Ath29^C3H/HeJ
QTL Variant Detail

Summary

• QTL variant: Ath29^C3H/HeJ
• Name: atherosclerosis 29; C3H/HeJ
• MGI ID: MGI:3628448
• QTL: Ath29 Location: Chr9:40419594-74607925 bp Genetic Position: Chr9, cM position of peak correlated region/allele: 35.3 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: C3H/HeJ

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers decreased atherosclerotic lesion size compared to C57BL/6J. (J:106521)
• Inheritance: Recessive

Expression

In Mice Carrying this Mutation:	1 RNA-Seq or microarray experiment(s)
In Structures Affected by this Mutation:	1 anatomical structure(s)

Notes

Wang et al (J:140288) identified Ath29 in F2 animals homozygous for Apoe^tm1Unc.

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

J:106521

Linkage analysis was performed on 234 female animals from a (C57BL/6J-Apoe^tm1Unc x C3H/HeJ-Apoe^tm1Unc)F2 intercross to identify QTLs associated with atherosclerotic lesion size, plasma lipids, and body weight. Animals were place on a Western diet at 6 weeks of age for a duration of 12 weeks. On a Western diet, parental strain C3H/HeJ-Apoa^tm1Unc exhibits 6-fold increased plasma HDL cholesterol and 10-fold increased aortic lesion size compared to parental strain C57BL/6J. 130 polymorphic markers at an average spacing of 13 cM were used for the genome scan.

Significant linkage to plasma lipids and body weight mapped to 2 peaks on distal mouse Chromosome 1. These 2 linkages are collectively named Bodwt1 (body weight 1). Marker D1Mit425 at 81.6 cM is linked to plasma LDL/VLDL cholesterol (LOD=5.7), triglycerides (LOD=2.5), and body weight (LOD=9). Marker D1Mit270 at 92.3 cM is linked to plasma LDL/VLDL cholesterol (LOD=6.3), HDL cholesterol (LOD=3), and triglycerides (LOD=3.8). C3H/HeJ-derived alleles at Bodwt1 confer increased HDL cholesterol, triglycerides, and body weight with dominant inheritance, and increased LDL/VLDL cholesterol with codominant inheritance. Previously identified QTL Bw17 (75 cM), Bw8q1 (100 cM), Cq2 (100 cM), and Hdlq15 (104 cM)map near this locus. Apoa2 (92.6 cM) and Soat1 (81.6 cM) are potential candidate genes for Bodwt1.

Significant linkage to atherosclerotic lesion size mapped to a broad region of mouse Chromosome 9. This QTL is named Ath29 (atherosclerosis 29). Three peaks are detected within Ath29 at D9Mit206 (20 cM, LOD=2.9, 11% of variance), D9Mit360 (35 cM, LOD=3.7, 24% of variance), and D9Mit156 (42 cM, LOD=4.1, 34% of variance). C57BL/6J-derived alleles at Ath29 confer increased atherosclerotic lesion size with dominant inheritance, while C3H/HeJ-derived alleles confer smaller lesion size with recessive inheritance.

Significant linkage to body weight mapped to 29.8 cM on mouse Chromosome 17 near D17Mit180 (LOD=3.4). This locus is named Bodwt2 (body weight 2). C57BL/6J-derived alleles at Bodwt2 confer increased body weight with recessive inheritance. Previously identified body weight QTL Wt3q3 (14 cM) maps near this locus.

Suggestive linkage to atherosclerotic lesion size mapped to 20 cM on mouse Chromosome 11 near D11Mit236 (LOD=2.4). This locus explains 5% of the variance. C3H/HeJ-derived alleles at D11Mit236 confer decreased atherosclerotic lesion size with a dominant mode of inheritance.

Suggestive linkage to plasma LDL/VLDL cholesterol mapped to 68 cM on mouse Chromosome 5 near D5Mit95 (LOD=2.2) and 56 cM on mouse Chromosome 9 near D9Mit15 (LOD=2.5).

Suggestive linkage to plasma HDL cholesterol mapped to 58.8 cM on mouse Chromosome 3 near D3Mit42 (LOD=2.3).

Suggestive linkage to triglycerides mapped to 41 cM on mouse Chromosome 8 near D8Mit41 (LOD=3.2). Previously identified triglyceride QTLs Tgl1 (51.5 cM) and Trigq2 (30 cM) map near this locus.

Suggestive linkage to body weight mapped to 66 cM on mouse Chromosome 4 near D4Mit251 (LOD=2.7). This locusoverlaps with Bw7 at 59 cM. Suggestive linkage to body weight also mapped to 54 cM on mouse Chromosome 14 near D14Mit185 (LOD=2.2). This locus overlaps with Bwnd2wk7 at 52 cM.

J:127711

Linkage analysis was performed on 135 CHOW-fed females from a (B6.129P2-Apoe^tm1Unc/J x C3.129P2-Apoe^tm1Unc/Lus)F2 intercross to identify QTLs associated with atherosclerosis resistance/susceptibility. This same cross was previously used to identify athersclerosis QTLs on a Western-fed diet. Inbred strain C3H/HeJ is resistant to atherosclerosis compared to C57BL/6J. Animals were sacrificed at 12 weeks of age and genome scan was performed using genetic markers at a 10 cM resolution.

Significant linkage to HDL (LOD=7.1) and triglycerides (LOD=4.4) mapped to 92 cM on mouse Chromosome 1 near D1Mit540. This locus is likely identical to previously identified QTL Bodwt1. Potential candidate genes for Bodwt1 include Apoa2 (92.6 cM) and Soat1 (81.6 cM).

Ath4on mouse Chromosome 4 was replicated in this study at 28 cM with suggestive significance near D4Mit327 (LOD=2.6). C57BL/6J-derived alleles at Ath4 confer atherosclerosis susceptibility. A potential candidate gene for Ath4 is Angptl3 (48 cM). Tlr4 was previously considered a candidate for Ath4 but authors excluded this gene based on congenic line analysis. Replacing the defective C3H/HeJ allele of Tlr4 with a functional allele from C3H/DNA did not result in increased atherosclerosis susceptibility.

Significant linkage to atherosclerosis susceptibility mapped to 27 cM on mouse Chromosome 9 with LOD=5 near D9Mit25. This locus is believed to be identical to Ath29, which was previously identified in a BXH Western-fed population. C57BL/6J-derived alleles at Ath29 confer atherosclerosis susceptibility in (B6.129P2-Apoe^tmiUnc/J x C3.129P2-Apoe^tm1Unc/Lus)F2 females. The Ath29 95% confidence interval spans 17 cM - 33 cM. Ath29 was confirmed in a congenic line carrying a C3H/HeJ-derived DNA segment from D9Mit297 (15 cM) to D9Mit16 (61 cM) on a B6.129P-Apoe^tm1Unc susceptible background. As expected congenic animals displayed decreased aortic lesion size compared to B6.129P2-Apoe^tm1Unc control animals. Potential candidate genes for Ath29 include Acat1 (30cM), Apoa1 (27 cM), Apoa4 (27 cM), Apoc3 (27 cM), Apoa5, Il10ra (26 cM), Il18 (29 cM), Nnmt (29 cM), Tirap (17 cM), Sorl1 (24 cM), Pafah1b2 (26 cM), Thsd4 (33 cM), and Loxl1 (33 cM).

Suggestive linkage to HDL (LOD=3.8) and triglycerides (LOD=2.5) mappedto 14 cM on mouse Chromosome 10. Suggestive linkage to atherosclerosis susceptibility mapped to 58 cM (LOD=2.5).

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 identifiedatherosclerosis 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-derived allelesconfer 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 nearrs3720626 (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 candidategenes 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 lesionareaand the 95% confidence intervalspans 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)aspotential candidate genes for Ath29.

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 aorticlesion size in female animals.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 nearrs3660479 (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 asdetermined by overlappingeQTLanalysis.

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) analysis identified 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 Ath26 confer increased aortic lesion area. The 95% confidence interval for Ath26 spans 22 cM to 28 cM.

References

• Original: J:106521 Su Z, et al., Quantitative Trait Locus Analysis of Atherosclerosis in an Intercross Between C57BL/6 and C3H Mice Carrying the Mutant Apolipoprotein E Gene. Genetics. 2006 Mar;172(3):1799-807
• All: 4 reference(s)