Identifying genetic risk loci for diabetic complications and showing evidence for heterogeneity of type 1 diabetes based on complications risk

<div><p>There is a growing body of evidence suggesting that type 1 diabetes (T1D) is a genetically heterogeneous disease. However, the extent of this heterogeneity, and what observations may distinguish different forms, is unclear. One indicator may be T1D-related microvascular complications (MVCs), which are familial, but occur in some families, and not others. We tested the hypothesis that T1D plus MVC is genetically distinct from T1D without MCV. We studied 415 families (2,462 individuals, 896 with T1D) using genome-wide linkage analysis, comparing families with and without MVC. We also tested for interaction between identified loci and alleles at the <i>HLA-DRB1</i> locus. We found significant linkage scores at 1p36.12, 1q32.1, 8q21.3, 12p11.21 and 22q11.21. In all regions except 1p36.12, linkage scores differed between MVC-based phenotype groups, suggesting that families with MVCs express different genetic influences than those without. Our linkage results also suggested gene-gene interaction between the above putative loci and the HLA region; HLA-based strata produced significantly increased linkage scores in some strata, but not others within a phenotype group. We conclude that families with type 1 diabetes plus MVCs are genetically different from those with diabetes alone.</p></div

Counts of (A) subjects and (B) pedigrees by specific MVCs, retinopathy, nephropathy, and neuropathy showing overlap across the three categories.

<p>Counts of (A) subjects and (B) pedigrees by specific MVCs, retinopathy, nephropathy, and neuropathy showing overlap across the three categories.</p

Hypothetical linkage score profiles expected under (A) absence of genetic heterogeneity, (B) presence of heterogeneity due to additional loci conferring MVC risk only, and (C) presence of heterogeneity due to different T1D risk conferring loci MVC vs. non-MVC pedigrees.

<p>Hypothetical linkage score profiles expected under (A) absence of genetic heterogeneity, (B) presence of heterogeneity due to additional loci conferring MVC risk only, and (C) presence of heterogeneity due to different T1D risk conferring loci MVC vs. non-MVC pedigrees.</p

Sample sizes for phenotype groups.

<p>Sample sizes for phenotype groups.</p

MMLS of T1D, Complications and No complications phenotype groups.

<p>Note: In each plot, solid lines represent T1D, dashed line Complications, and dotted lines No Complications; x-axis represents genetic position on the chromosome in cM; y-axis represents MMLS score. Each plot shows a region spanning approximately 30 cM around the peak position.</p

Regions with significant linkage MMLS.

<p>Regions with significant linkage MMLS.</p

T2D Odd Ratios (95% confidence limits).

<p>T2D Odd Ratios (95% confidence limits).</p

Number of patients per age at presentation.

<p>Age at presentation of T2D began to overlap age at presentation of T2D at age 8 or 9. (•) T1D, (o) T2D.</p

Glycated hemoglobin at onset of diabetes.

*<p>mean T1D vs. mean T2D.</p

Functional annotation of the <i>MICB-LST1</i>.

<p>The first 6 rows are H3K4me3 (green) data for CD4 memory primary cells, CD4 naïve primary cells, CD8 memory primary cells, CD8 naïve primary cells, Treg primary cells, and GM12878 cell line (B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Utah - European Caucasion, Epstein-Barr Virus). The next 5 rows display H3K27ac (blue) data for CD4 memory primary cells, CD4 naïve primary cells, CD8 memory primary cells, CD8 naïve primary cells, and GM12878 cell line, respectively. Then there are the H3K36me3 (green) data for CD4 memory primary cells, CD4 naïve primary cells, CD8 memory primary cells, CD8 naïve primary cells, Treg primary cells, and GM12878 cell line. The chomatin states displayed are for CD4 memory primary cells, CD4 naïve primary cells, CD8 memory primary cells, CD8 naïve primary cells, and GM12878 cell line. The DNase hypersensitivity sites are for CD4 primary cells, CD8 primary cells, CD14+ monocytes, Treg, Th1, Th2, Th17 and GM12878 cell line, respectively. The detailed colorscheme of the chromatin states is listed in the Supplementary material. Briefly, red corresponds to transcription start sites (TSSs) and/or active promoters, orange/yellow to enhancers, green to transcription, and white/grey to heterochromain. All data are publicly available data from ENCODE and NIH Roadmap. The last row displays the −log10(p) of the SNPs in the LD block after adjustment with the <i>HLA-DRB1*15:01</i> effect.</p