Knoblauch H, Müller-Myhsok B, Busjahn A, Ben Avi L, Bähring S, Baron H, Heath S C, Uhlmann R, Faulhaber H D, Shpitzen S, Aydin A, Reshef A, Rosenthal M, Eliav O, Mühl A, Lowe A, Schurr D, Harats D, Jeschke E, Friedlander Y, Schuster H, Luft F C, Leitersdorf E
Franz Volhard Clinic and Max Delbrück Center for Molecular Medicine and Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
Am J Hum Genet. 2000 Jan;66(1):157-66. doi: 10.1086/302704.
A cholesterol-lowering gene has been postulated from familial hypercholesterolemia (FH) families having heterozygous persons with normal LDL levels and homozygous individuals with LDL levels similar to those in persons with heterozygous FH. We studied such a family with FH that also had members without FH and with lower-than-normal LDL levels. We performed linkage analyses and identified a locus at 13q, defined by markers D13S156 and D13S158. FASTLINK and GENEHUNTER yielded LOD scores >5 and >4, respectively, whereas an affected-sib-pair analysis gave a peak multipoint LOD score of 4.8, corresponding to a P value of 1.26x10-6. A multipoint quantitative-trait-locus (QTL) linkage analysis with maximum-likelihood binomial QTL verified this locus as a QTL for LDL levels. To test the relevance of this QTL in an independent normal population, we studied MZ and DZ twin subjects. An MZ-DZ comparison confirmed genetic variance with regard to lipid concentrations. We then performed an identity-by-descent linkage analysis on the DZ twins, with markers at the 13q locus. We found strong evidence for linkage at this locus with LDL (P<.0002), HDL (P<.004), total cholesterol (P<.0002), and body-mass index (P<.0001). These data provide support for the existence of a new gene influencing lipid concentrations in humans.
从家族性高胆固醇血症（FH）家族中推测出一种降胆固醇基因，该家族中有LDL水平正常的杂合子个体以及LDL水平与杂合子FH患者相似的纯合子个体。我们研究了这样一个患有FH的家族，其中也有未患FH且LDL水平低于正常的成员。我们进行了连锁分析，确定了位于13q的一个位点，由标记D13S156和D13S158定义。FASTLINK和GENEHUNTER分别得出LOD分数>5和>4，而受累同胞对分析给出的多点LOD分数峰值为4.8，对应P值为1.26×10-6。采用最大似然二项式QTL的多点数量性状位点（QTL）连锁分析证实该位点是LDL水平的QTL。为了在一个独立的正常人群中检验这个QTL的相关性，我们研究了同卵双胞胎（MZ）和异卵双胞胎（DZ）受试者。MZ-DZ比较证实了脂质浓度方面的遗传方差。然后我们对DZ双胞胎进行了基于同源性的连锁分析，使用13q位点的标记。我们发现该位点与LDL（P<0.0002）、HDL（P<0.004）、总胆固醇（P<0.0002）和体重指数（P<0.0001）存在强烈的连锁证据。这些数据为人类中存在一种影响脂质浓度的新基因提供了支持。
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