Genetics of obesity and type 2 diabetes: tracking pathogenic traits during the predisease period.

The modern generalization of sedentary life and caloric abundance has created new physiological conditions capable of changing the level of expression of a number of genes involved in fuel metabolism and body weight regulation. It is likely that the genetic variants or alleles of these genes have in the past participated in the adaptation of human physiology to its evolutionary constraints. The nature and prevalence of polymorphisms responsible for the quantitative variation of complex metabolic traits may have been different among human populations, depending on their environment and ancestral genetic background. These polymorphisms could likely explain differences in disease susceptibility and prevalence among groups of humans. From complex traits to potentially complex alleles, understanding the molecular genetic basis underlying quantitative variation will continue to be a growing concern among geneticists dealing with obesity and type 2 diabetes, the main fuel disorders of the modern era. Genomics and genetic epidemiology now allow high-level linkage and association studies to be designed. But the pooling of large trans-geographic cohorts may in fact increase the genetic heterogeneity of studied traits and dilute genotype-phenotype associations. In this article, we underscore the importance of selecting the traits to be subjected to quantitative genetic analysis. Although this is not possible for most other multifactorial diseases, obesity and type 2 diabetes can be subjected to a pregenetic dissection of complexity into simpler quantitative traits (QTs). This dissection is based on the pathogenic mechanisms, and the time course of the traits, and the individuals' age, within the predisease period rather than on descriptive parameters after disease diagnosis. We defend that this approach of phenotypes may ease future associations to be established between QTs of intermediate complexity and genetic polymorphisms.

[1]  G I Bell,et al.  Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. , 2001, The New England journal of medicine.

[2]  N. Schork,et al.  Genetics of complex disease: approaches, problems, and solutions. , 1997, American journal of respiratory and critical care medicine.

[3]  N. Schork,et al.  Adaptation, allometry, and hypertension. , 1994, Hypertension.

[4]  D. Cooper.  Variation in the Human Genome , 1996 .

[5]  N. Barton,et al.  Multifactorial genetics: Understanding quantitative genetic variation , 2002, Nature Reviews Genetics.

[6]  M. Kimura,et al.  Recent development of the neutral theory viewed from the Wrightian tradition of theoretical population genetics. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[7]  N Risch,et al.  The Future of Genetic Studies of Complex Human Diseases , 1996, Science.

[8]  D. Goldstein.  Islands of linkage disequilibrium , 2001, Nature Genetics.

[9]  N. Morton.  Complex inheritance: the 21st century. , 2001, Advances in genetics.

[10]  P. Albert,et al.  Models for longitudinal data: a generalized estimating equation approach. , 1988, Biometrics.

[11]  Beyond the thrifty gene: metabolic implications of prehistoric migration into the New World. , 1989, Medical anthropology.

[12]  P. Kovacs,et al.  EFFECTS OF QUANTITATIVE TRAIT LOCI FOR LIPID PHENOTYPES IN THE RAT ARE INFLUENCED BY AGE , 1998, Clinical and Experimental Pharmacology and Physiology.

[13]  P. Raskin,et al.  Report of the expert committee on the diagnosis and classification of diabetes mellitus. , 1999, Diabetes care.

[14]  E. Ferrannini,et al.  Insulin resistance and hypersecretion in obesity. European Group for the Study of Insulin Resistance (EGIR). , 1997, The Journal of clinical investigation.

[15]  N. Hollenberg,et al.  A genomic-systems biology map for cardiovascular function. , 2002, Current hypertension reports.

[16]  N. Schork,et al.  A common promoter variant of the leptin gene is associated with changes in the relationship between serum leptin and fat mass in obese girls. , 2000, Diabetes.

[17]  J. Peters,et al.  Environmental contributions to the obesity epidemic. , 1998, Science.

[18]  T. Cole,et al.  Establishing a standard definition for child overweight and obesity worldwide: international survey , 2000, BMJ : British Medical Journal.

[19]  N. Wareham,et al.  The 30 Minute Insulin Incremental Response in an Oral Glucose Tolerance Test as a Measure of Insulin Secretion , 1995, Diabetic medicine : a journal of the British Diabetic Association.

[20]  R. Cone,et al.  Genetic models of obesity and energy balance in the mouse. , 2000, Annual review of genetics.

[21]  T. Mackay.  The genetic architecture of quantitative traits. , 2001, Annual review of genetics.

[22]  R. Fisher.  XV.—The Correlation between Relatives on the Supposition of Mendelian Inheritance. , 1919, Transactions of the Royal Society of Edinburgh.

[23]  K. Liang,et al.  Body weight patterns from 20 to 49 years of age and subsequent risk for diabetes mellitus: the Johns Hopkins Precursors Study. , 1999, Archives of internal medicine.

[24]  D. Fallin,et al.  Paternal transmission of the very common class I INS VNTR alleles predisposes to childhood obesity , 2001, Nature Genetics.

[25]  J. Josse,et al.  Quantitative trait loci underlying gene product variation: a novel perspective for analyzing regulation of genome expression. , 1994, Genetics.

[26]  N. Schork,et al.  The insulin gene VNTR is associated with fasting insulin levels and development of juvenile obesity , 2000, Nature Genetics.

[27]  C. Bogardus,et al.  Evaluation of simple indices of insulin sensitivity and insulin secretion for use in epidemiologic studies. , 2000, American journal of epidemiology.

[28]  N. Risch.  Searching for genetic determinants in the new millennium , 2000, Nature.

[29]  M. Engelgau,et al.  Diabetes trends in the U.S.: 1990-1998. , 2000, Diabetes care.

[30]  R. Elston,et al.  The investigation of linkage between a quantitative trait and a marker locus , 1972, Behavior genetics.

[31]  Andrew G Clark,et al.  Linkage disequilibrium and the mapping of complex human traits. , 2002, Trends in genetics : TIG.

[32]  W. Dietz,et al.  Long-term morbidity and mortality of overweight adolescents. A follow-up of the Harvard Growth Study of 1922 to 1935. , 1992, The New England journal of medicine.

[33]  C. Sing,et al.  Genetic architecture of common multifactorial diseases. , 1996, Ciba Foundation symposium.

[34]  I. Wickelgren,et al.  Obesity: How Big a Problem? , 1998, Science.

[35]  Francis S. Collins,et al.  Variations on a Theme: Cataloging Human DNA Sequence Variation , 1997, Science.

[36]  K. J. Moore,et al.  Complex trait analysis in the mouse: The strengths, the limitations and the promise yet to come. , 2000, Annual review of genetics.

[37]  A. Hajeer.  The Genetic Variation and Human Disease: Principles and Evolutionary Approaches , 1996 .

[38]  M. Neale,et al.  Quantitative Genetics , 2018, Population Genetics and Microevolutionary Theory.

[39]  J. McGarry,et al.  What if Minkowski had been ageusic? An alternative angle on diabetes. , 1992, Science.

[40]  J. Neel.  Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"? , 1962, American journal of human genetics.

[41]  T. Gura.  Can SNPs Deliver on Susceptibility Genes? , 2001, Science.

[42]  R C Elston,et al.  Linkage and association , 1998, Genetic epidemiology.

[43]  N. Schork,et al.  Detection of genetic heterogeneity for complex quantitative phenotypes , 1992, Genetic epidemiology.

[44]  M. Province,et al.  19 Classification methods for confronting heterogeneity , 2001 .

[45]  N. Schork,et al.  The future of genetic case-control studies. , 2001, Advances in genetics.

[46]  M. Konner,et al.  Stone Agers in the Fast Lane: Chronic Degenerative Diseases in Evolutionary Perspective , 1988 .

[47]  J. Witte,et al.  Genetic dissection of complex traits , 1996, Nature Genetics.

[48]  L. Almasy,et al.  Variance component methods for detecting complex trait loci. , 2001, Advances in genetics.

[49]  J. Stephens,et al.  Haplotype Variation and Linkage Disequilibrium in 313 Human Genes , 2001, Science.

[50]  M. Province,et al.  Classification methods for confronting heterogeneity. , 2001, Advances in genetics.

[51]  Alberto Piazza,et al.  The History and Geography of Human Genes: Abridged paperback Edition , 1996 .

[52]  A. Griffiths.  Introduction to Genetic Analysis , 1976 .

[53]  E. Lander,et al.  Genetic dissection of complex traits science , 1994 .

[54]  M. Province,et al.  Genetic dissection of complex traits , 2001 .

[55]  Deciphering the genetic architecture of a multivariate phenotype. , 2001, Advances in genetics.

[56]  N Risch,et al.  Extreme discordant sib pairs for mapping quantitative trait loci in humans. , 1995, Science.

[57]  C. Gu,et al.  Optimum study designs. , 2001, Advances in genetics.

[58]  D. Cooper.  Human Gene Evolution , 1999 .

[59]  J. Rice,et al.  Definition of the phenotype. , 2001, Advances in genetics.

[60]  O. Kempthorne.  The correlation between relatives on the supposition of mendelian inheritance , 1968 .

[61]  J. Thoday,et al.  Location of Polygenes , 1961, Nature.

[62]  N. Schork,et al.  Who's afraid of epistasis? , 1996, Nature Genetics.

[63]  C. L. Stunff,et al.  TIME COURSE OP INCREASED LIPID AND GLUCOSE OXIDATION DURING THE EARLY PHASE OF CHILDHOOD OBESITY , 1993, Pediatric Research.

[64]  D. F. Roberts,et al.  The History and Geography of Human Genes , 1996 .

[65]  N. Morton,et al.  Genetic regulation of the kinetics of glucose‐induced insulin release in man Studies in families with diabetic and non‐diabetic probands , 1985, Clinical genetics.

[66]  E. Boerwinkle,et al.  The use of measured genotype information in the analysis of quantitative phenotypes in man , 1986, Annals of human genetics.

[67]  D. Allison,et al.  Risch's lambda values for human obesity. , 1996, International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity.

[68]  M. Fantone,et al.  Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus , 1997, Diabetes Care.

[69]  D E Weeks,et al.  Polygenic disease: methods for mapping complex disease traits. , 1995, Trends in genetics : TIG.

[70]  J. Terwilliger.  Genetic Variation and Human Disease: Principles and Evolutionary Approaches , 1997 .

[71]  L. Penrose,et al.  THE CORRELATION BETWEEN RELATIVES ON THE SUPPOSITION OF MENDELIAN INHERITANCE , 2022 .

[72]  A. Chakravarti.  Population genetics—making sense out of sequence , 1999, Nature Genetics.

[73]  M. Matsuda,et al.  Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. , 1999, Diabetes care.

[74]  S. Le Fur,et al.  Increased insulin resistance in obese children who have both 972 IRS-1 and 1057 IRS-2 polymorphisms. , 2002, Diabetes.

[75]  F. Vogel,et al.  Human Genetics: Problems and Approaches , 1979 .

[76]  Gregory S. Barsh,et al.  Genetics of body-weight regulation , 2000, Nature.

[77]  John A. Todd,et al.  Parameters for reliable results in genetic association studies in common disease , 2002, Nature Genetics.

[78]  E. Lander.  The New Genomics: Global Views of Biology , 1996, Science.

[79]  P. Bougnères,et al.  Early Changes in Postprandial Insulin Secretion, Not in Insulin Sensitivity, Characterize Juvenile Obesity , 1994, Diabetes.