility to type 2 diabetes. Hum Mol Genet 19: 2706-2715.

Tsai FJ, Yang CF, Chen CC, Chuang LM, Lu CH, et al. (2010) A genome-wide association study identifies susceptibility variants for type 2 diabetes in Han Chinese. PLoS Genet 6: e1000847. doi:10.1371/journal.pgen.1000847.

9. Prokopenko I, Langenberg C, Florez JC, Saxena R, Soranzo N, et al. (2009) Variants in MTNR1B influence fasting glucose levels. Nat Genet 41: 77-81.

10. Freathy RM, Mook-Kanamori DO, Sovio U, Prokopenko I, Timpson NJ, et al. (2010) Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight. Nat Genet 42: 430-435.

11. Perry JR, Weedon MN, Langenberg C, Jackson AU, Lyssenko V, et al. (2010) Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes. Hum Mol Genet 19: 535-544. [OpenAIRE]

12. Tuomi T, Carlsson A, Li H, Isomaa B, Miettinen A, et al. (1999) Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies. Diabetes 48: 150-157. [OpenAIRE]

13. Pearson ER, Flechtner I, Njolstad PR, Malecki MT, Flanagan SE, et al. (2006) Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med 355: 467-477.

14. Timpson NJ, Lindgren CM, Weedon MN, Randall J, Ouwehand WH, et al. (2009) Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data. Diabetes 58: 505-510. [OpenAIRE]

15. Cauchi S, Nead KT, Choquet H, Horber F, Potoczna N, et al. (2008) The genetic susceptibility to type 2 diabetes may be modulated by obesity status: implications for association studies. BMC Med Genet 9: 45. [OpenAIRE]

16. Cauchi S, Choquet H, Gutierrez-Aguilar R, Capel F, Grau K, et al. (2008) Effects of TCF7L2 polymorphisms on obesity in European populations. Obesity (Silver Spring) 16: 476-482.

17. Guey LT, Kravic J, Melander O, Burtt NP, Laramie JM, et al. (2011) Power in the phenotypic extremes: a simulation study of power in discovery and replication of rare variants. Genet Epidemiol. [OpenAIRE]

18. Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, et al. (2010) Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 42: 937-948. [OpenAIRE]

19. Zhou K, Bellenguez C, Spencer CC, Bennett AJ, Coleman RL, et al. (2011) Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nat Genet 43: 117-120. [OpenAIRE]

45 references, page 1 of 3
Abstract
Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m2) compared to obese cases (BMI≥30 Kg/m2). We performed two case-control genome-wide studies using two accepted cut-offs for defining individuals as overweight or obese. We used 2,112 lean type 2 diabetes cases (BMI<25 kg/m2) or 4,123 obese cases (BMI≥30 kg/m2), and 54,412 un-stratified controls. Replication was performed in 2,881 lean cases or 8,702 obese cases, and 18,957 un-stratified con...
Subjects
free text keywords: Laminin, Obesity, Polymorphism, Single Nucleotide, High Mobility Group Proteins, Humans, Aged, Body Mass Index, Genome-Wide Association Study, Asian Continental Ancestry Group, Alleles, Risk Factors, European Continental Ancestry Group, Diabetes Mellitus, Type 2, Case-Control Studies, Middle Aged, Genetic Predisposition to Disease, Male, Female, /dk/atira/pure/subjectarea/asjc/1100/1105, Ecology, Evolution, Behavior and Systematics, /dk/atira/pure/subjectarea/asjc/1300/1311, Genetics, /dk/atira/pure/subjectarea/asjc/1300/1312, Molecular Biology, /dk/atira/pure/subjectarea/asjc/2700/2716, Genetics(clinical), /dk/atira/pure/subjectarea/asjc/1300/1306, Cancer Research, Endocrinology and Diabetes, QH426-470, Research Article, Biology, Heredity, Complex Traits, Phenotypes, Human Genetics, Genome-Wide Association Studies, Medicine, Endocrinology, Diabetic Endocrinology, Diabetes Mellitus Type 2, Epidemiology, Genetic Epidemiology, Molecular Epidemiology, Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, GENOME-WIDE ASSOCIATION, SUSCEPTIBILITY LOCI, EXPRESSION, CELLS, DIFFERENTIATION, INSULIN, DISEASE, GLUCOSE, MOUSE, PROTEIN, MAGIC, DIAGRAM Consortium, GIANT Consortium, Developmental Biology, 0604 Genetics, Aged, Alleles, Asian Continental Ancestry Group, Body Mass Index, Case-Control Studies, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, High Mobility Group Proteins, Humans, Laminin, Male, Middle Aged, Obesity, Polymorphism, Single Nucleotide, Risk Factors
Funded by
NIH| Targeted Genetic Analysis of T2D and Quantitative Traits
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 2R01DK072193-10
  • Funding stream: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
,
NIH| A Whole Genome Admixture Scan For Prostate Cancer Genes
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 3R01CA063464-09S1
  • Funding stream: NATIONAL CANCER INSTITUTE
,
NIH| Study of Addiction: Genetics and Environment
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1U01HG004422-01
  • Funding stream: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
,
NIH| Genome-Wide Association Studies
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1Z01CP010200-01
  • Funding stream: NATIONAL CANCER INSTITUTE
,
NIH| Dental Caries: Whole Genome Association and Gene x Environment Studies
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 3U01DE018903-02S1
  • Funding stream: NATIONAL INSTITUTE OF DENTAL &CRANIOFACIAL RESEARCH
45 references, page 1 of 3

Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, et al. (2010) Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 42: 579-589.

Dupuis J, Langenberg C, Prokopenko I, Saxena R, Soranzo N, et al. (2010) New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 42: 105-116.

Qi L, Cornelis MC, Kraft P, Stanya KJ, Linda Kao WH, et al. (2010) Genetic variants at 2q24 are associated with susceptibility to type 2 diabetes. Hum Mol Genet 19: 2706-2715.

Tsai FJ, Yang CF, Chen CC, Chuang LM, Lu CH, et al. (2010) A genome-wide association study identifies susceptibility variants for type 2 diabetes in Han Chinese. PLoS Genet 6: e1000847. doi:10.1371/journal.pgen.1000847.

9. Prokopenko I, Langenberg C, Florez JC, Saxena R, Soranzo N, et al. (2009) Variants in MTNR1B influence fasting glucose levels. Nat Genet 41: 77-81.

10. Freathy RM, Mook-Kanamori DO, Sovio U, Prokopenko I, Timpson NJ, et al. (2010) Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight. Nat Genet 42: 430-435.

11. Perry JR, Weedon MN, Langenberg C, Jackson AU, Lyssenko V, et al. (2010) Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes. Hum Mol Genet 19: 535-544. [OpenAIRE]

12. Tuomi T, Carlsson A, Li H, Isomaa B, Miettinen A, et al. (1999) Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies. Diabetes 48: 150-157. [OpenAIRE]

13. Pearson ER, Flechtner I, Njolstad PR, Malecki MT, Flanagan SE, et al. (2006) Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med 355: 467-477.

14. Timpson NJ, Lindgren CM, Weedon MN, Randall J, Ouwehand WH, et al. (2009) Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data. Diabetes 58: 505-510. [OpenAIRE]

15. Cauchi S, Nead KT, Choquet H, Horber F, Potoczna N, et al. (2008) The genetic susceptibility to type 2 diabetes may be modulated by obesity status: implications for association studies. BMC Med Genet 9: 45. [OpenAIRE]

16. Cauchi S, Choquet H, Gutierrez-Aguilar R, Capel F, Grau K, et al. (2008) Effects of TCF7L2 polymorphisms on obesity in European populations. Obesity (Silver Spring) 16: 476-482.

17. Guey LT, Kravic J, Melander O, Burtt NP, Laramie JM, et al. (2011) Power in the phenotypic extremes: a simulation study of power in discovery and replication of rare variants. Genet Epidemiol. [OpenAIRE]

18. Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, et al. (2010) Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 42: 937-948. [OpenAIRE]

19. Zhou K, Bellenguez C, Spencer CC, Bennett AJ, Coleman RL, et al. (2011) Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nat Genet 43: 117-120. [OpenAIRE]

45 references, page 1 of 3
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publication . Article . Other literature type . 2012

Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases

Andrew Hattersley;