Fine Mapping of the Diabetes-Susceptibility Locus, on Chromosome 11q13

Abstract

Genomewide linkage studies of type 1 diabetes (or insulin-dependent diabetes mellitus [IDDM]) indicate that several unlinked susceptibility loci can explain the clustering of the disease in families. One such locus has been mapped to chromosome 11q13 (IDDM4). In the present report we have analyzed 707 affected sib pairs, obtaining a peak multipoint maximum LOD score (MLS) of 2.7 (lambda(s)=1.09) with linkage (MLS>=0.7) extending over a 15-cM region. The problem is, therefore, to fine map the locus to permit structural analysis of positional candidate genes. In a two-stage approach, we first scanned the 15-cM linked region for increased or decreased transmission, from heterozygous parents to affected siblings in 340 families, of the three most common alleles of each of 12 microsatellite loci. One of the 36 alleles showed decreased transmission (50% expected, 45.1% observed [P=.02, corrected P=.72]) at marker D11S1917. Analysis of an additional 1,702 families provided further support for negative transmission (48%) of D11S1917 allele 3 to affected offspring and positive transmission (55%) to unaffected siblings (test of heterogeneity P=3x10-4, corrected P=. 01]). A second polymorphic marker, H0570polyA, was isolated from a cosmid clone containing D11S1917, and genotyping of 2,042 families revealed strong linkage disequilibrium between the two markers (15 kb apart), with a specific haplotype, D11S1917*03-H0570polyA*02, showing decreased transmission (46.4%) to affected offspring and increased transmission (56.6%) to unaffected siblings (test of heterogeneity P=1.5x10-6, corrected P=4.3x10-4). These results not only provide sufficient justification for analysis of the gene content of the D11S1917 region for positional candidates but also show that, in the mapping of genes for common multifactorial diseases, analysis of both affected and unaffected siblings is of value and that both predisposing and nonpredisposing alleles should be anticipated.

Genetics of type 1 diabetes mellitus

“…In a two-stage approach 2042 families were genotyped for markers from this region, and a specific haplotype comprising alleles of the two polymorphic markers, D11S1917 and H0570polyA, showed decreased transmission (46.4%) to affected offspring and increased transmission (56.6%) to unaffected siblings. 117 Several potential candidate genes map to the region near FGF3 in humans, including ZFM1 (zinc finger protein 162), which encodes a putative nuclear protein demonstrable in the pancreas. 118 The gene encoding the Fas-associated death domain protein (FADD) has also been mapped to this region.…”

Genetic linkage and association studies of Type I diabetes: challenges and rewards

“…However, this process is fraught with difficulties. For example, IDDM4 was mapped to FGF3 on chromosome 11q13 by three groups [58,61,62] and subsequent studies showed maximal linkage at D11S1337 just proximal to FGF3, with MLS 3.9 [59,63] and MLS 2.7 [64]. Thus, it is likely that this represents a true linkage.…”

“…Thus, it is likely that this represents a true linkage. However, MLS values of at least 1.7 extended over a wide 15 cM region [64]. It is characteristic of linkages for genes predisposing to complex disorders that true linkage peaks tend to be broader than false peaks [118], but this also makes it difficult to define a reasonable interval for intensive disequilibrium mapping.…”

“…It is characteristic of linkages for genes predisposing to complex disorders that true linkage peaks tend to be broader than false peaks [118], but this also makes it difficult to define a reasonable interval for intensive disequilibrium mapping. Nevertheless, significant association has been found with markers near D11S1337 and positional candidates for IDDM4 have been proposed [64,65,119].…”

Evidence for a locus (IDDM16) in the immunoglobulin heavy chain region on chromosome 14q32.3 producing susceptibility to type 1 diabetes

“…[1][2][3] However, theoretical studies in the mid-1980s suggested that genes outside the HLA region may contribute more than half of the genetic susceptibility to this form of diabetes. 4 Since then, many putative diabetes-predisposing genes outside the HLA region have been localised, including IDDM2 in the insu-lin gene region 5 (HLA region predisposition is now collectively referred to as IDDM1), IDDM3, [6][7][8] IDDM4, 6,[9][10][11][12] IDDM5, 9,11 IDDM6, 13 IDDM7, 14,15 IDDM8, 7,11 IDDM10, 16,17 IDDM11, 18 IDDM12, [19][20][21] IDDM13, 21,22 IDDM15, 23 IDDM17, 24 IDDM18, 25 and other putative localisations currently without an IDDM designation. 17,[26][27][28][29] Thus, it is now clear that while HLA region genes contribute the major predisposition to type 1 diabetes, there are numerous other genes with smaller effects on susceptibility.…”