Tnfsf4^{Ath1-C57BL/6J}
QTL Variant Detail

Summary

• QTL variant: Tnfsf4^{Ath1-C57BL/6J}
• Name: tumor necrosis factor (ligand) superfamily, member 4; C57BL/6J
• MGI ID: MGI:3044290
• Synonyms: Ath1^s
• QTL: Tnfsf4 Location: Chr1:161223009-161245777 bp, + strand Genetic Position: Chr1, 69.75 cM

Variant origin

• Strain of Specimen: C57BL/6J

Variant description

• Allele Type: QTL
• Mutation: Undefined
• Mutation details: This allele confers susceptibility to atherosclerosis and decreased HDL cholesterol levels on an atherogenic diet compared to BALB/cJ, C3H/HeJ, and SPRET/EiJ. This allele confers increased aortic lesion area in females on a high fat diet compared to C3H/HeJ. (J:8735, J:140288)

Expression

In Structures Affected by this Mutation:

3 anatomical structure(s)

Notes

Homozygosity for C57BL/6J-derived alleles at both Ath1 and Ath2 confers susceptibility to atherosclerosis.

Wang et al (J:140288) identified Ath1 in F2 animals homozygous for Apoe^tm1Unc.

Mapping and Phenotype information for this QTL, its variants and associated markers

J:101842

Modifiers of the cystic fibrosis (CF) phenotype were mapped to mouse Chromosomes 1, 9, and 10 using allele comparison between B6;129-Cftr^tm1Unc and C57BL/6J-Cftr^tm1Unc. 108 polymorphic loci at an average spacing of 12 cM - 13 cM were compared betweenthe 2 strains. B6;129-Cftr^tm1Unc is a mixed line composed of 95% C57BL/6J and 5% 129X1/SvJ. Although B6;129-Cftr^tm1Unc carries the Cftr mutation, these animals exhibit a mild cystic fibrosis phenotype (increased survival, reduced intestinal inflammation, near normal body weight, and reduced mucus accumulation in intestinal crypts) compared to C57BL/6J-Cftr^tm1Unc.

Linkage to the mild CF phenotype is linked to D1Mit36 (92.3 cM) on mouse Chromosome 1. This locus is named Cfmq1 (cystic fibrosis modifier QTL 1). Heterozygosity at Cfmq1 appears to confer milder CF traits. Potential candidate genes for Cfmq1 include Kcnj9 (94.2 cM), Kcnj10 (93.5 cM), Tnfsf4 (84.9 cM), Fasl (89 cM), Sele (86.6 cM), Sell (86.6 cM), Selp (86.6 cM), Slamf1 (93.3 cM),Cd48 (93.3 cM), Cd84 (93.3 cM), Slamf6 (89.5 cM), Slamf9, Xcl1 (87 cM), Fcgr2b (92.3 cM), Fcgr3 (92.3 cM), Fcer1g (93.3 cM), Fcer1a (94.2 cM), and Tlr5 (98 cM). Previously identified body weight QTL mapping near Cfmq1 are Cfbw1 (85 cM), Obq9 (88.4 cM), and Bw8q1 (100 cM).

Linkage to the mild CF phenotype is linked to D9Mit90 (9 cM) on mouse Chromosome 9. This locus is named Cfmq2 (cystic fibrosis modifier QTL 2). Homozygosity for 129X1/SvJ-derived alleles at Cfmq2 appears to confer milder CF traits. Potential candidate genes for Cfmq2 include Kcnj5 (11 cM), Mmp3 (1 cM), and Mmp7 (1 cM). Previously identified body weight QTL mapping near Cfmq2 are Lbm6 (7.7 cM) and Bwtq4 (8 cM).

Linkage to the mild CF phenotype is linked to D10Mit14 (65 cM) on mouse Chromosome 10. This locus is named Cfmq3 (cystic fibrosis modifier QTL 3). Heterozygosity at Cfmq3 appears to confer milder CF traits. Potential candidate genes for Cfmq3 include Kcnc2 (62 cM), Kitl (57 cM), Lyzs (66 cM), Ifng (67 cM), Il22 (67 cM), Stat2 (70 cM), and Stat6 (70 cM). Previously identified QTL mapping near Cfmq3 are Bgeq8 (57 cM), Pbwg5 (68 cM), and Im5 (65 cM).

J:140288

Linkage analysis was performed on 334 animals from a (B6.129P2-Apoe^tm1Unc/J x C3.129P2(B6)-Apoe^tm1Unc)F2 intercross to identify genetic loci associated with atherosclerosis susceptibility. Animals were fed a CHOW diet until 8 weeks of age and then placed onan atherogenic diet for 16 weeks until sacrifice at 24 weeks of age for phenotype analysis on aortic section histology and plasma lipids. A panel of 1353 SNP markers spaced approximately 1.5 Mb apart was used for genome scan. Several previously identified atherosclerosis QTL were detected and five new QTL were identified in this study.

On mouse Chromosome 1, a new atherosclerosis susceptibility locus named Ath30 was identified at 76.4 Mb near rs3689327 (LOD=6.47). This QTL appears to be female-specific(LOD=5.98 in females only). The 95% confidence interval for Ath30 spans 72 Mb to 80 Mb. C57BL/6J-derived alleles at Ath30 confer increased aortic lesion area in female animals. A potential candidate gene for Ath30 is 2310007B03Rik (95 Mb), as identified by eQTL analysis. A previously identified QTL named Ath1 (currently Tnfsf4) was detected at 155.9 Mb near rs3716472 (LOD=7.08). The 95% confidence interval for Ath1 spans 135 Mb to 161 Mb. This locus also appears to be female-specific with C57BL/6J-derived alleles conferring increased aortic lesion area.

On mouse Chromosome 4, QTL Athsq3 was detected at 148.9 Mb near rs3686555 (LOD=4.97). The 95% confidence interval spans 145 Mb to 153 Mb. This locus exhibits sexual antagonism where C57BL/6J-derivedalleles confer increased aortic lesion area in females and C3H/HeJ-derived alleles confer increased aortic lesion area in males.

On mouse Chromosome 5, a suggestive atherosclerosis susceptibility locus was detected at 75.8 Mb near rs3720626 (LOD=3.99).C57BL/6J-derived alleles confer increase aortic lesion size at this locus.

A novel atherosclerosis QTL was detected at 61.7 Mb on mouse Chromosome 7 near rs3677657 (LOD=6.62). This locus is named Ath31 and appears to be female-specific (LOD=5.32 in females only). C57BL/6J-derived alleles at Ath31 confer increased aortic lesion area in females. The 95% confidence interval spans 50 Mb to 100 Mb. Plekhb1, Blm (87.6 Mb), Iqgap1 (87.8 Mb), Phca (105.3 Mb), and Ndufc2 (104.5 Mb) were identified as potential candidate genes for Ath31 by eQTL analysis.

Previously identified atherosclerosis QTL Ath29 was detected at 84.1 Mb on mouse Chromosome 9 near rs367897 (LOD=8.05). C57BL/6J-derived alleles at Ath29 confer increased aortic lesionarea and the 95% confidenceinterval spans 45 Mb to 89 Mb. Expression QTL (eQTL analysis) identified Rbp1 (98.3 Mb), Bco2 (formerly Bcdo2; 50.3 Mb), 23100030G06Rik, Cryab (50.56 Mb), Slc17a5 (78.38 Mb), Anp32a (62.1 Mb), and Cadm1 (formerly Igsf4a; 47.3 Mb)as potential candidate genes forAth29.

A female-specific QTL Ath15 was detected at 104.1 Mb on mouse Chromosome 11 near rs3722158 (LOD=7.76). The 95% confidence interval for Ath15 spans 64 Mb to 113 Mb. C57BL/6J-derived alleles at Ath15 confer increased aortic lesion size in femaleanimals. Potential candidate genes for Ath15 as determined by overlapping eQTL analysis include 5530600A18Rik (94.1 Mb) and Syngr2 (117.67 Mb).

A novel atherosclerosis locus named Ath32 mapped to 89.6 Mb on mouse Chromosome 13 near rs3660479 (LOD=6.93).The 95% confidence interval for Ath32 spans 86 Mb to 110 Mb with C57BL/6J-derived alleles conferring increased aortic lesion area. Serinc5 (formerly A130038L21Rik; 93.3 Mb) and Hexb (97.9 Mb) are potential candidate genes for Ath32 as determined by overlappingeQTL analysis.

Ath33 mapped to 71.4 Mb on mouse Chromosome 15 near rs3696862 (LOD=6.2). C3H/HeJ-derived alleles at Ath33 confer increased aortic lesion area. The 95% confidence interval for Ath33 spans 67 Mb to 78 Mb. Expression QTL (eQTL) analysisidentified Csf2rb2 (78.1 Mb) and Slc39a4 (76.4 Mb) as potential candidate genes for Ath33.

A previously identified atherosclerosis QTL named Ath26 was detected at 26.1 Mb on mouse Chromosome 17 near rs4231406 (LOD=4.28). C57BL/6J-derived alleles at Ath26confer increased aortic lesion area. The 95% confidence interval for Ath26 spans 22 cM to 28 cM.

References

• Original: J:9135 Paigen B, et al., Genetic analysis of murine strains C57BL/6J and C3H/HeJ to confirm the map position of Ath-1, a gene determining atherosclerosis susceptibility. Biochem Genet. 1987 Aug;25(7-8):501-11
• All: 8 reference(s)