title: A genetic explanation for the rising incidence of type 1 diabetes, a polygenic disease.
abstract: 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.
authors.affiliation: The CBR Institute for Biomedical Research, Boston, MA 02115, USA. awdeh@cbr.med.harvard.edu
authors.forename: Z L
authors.initials: ZL
authors.lastname: Awdeh
authors.forename: Edmond J
authors.initials: EJ
authors.lastname: Yunis
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Audeh
authors.forename: Dolores
authors.initials: D
authors.lastname: Fici
authors.forename: Alberto
authors.initials: A
authors.lastname: Pugliese
authors.forename: Charles E
authors.initials: CE
authors.lastname: Larsen
authors.forename: Chester A
authors.initials: CA
authors.lastname: Alper
mesh_terms: D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D015234:HLA-A Antigens / Q000235:genetics; D015803:HLA-DR3 Antigen / Q000235:genetics*; D015804:HLA-DR4 Antigen / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D015994:Incidence; D007328:Insulin / Q000235:genetics*; D008297:Male; D018598:Minisatellite Repeats / Q000235:genetics; D020412:Multifactorial Inheritance; D010375:Pedigree
chemical_list: D015234:HLA-A Antigens; D015803:HLA-DR3 Antigen; D015804:HLA-DR4 Antigen; D007328:Insulin