A genetic explanation for the rising incidence of type 1 diabetes, a polygenic disease

• Published in: Journal of autoimmunity 2006-11, Vol.27 (3), p.174-181
• Main Authors: Awdeh, Z.L., Yunis, Edmond J., Audeh, Mark J., Fici, Dolores, Pugliese, Alberto, Larsen, Charles E., Alper, Chester A.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Diabetes Mellitus, Type 1 - epidemiology; Diabetes Mellitus, Type 1 - genetics; Excess heterozygosity; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Frequency; General aspects; Genetic Predisposition to Disease; Heterozygote; HLA-A Antigens - genetics; HLA-DR3 Antigen - genetics; HLA-DR4 Antigen - genetics; Humans; Immunopathology; Incidence; Insulin - genetics; Male; Medical sciences; Minisatellite Repeats - genetics; Multifactorial Inheritance; Pedigree; Rising incidence of type 1 diabetes; Type 1 diabetes
• ISSN: 0896-8411; 1095-9157
• DOI: 10.1016/j.jaut.2006.08.004

We had earlier hypothesized, if parents originated from previously isolated populations that had selected against different critical susceptibility genes for a polygenic disease, their offspring could have a greater risk of that disease than either parent. We therefore studied parents of patients with type 1 diabetes (T1D). We found that parents who transmitted HLA-DR3 to HLA-DR3/DR4 patients had different HLA-A allele frequencies on the non-transmitted HLA haplotype than HLA-DR4-transmitters. HLA-DR3-positive parents also had different insulin ( INS) gene allele frequencies than HLA-DR4-positive parents. Parent pairs of patients had greater self-reported ethnicity disparity than parent pairs in control families. Although there was an excess of HLA-DR3/DR4 heterozygotes among type 1 diabetes patients, there were significantly fewer HLA-DR3/DR4 heterozygous parents of patients than expected. These findings are consistent with HLA-DR and INS VNTR alleles marking both disease susceptibility and separate Caucasian parental subpopulations. Our hypothesis thus explains some seemingly disconnected puzzling phenomena, including (1) the rising world-wide incidence of T1D, (2) the excess of HLA-DR3/DR4 heterozygotes among patients, (3) the changing frequency of HLA-DR3/DR4 heterozygotes and of susceptibility alleles in general in patients over the past several decades, and (4) the association of INS alleles with specific HLA-DR alleles in patients with T1D.