Experiment
To identify genetic loci responsible for artherosclerosis susceptibility a pool of 376 F2 mice were generated by intercrossing atherosclerosis-suscptible C57BL/6J and atherosclerosis-resistant BALB/cByJ mice on a low-density lipoprotein receptor background.
Atherosclerotic lesion size and a panel of 61 additional phenotypes were exmined in the entire F2 population. QTL mapping was performed for all 62 phenotypes.
F1 and F2 mice were generated in 2 ways:
In cross B6.129S7-Ldlrtm1Her/J x CByJ.129S7(B6)-Ldlrtm1Her the resulting F1s were intercrossed to generate 95 male and 95 female F2s.
In cross CByJ.129S7(B6)-Ldlrtm1Her x B6.129S7-Ldlrtm1Her/J the resulting F1s were intercrossed to generate 94 male and 92 female mice.
A novel QTL for atherosclerotic lesion size, Ath39, was indentified on proximal Chromosome 2. This QTL was present in male mice only with a LOD=6.18 near D2Mit27 at 28.0cM, 38.1Mb.
12.01.2015 Curator Note: Another QTL was identified on proximal Chromosome 2 in female mice which the authors also refer to as Ath39. We have named this QTL Ath47 since different LOD scores, a bimodal peak, and a different mapped location are clearly reported.
QTL Ath47 was detected in female mice with a LOD=6.20 with bimodal LOD peaks and a maximum peak near rs27192030, at 34.4 Mb.
The QTLs in both sexes were associted with 14% of the variation in atherosclerotic lesion size; and the B6 allele was determined to be the at risk allele conferring atherosclerosis susceptibility at D2Mit7 in both male and female mice [Fig 1C and 1D], with fit in both the additive and dominant mode of inheritance.
Additional QTL were identified cosegregating with traits related to lipid and sterol metabolism with Chr 2 atherosclerosis QTL Ath39 and Ath47. Highly significant QTLs, more pronounced in males, were identified:
Ptslbq1, phytosterol brassicasterol level QTL 1, LOD=5.7, p<0.001;
Lanq1, lanosterol level QTL 1, LOD=5.3, p<0.001;
Pvldlc1, plasma VLDL-cholesterol 1, LOD=3.64, p<0.03;
and Hdl8, high densitylipoprotein cholesterol (HDL) level 8, LOD=3.56, p<0.036;
which all mapping between D2Mit7 (38.1 Mb) and rs13476554 (67.1 Mb), The B6 alleles increased plasma brassicasterol, lanosterol and VLDL-C and decreased plasma HDL-C. No effect was observed for plasma LDL-C.
In addition a second novel QTL cluster was identified on Chr 8 for plasma plant sterols that colocalized with a suggestive QTL (Ath40) for atherosclerotic lesion size.
Ath40 was also a male specific QTL. It mapped with suggestive significanceto a peak near D8Mit65, LOD=3.28,p=0.09. The B6 allele displayed an additive effect, increasing atherosclerotic lesion size.
The Chromosome 8 QTL for plasma concerntrations:
Ptslbq2, phytosterol brassicasterol level QTL 2, LOD=5.29, p<0.001;
Ptslsq1, phytosterol sitosterol level QTL 1, LOD=5.86,p<0.001; and
Ptslcq1, phytosterol campesterol level QTL 1, LOD=3.28,p=0.09 also mapped near D8Mit65. This cluster was also male specific. The B6 allele displayed an additive effect increasing plasmalevels of phytosterols.
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