title: Genetic risk score of 46 type 2 diabetes risk variants associates with changes in plasma glucose and estimates of pancreatic β-cell function over 5 years of follow-up.
abstract: More than 40 genetic risk variants for type 2 diabetes have been validated. We aimed to test whether a genetic risk score associates with the incidence of type 2 diabetes and with 5-year changes in glycemic traits and whether the effects were modulated by changes in BMI and lifestyle. The Inter99 study population was genotyped for 46 variants, and a genetic risk score was constructed. During a median follow-up of 11 years, 327 of 5,850 individuals developed diabetes. Physical examinations and oral glucose tolerance tests were performed at baseline and after 5 years (n = 3,727). The risk of incident type 2 diabetes was increased with a hazard ratio of 1.06 (95% CI 1.03-1.08) per risk allele. While the population in general had improved glucose regulation during the 5-year follow-up period, each additional allele in the genetic risk score was associated with a relative increase in fasting, 30-min, and 120-min plasma glucose values and a relative decrease in measures of β-cell function over the 5-year period, whereas indices of insulin sensitivity were unaffected. The effect of the genetic risk score on 5-year changes in fasting plasma glucose was stronger in individuals who increased their BMI. In conclusion, a genetic risk score based on 46 variants associated strongly with incident type 2 diabetes and 5-year changes in plasma glucose and β-cell function. Individuals who gain weight may be more susceptible to the cumulative impact of type 2 diabetes risk variants on fasting plasma glucose.
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics.
authors.forename: Ehm A
authors.initials: EA
authors.lastname: Andersson
authors.forename: Kristine H
authors.initials: KH
authors.lastname: Allin
authors.forename: Camilla H
authors.initials: CH
authors.lastname: Sandholt
authors.forename: Anders
authors.initials: A
authors.lastname: Borglykke
authors.forename: Cathrine J
authors.initials: CJ
authors.lastname: Lau
authors.forename: Rasmus
authors.initials: R
authors.lastname: Ribel-Madsen
authors.forename: Thomas
authors.initials: T
authors.lastname: Sparsø
authors.forename: Johanne M
authors.initials: JM
authors.lastname: Justesen
authors.forename: Marie N
authors.initials: MN
authors.lastname: Harder
authors.forename: Marit E
authors.initials: ME
authors.lastname: Jørgensen
authors.forename: Torben
authors.initials: T
authors.lastname: Jørgensen
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000235:genetics / Q000378:metabolism*; D015992:Body Mass Index; D003718:Denmark / Q000453:epidemiology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015994:Incidence; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008019:Life Style; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D013997:Time Factors
chemical_list: D001786:Blood Glucose; D006442:Glycated Hemoglobin; C517652:hemoglobin A1c protein, human