Stepwise or Linear Decrease in Penetrance of Type 1 Diabetes with Lower-risk HLA Genotypes over the Past 40 Years

Overview

Journal Diabetes

Specialty Endocrinology

Date 2011 Feb 11

PMID 21307077

Citations 37

Authors

Andrea K Steck

Taylor K Armstrong

Sunanda R Babu

George S Eisenbarth

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

High BMI and the risk for incident type 1 Diabetes Mellitus: a systematic review and meta-analysis of aggregated cohort studies.

Nitecki M, Gerstein H, Balmakov Y, Tsur E, Babushkin V, Michaeli T Cardiovasc Diabetol. 2023; 22(1):300.

PMID: 37919779 PMC: 10623818. DOI: 10.1186/s12933-023-02007-y.

The Impact of Dietary Factors during Pregnancy on the Development of Islet Autoimmunity and Type 1 Diabetes: A Systematic Literature Review.

Johansen V, Josefsen K, Antvorskov J Nutrients. 2023; 15(20).

PMID: 37892409 PMC: 10609322. DOI: 10.3390/nu15204333.

Identification of Autoantibodies to a Hybrid Insulin Peptide in Type 1 Diabetes.

Wenzlau J, Gu Y, Michels A, Rewers M, Haskins K, Yu L Diagnostics (Basel). 2023; 13(17).

PMID: 37685398 PMC: 10487141. DOI: 10.3390/diagnostics13172859.

and Enteroviruses as Synergistic Triggers of Type 1 Diabetes Mellitus.

Root-Bernstein R, Chiles K, Huber J, Ziehl A, Turke M, Pietrowicz M Int J Mol Sci. 2023; 24(9).

PMID: 37176044 PMC: 10179352. DOI: 10.3390/ijms24098336.

Higher ultraviolet radiation during early life is associated with lower risk of childhood type 1 diabetes among boys.

Miller K, Hart P, Lucas R, Davis E, de Klerk N Sci Rep. 2021; 11(1):18597.

PMID: 34545118 PMC: 8452739. DOI: 10.1038/s41598-021-97469-z.

References

Fourlanos S, Narendran P, Byrnes G, Colman P, Harrison L . Insulin resistance is a risk factor for progression to type 1 diabetes. Diabetologia. 2004; 47(10):1661-7. DOI: 10.1007/s00125-004-1507-3. View

Noble J, Valdes A, Cook M, Klitz W, Thomson G, Erlich H . 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(5):1134-48. PMC: 1914851. View

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. 2000; 42(12):1395-403. DOI: 10.1007/s001250051309. View

Mychaleckyj J, Noble J, Moonsamy P, Carlson J, Varney M, Post J . HLA genotyping in the international Type 1 Diabetes Genetics Consortium. Clin Trials. 2010; 7(1 Suppl):S75-87. PMC: 2917849. DOI: 10.1177/1740774510373494. View

Etminan M, Sadatsafavi M, Jafari S, Doyle-Waters M, Aminzadeh K, FitzGerald J . Acetaminophen use and the risk of asthma in children and adults: a systematic review and metaanalysis. Chest. 2009; 136(5):1316-1323. DOI: 10.1378/chest.09-0865. View

Wilkin T . The accelerator hypothesis: weight gain as the missing link between Type I and Type II diabetes. Diabetologia. 2001; 44(7):914-22. DOI: 10.1007/s001250100548. View

Gillespie K, Bain S, Barnett A, Bingley P, Christie M, Gill G . The rising incidence of childhood type 1 diabetes and reduced contribution of high-risk HLA haplotypes. Lancet. 2004; 364(9446):1699-700. DOI: 10.1016/S0140-6736(04)17357-1. View

Vehik K, Hamman R, Lezotte D, Norris J, Klingensmith G, Rewers M . Trends in high-risk HLA susceptibility genes among Colorado youth with type 1 diabetes. Diabetes Care. 2008; 31(7):1392-6. PMC: 2453682. DOI: 10.2337/dc07-2210. View

Awa W, Boehm B, Kapellen T, Rami B, Rupprath P, Marg W . HLA-DR genotypes influence age at disease onset in children and juveniles with type 1 diabetes mellitus. Eur J Endocrinol. 2010; 163(1):97-104. DOI: 10.1530/EJE-09-0921. View

10.

Fourlanos S, Varney M, Tait B, Morahan G, Honeyman M, Colman P . The rising incidence of type 1 diabetes is accounted for by cases with lower-risk human leukocyte antigen genotypes. Diabetes Care. 2008; 31(8):1546-9. PMC: 2494654. DOI: 10.2337/dc08-0239. View

11.

Gale E . The rise of childhood type 1 diabetes in the 20th century. Diabetes. 2002; 51(12):3353-61. DOI: 10.2337/diabetes.51.12.3353. View

12.

Erlich H, Valdes A, Noble J, Carlson J, Varney M, Concannon P . HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families. Diabetes. 2008; 57(4):1084-92. PMC: 4103420. DOI: 10.2337/db07-1331. View

13.

Peng H, Hagopian W . Environmental factors in the development of Type 1 diabetes. Rev Endocr Metab Disord. 2007; 7(3):149-62. DOI: 10.1007/s11154-006-9024-y. View

14.

Hermann R, Knip M, Veijola R, Simell O, Laine A, Akerblom H . Temporal changes in the frequencies of HLA genotypes in patients with Type 1 diabetes--indication of an increased environmental pressure?. Diabetologia. 2003; 46(3):420-5. DOI: 10.1007/s00125-003-1045-4. View

15.

DESCHAMPS I, Boitard C, Hors J, Busson M, Marcelli-Barge A, Mogenet A . Life table analysis of the risk of type 1 (insulin-dependent) diabetes mellitus in siblings according to islet cell antibodies and HLA markers. An 8-year prospective study. Diabetologia. 1992; 35(10):951-7. DOI: 10.1007/BF00401424. View

16.

Beasley R, Clayton T, Crane J, Lai C, Montefort S, von Mutius E . Acetaminophen use and risk of asthma, rhinoconjunctivitis, and eczema in adolescents: International Study of Asthma and Allergies in Childhood Phase Three. Am J Respir Crit Care Med. 2010; 183(2):171-8. DOI: 10.1164/rccm.201005-0757OC. View

17.

Gale E . A missing link in the hygiene hypothesis?. Diabetologia. 2002; 45(4):588-94. DOI: 10.1007/s00125-002-0801-1. View

18.

Vehik K, Hamman R, Lezotte D, Norris J, Klingensmith G, Bloch C . Increasing incidence of type 1 diabetes in 0- to 17-year-old Colorado youth. Diabetes Care. 2007; 30(3):503-9. DOI: 10.2337/dc06-1837. View

19.

SHEEHY M, Scharf S, ROWE J, Neme de Gimenez M, Meske L, Erlich H . A diabetes-susceptible HLA haplotype is best defined by a combination of HLA-DR and -DQ alleles. J Clin Invest. 1989; 83(3):830-5. PMC: 303755. DOI: 10.1172/JCI113965. View

20.

Hathout E, Hartwick N, Fagoaga O, Colacino A, Sharkey J, Racine M . Clinical, autoimmune, and HLA characteristics of children diagnosed with type 1 diabetes before 5 years of age. Pediatrics. 2003; 111(4 Pt 1):860-3. DOI: 10.1542/peds.111.4.860. View