Stepwise or Linear Decrease in Penetrance of Type 1 Diabetes With Lower-Risk HLA Genotypes Over the Past 40 Years
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OBJECTIVE: The objective of this study was to test if the proportion of new-onset diabetic subjects with the HLA-DR3/4-DQB1*0302 genotype is decreasing over time. RESEARCH DESIGN AND METHODS: We analyzed HLA class II genotype frequencies over time in two large populations with type 1 diabetes diagnosed at ≤18 years of age. There were 4,075 subjects from the Type 1 Diabetes Genetics Consortium (T1DGC) and 1,675 subjects from the Barbara Davis Center (BDC). RESULTS: Both T1DGC and BDC cohorts showed a decrease of the highest-risk HLA-DR3/4-DQB1*0302 genotype over time. This decrease was greatest over time in T1DGC subjects with age of onset ≤5 years (P = 0.004) and onset between ages 6 and 10 years (P = 0.002). The overall percent of HLA-DR3/4-DQB1*0302 was greater in the T1DGC population compared with the BDC population. There was an increased percent over time of other HLA genotypes without HLA-DR3 or -DR4 in T1DGC new onsets (P = 0.003), and the trend was similar in BDC subjects (P = 0.08). Analyzing time trend, there appears to be a large stepwise decrease in percent DR3/4 in the 1980s in T1DGC subjects with onset age <5 years (P = 0.0001). CONCLUSIONS: The change in frequency of multiple different genotypes and a possible stepwise decrease in percent DR3/4 suggest a change in genetic risk factors and environmental determinants of type 1 diabetes. Larger studies are needed to confirm the changing pattern of genetic risk because a stepwise change may have direct bearing on defining critical environmental determinants of type 1 diabetes.
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Genetic predisposition seems to be less of a factor now than it was in the past as a prerequisite for developing type 1 diabetes.
“Finally, genetic predisposition seems to be less of a factor now than it was in the past as a prerequisite for developing type 1 diabetes.23,24”
From Type 1 diabetes (2014) · cites this paper as [24]
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References 25 · Cited by 60
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- [1]Gale EA The rise of childhood type 1 diabetes in the 20th century. Diabetes 2002; 51: 3353– 3361 12453886
- [2]Onkamo P Vaananen S Karvonen M Tuomilehto J Worldwide increase in incidence of Type I diabetes—the analysis of the data on published incidence trends. Diabetologia 1999; 42: 1395– 1403 10651256
- [4]Hathout EH Hartwick N Fagoaga OR Clinical, autoimmune, and HLA characteristics of children diagnosed with type 1 diabetes before 5 years of age. Pediatrics 2003; 111: 860– 863 12671124
- [5]Sheehy MJ Scharf SJ Rowe JR A diabetes-susceptible HLA haplotype is best defined by a combination of HLA-DR and -DQ alleles. J Clin Invest 1989; 83: 830– 835 2784133 PMC303755
- [6]Noble JA Valdes AM Cook M Klitz W Thomson G Erlich HA The role of HLA class II genes in insulin-dependent diabetes mellitus: molecular analysis of 180 Caucasian, multiplex families. Am J Hum Genet 1996; 59: 1134– 1148 8900244 PMC1914851
- [7]Komulainen J Kulmala P Savola K Clinical, autoimmune, and genetic characteristics of very young children with type 1 diabetes: Childhood Diabetes in Finland (DiMe) Study Group. Diabetes Care 1999; 22: 1950– 1955 10.2337/diacare.22.12.1950 10587824 · DOI
- [9]Rewers M Bugawan TL Norris JM Newborn screening for HLA markers associated with IDDM: Diabetes Autoimmunity Study in the Young (DAISY). Diabetologia 1996; 39: 807– 812 8817105
- [10]Deschamps I Boitard C Hors J Life table analysis of the risk of type I (insulin-dependent) diabetes mellitus in siblings according to islet cell antibodies and HLA markers. An 8-year prospective study. Diabetologia 1992; 35: 951– 957 1451952
- [11]Aly TA Ide A Jahromi MM Extreme genetic risk for type 1A diabetes. Proc Natl Acad Sci USA 2006; 103: 14074– 14079 10.1073/pnas.0606349103 16966600 PMC1563993 · DOI
- [12]Vehik K Hamman RF Lezotte D Trends in high-risk HLA susceptibility genes among Colorado youth with type 1 diabetes. Diabetes Care 2008; 31: 1392– 1396 10.2337/dc07-2210 18356404 PMC2453682 · DOI · Paper page
- [14]Fourlanos S Varney MD Tait BD The rising incidence of type 1 diabetes is accounted for by cases with lower-risk human leukocyte antigen genotypes. Diabetes Care 2008; 31: 1546– 1549 10.2337/dc08-0239 18487476 PMC2494654 · DOI
- [16]Mychaleckyj JC Noble JA Moonsamy PV HLA genotyping in the international Type 1 Diabetes Genetics Consortium. Clin Trials 2010; 7(Suppl. 1): S75– S87 10.1177/1740774510373494 20595243 PMC2917849 · DOI
- [17]Awa WL Boehm BO Kapellen T; DPV-Wiss Study Group and the German Competence Network Diabetes Mellitus. HLA-DR genotypes influence age at disease onset in children and juveniles with type 1 diabetes mellitus. Eur J Endocrinol 2010; 163: 97– 104 10.1530/EJE-09-0921 20371654 · DOI
- [18]Gale EA A missing link in the hygiene hypothesis? Diabetologia 2002; 45: 588– 594 12032638
- [19]Peng H Hagopian W Environmental factors in the development of Type 1 diabetes. Rev Endocr Metab Disord 2006; 7: 149– 162 10.1007/s11154-006-9024-y 17203405 · DOI
- [20]Fourlanos S Narendran P Byrnes GB Colman PG Harrison LC Insulin resistance is a risk factor for progression to type 1 diabetes. Diabetologia 2004; 47: 1661– 1667 15480539
- [21]Wilkin TJ The accelerator hypothesis: weight gain as the missing link between Type I and Type II diabetes. Diabetologia 2001; 44: 914– 922 11508279
- [22]Londono P Komura A Hara N Zipris D Brief dexamethasone treatment during acute infection prevents virus-induced autoimmune diabetes. Clin Immunol 2010; 135: 401– 411 10.1016/j.clim.2010.01.007 20167539 · DOI
- [23]Etminan M Sadatsafavi M Jafari S Doyle-Waters M Aminzadeh K Fitzgerald JM Acetaminophen use and the risk of asthma in children and adults: a systematic review and metaanalysis. Chest 2009; 136: 1316– 1323 10.1378/chest.09-0865 19696122 · DOI
- [24]Beasley RW Clayton TO Crane J Acetaminophen use and risk of asthma, rhinoconjunctivitis and eczema in adolescents: ISAAC phase three. Am J Respir Crit Care Med. 13 August 2010 [Epub ahead of print] 20709817
- Authors
- Steck, A. K., Armstrong, T. K., Babu, S. R., Eisenbarth, G. S., & the Type 1 Diabetes Genetics Consortium
- Affiliations
- University of Colorado Denver (US)
- Corresponding author
- Steck, Andrea K.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2011-02-21
- Volume
- 60
- Issue
- 3
- Pages
- 1045-1049
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC3046823
- OpenAlex
- W2130672812
- Cited by
- 60
- References
- 25
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 5 · 2022: 1 · 2021: 2 · 2020: 2 · 2019: 4 · 2018: 5 · 2017: 4 · 2016: 4 · 2015: 9 · 2014: 4 · 2013: 5 · 2012: 8
- FWCI
- 4.19
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK057516, DK-057516, U01DK062418, DK-320083)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- type 1 diabetes, genetic risk, temporal trends, disease penetrance, age of onset, environmental determinants
- MeSH terms
- Adolescent, Child, Diabetes Mellitus, Type 1, Female, Gene Frequency, Genotype, Humans, Male, Risk Factors, HLA-DR3 Antigen, Incidence, Age of Onset, Penetrance
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