Interaction and Association Analysis of a Type 1 Diabetes Susceptibility Locus on Chromosome 5q11-q13 and the 7q32 Chromosomal Region in Scandinavian Families
Article Figures & Tables
Figures
- FIG. 1.
Location of ISL1 gene and markers on chromosome 5p11-q13 used in this investigation. The distances in bases are shown between markers. TSC1637118 was identified by sequencing but not analyzed in our families. In the lower part of the figure, the 5′- and 3′UTRs of the ISL1 gene are shown as white boxes and exons as black boxes. ISL1:1 = rs3917084, ISL1:2 = TSC0312199, ISL1:3 = TSC0312200, ISL1:4 = TSC0424949, ISL1:5 is a newly discovered microsatellite marker (see Table 2), ISL1:6 = rs4151674, and ISL1:7 = rs4151675.
- FIG. 2.
Linkage of type 1 diabetes to 50 cM on either side of D5S407 in the centromeric region of chromosome 5. The linkage contribution from each family was weighted by its LOD at D7S530 to generate a measure for interaction. The thin solid line denotes equal weight, thick solid line positive weight, and thin dotted line negative weight (see research design and methods for details). The markers used in the genome scan are indicated below the abscissa, and the centromere and the ISL1 gene are shown for location information.
Tables
- TABLE 1
Transcription factors and other key genes involved in the development and maintenance of the endocrine pancreas
Gene Chromosome Closest marker Estimated distance between marker and gene Multipoint LOD at D5S407 Positive Negative PBX1 1q23 D1S196 3 cM 1.13 1.25 NeuroD/β2 2q32 D2S152 2.5 cM 0.00 2.38 NKX6.1 4q21.2-22 D4S1538 0.8 cM 2.07 0.24 ISL1 5p11-q13 D5S407 5 cM ND ND PAX4 7q32 D7S530 1.7 cM 5.26 0.20 NGN3 10q21.3 D10S537 2.0 cM 0.42 1.51 INS 11p15.5 TH 8,000 bp 2.00 0.58 PAX6 11p13 D11S904 4 cM 0.89 0.61 D11S907 1 cM 0.38 2.04 HNF1A 12q24.2 D12S366 1 cM 0.40 1.11 D12S342 4 cM 0.00 2.02 IPF1/PDX1 13q12.1 D13S192 0.2 cM 0.00 2.74 HNF6A 15q21.1-q21.2 CYP19 1 cM 2.06 0.53 ISL2 15q23 D15S114 0.1 cM 0.75 1.02 D15S125 1 cM 0.99* 1.25 HNF3B 20p11 D20S112 5 cM 0.32 1.75 IA-1 20p11 D20S112 3 cM 0.32 1.75 D20S107 4 cM 0.00 3.13 HNF4A 20q12-q13.1 D20S178 3 cM 0.46 1.36 Genotypes used for this interaction analysis were produced during a genome-wide scan for type 1 diabetes susceptibility genes (5). The interaction analysis was not presented in this report.
- *
* LOD for positive multipoint interaction between D15S125 and chromosome 5 was 3.2 at D5S647. ND, not determined.
- TABLE 2
Haplotypes in intron 1 of the ISL1 gene
Haplotype ISL1:5 ISL1:6 ISL1:7 Observed (non-type 1 diabetes/ type 1 diabetes) Sequence, starting at intron position + 695, counting first base after first exon as +1 1 WT A A 565/561 GCAATGCTCTAAAAAAAAAAAAAAAGAAAGAAAGAAAGAAAGAAAAAAACCTCCCAGAGTA* 2 WT G A 36/25 ---------------------G---------------------------------------* 3 WT-4 bp A A 10/8 ---------------------------------------------------------* 4 WT+8 bp G G 1/2 ------------------------GAAAGAAA--------------------G---------------* - *
* This position is 86 bp from the 5′ end of exon 2. No significant difference in frequency of the different haplotypes between patients and control subjects was observed.
- *
- TABLE 3
Familial association between ISL1 and PAX4 haplotypes
Gene Markers included in haplotype Global TDT*P value Number of families with transmissions to affected offspring ISL1 ISL1:2-ISL1:3 0.03 209 ISL1 ISL1:1-ISL1:2-ISL1:3 0.04 208 ISL1 ISL1:1-ISL1:5-ISL1:6-ISL1:7-ISL1:2-ISL1:3 0.04 193 PAX4 PAX4:1-PAX4:2 0.02 209 PAX4 PAX4:2-PAX4:3 0.05 205 PAX4 PAX4:1-PAX4:2-PAX4:3 0.02 203 - *
* TDT analysis was performed using the TRANSMIT program.
- *
- TABLE 4
Association analysis of ISL1 and PAX4 SNP haplotypes
Gene ISL1:1 ISL1:5 ISL1:6 ISL1:7 ISL1:2 ISL1:3 ISL1:4 TDT*P value Transmission (%) Observed number of transmissions Expected number of transmissions ISL1 T WT A A G C A 0.02 16.1 0.66 2.08 ISL1 T WT A A G C T 0.04 30.6 1.04 1.70 ISL1 T WT G A G C T 0.04 0.16 0 1.26 ISL1 C WT A A G T T 0.02 65.0 36.9 28.4 Gene PAX4:1 PAX4:2 PAX4:3 TDT*P value PAX4 T C C 0.001 6.6 0.59 4.5 PAX4 C T C 0.05 52.9 330.9 312.5 - *
* TDT analysis was performed using the TRANSMIT program. Because the number of transmissions are also estimated when there is not complete information in the family, the number of observed transmissions are not always integers. For ISL1 markers, haplotypes formed by 2, 3, 4, 5, and 6 markers were also analyzed, which resulted in the same haplotypes being associated as shown above. For PAX4 markers, haplotypes formed by two markers were also analyzed, resulting in the same haplotypes being associated as shown above.
- *
- TABLE 5
LD estimates between markers close to ISL1 and PAX4 in 196 Swedish type 1 diabetic families
Marker 1 Marker 2 Distance between markers (kb) No. df χ2 P value (<) D′ Chromosome 5p11-q13 D5S430 ISL1:1 9,657 600 3 13.3 0.004 0.32 D5S822 ISL1:1 168 601 4 347.6 0.0001 0.97 D5S822 ISL1:2 177 605 4 97.2 0.0001 0.39 D5S822 ISL1:3 178 608 4 116.4 0.0001 0.43 D5S822 ISL1:4 179 382 4 62.4 0.0001 0.40 D5S822 ISL1:5 169 567 4 10.2 0.04 0.84 D5S822 ISL1:6 169 545 4 110.8 0.0001 0.79 ISL1:1 ISL1:2 9.1 593 1 45.8 0.0001 1.00 ISL1:1 ISL1:3 9.3 596 1 40.7 0.0001 0.95 ISL1:1 ISL1:4 11 376 1 19.5 0.0001 0.83 ISL1:5 ISL1:7 0.02 545 1 97.5 0.0001 1.00 ISL1:6 ISL1:7 0.02 548 1 33.5 0.0001 1.00 ISL1:6 ISL1:2 8.2 538 1 16.2 0.0001 0.61 ISL1:6 ISL1:3 8.5 535 1 18.6 0.0001 0.65 ISL1:6 ISL1:4 9.8 426 1 23.8 0.0001 0.85 ISL1:2 ISL1:3 0.3 600 1 476.4 0.0001 0.90 ISL1:2 ISL1:4 1.6 377 1 299.8 0.0001 0.89 ISL1:3 ISL1:4 1.3 377 1 325.8 0.0001 0.94 Chromosome 7q32 CFTR PAX4:1 10,128 609 3 8.1 0.05 0.12 PAX4:1 PAX4:2 1 557 1 371.1 0.0001 0.82 PAX4:1 PAX4:3 4 639 1 80.1 0.0001 0.94 PAX4:1 D7S530 2,851 613 4 10.2 0.04 0.16 PAX4:2 PAX4:3 3 611 1 70.5 0.0001 0.89 Only combinations of markers that show significant evidence of LD (P < 0.05) are shown.
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