Fox Caroline S, Cupples L Adrienne, Chazaro Irmarie, Polak Joseph F, Wolf Philip A, D'Agostino Ralph B, Ordovas Jose M, O'Donnell Christopher J
National Heart, Lung, and Blood Institute's Framingham Heart Study, National Institutes of Health, MA 01702, USA.
Am J Hum Genet. 2004 Feb;74(2):253-61. doi: 10.1086/381559. Epub 2004 Jan 16.
Carotid intimal medial thickness (IMT) is a heritable quantitative measure of atherosclerosis. A genomewide linkage analysis was conducted to localize a quantitative-trait locus (QTL) influencing carotid IMT. Carotid IMT was measured in 596 men and 629 women from 311 extended families (1,242 sib pairs) in the Framingham Heart Study Offspring cohort. B-mode carotid ultrasonography was used to define mean IMT of the carotid artery segments. Multipoint variance-component linkage analysis was performed. Evidence for significant linkage to internal carotid artery (ICA) IMT (two-point log odds [LOD] score 4.1, multipoint LOD score 3.4) was found 161 cM from the tip of the short arm of chromosome 12; these results were confirmed using the GENEHUNTER package (multipoint LOD score 4.3). No LOD scores >2.0 were observed for common carotid artery (CCA) IMT. Association analysis of a single-nucleotide-polymorphism variant of SCARB1 (minor allele frequency 0.13), a gene in close proximity to the region of peak linkage, revealed a protective association of the missense variant allele in exon 1 of SCARB1, with decreased ICA IMT compared with subjects homozygous for the common allele. Although the exon 1 variant contributed 2% to overall variation in ICA IMT, there was no significant change in the peak LOD score after adjustment in the linkage analyses. These data provide substantial evidence for a QTL on chromosome 12 influencing ICA IMT and for association of a rare variant of SCARB1, or a nearby locus, with ICA IMT. Because this rare SCARB1 variant does not account for our observed linkage, further investigations are warranted to identify additional candidate-gene variants on chromosome 12 predisposing to atherosclerosis phenotypes and clinical vascular disease.
颈动脉内膜中层厚度（IMT）是动脉粥样硬化的一种可遗传的定量指标。进行了全基因组连锁分析，以定位影响颈动脉IMT的数量性状基因座（QTL）。在弗雷明汉心脏研究后代队列中的311个大家庭（1242对同胞）的596名男性和629名女性中测量了颈动脉IMT。使用B型颈动脉超声来确定颈动脉段的平均IMT。进行了多点方差成分连锁分析。在距12号染色体短臂末端161厘摩处发现了与颈内动脉（ICA）IMT显著连锁的证据（两点对数优势[LOD]分数为4.1，多点LOD分数为3.4）；使用GENEHUNTER软件包证实了这些结果（多点LOD分数为4.3）。对于颈总动脉（CCA）IMT，未观察到LOD分数>2.0。对与连锁峰值区域紧邻的基因SCARB1的单核苷酸多态性变体（次要等位基因频率为0.13）进行关联分析，结果显示，与常见等位基因纯合子的受试者相比，SCARB1外显子1中的错义变体等位基因具有保护作用，可降低ICA IMT。尽管外显子1变体对ICA IMT的总体变异贡献了2%，但在连锁分析调整后，峰值LOD分数没有显著变化。这些数据为12号染色体上影响ICA IMT的QTL以及SCARB1的罕见变体或附近基因座与ICA IMT的关联提供了大量证据。由于这种罕见的SCARB1变体并不能解释我们观察到的连锁现象，因此有必要进一步研究，以确定12号染色体上其他易患动脉粥样硬化表型和临床血管疾病的候选基因变体。
