Whitcomb D C, Preston R A, Aston C E, Sossenheimer M J, Barua P S, Zhang Y, Wong-Chong A, White G J, Wood P G, Gates L K, Ulrich C, Martin S P, Post J C, Ehrlich G D
Department of Medicine, University of Pittsburgh, Pennsylvania 15261, USA. Whitcomb+@pitt.edu
Gastroenterology. 1996 Jun;110(6):1975-80. doi: 10.1053/gast.1996.v110.pm8964426.
BACKGROUND & AIMS: Hereditary pancreatitis (HP) is an autosomal-dominant disorder with incomplete penetrance characterized by recurrent bouts of severe epigastric pain with onset usually at 5-10 years of age. A genetic linkage study was designed to identify the HP gene.
A 500-member pedigree was constructed from a U.S. kindred centered in eastern Kentucky and western Virginia. A genome-wide search strategy was employed using a 36-member subset of this family to determine the genetic locus for HP. Testing for linkage to microsatellite loci was performed at 20-cM intervals.
Linkage was established between the HP phenotype and chromosome 7q in this subset of the family. Modeled as an autosomal dominant disorder with 80% penetrance, a maximal multipoint logarithm of the odds score of 4.3 was obtained using a four-point analysis consisting of markers D7S684, D7S661, D7S505, and the HP locus. Two microsatellite markers, D7S661 and D7S505, that correspond to the 7q35 region of chromosome 7 spanning a 6-cM region did not evidence obligate recombinations with HP. The centromeric and telomeric limits are defined by recombinations at D7S684 and D7S483, respectively, which generates a 19-cM locus for HP. Utilizing family members from the extended pedigree, a break in the high-risk haplotype between D7S684 and D7S661 was observed, which suggests it may be possible to exclude an additional 8 cM from the HP locus. A maximal pairwise logarithm of the odds score of 4.73 at a recombination fraction of theta at D7S684 was obtained with the addition of these extended family members.
Linkage of HP to 7q35 represents a major advancement in our understanding of the genetic basis of this disorder.
遗传性胰腺炎（HP）是一种常染色体显性疾病，外显率不完全，其特征为反复出现严重的上腹部疼痛，通常在5至10岁发病。设计了一项基因连锁研究以鉴定HP基因。
从以肯塔基州东部和弗吉尼亚州西部为中心的一个美国家族构建了一个包含500名成员的家系。采用全基因组搜索策略，使用该家族的一个36名成员的子集来确定HP的基因座。以20厘摩的间隔对微卫星基因座进行连锁检测。
在该家族的这个子集中，HP表型与7号染色体q臂之间建立了连锁关系。建模为外显率80%的常染色体显性疾病，使用由标记D7S684、D7S661、D7S505和HP基因座组成的四点分析，获得了最大多点优势对数分数为4.3。两个对应于7号染色体7q35区域、跨度为6厘摩区域的微卫星标记D7S661和D7S505，未显示与HP有必然的重组。着丝粒和端粒界限分别由D7S684和D7S483处的重组定义，这为HP产生了一个19厘摩的基因座。利用扩展家系中的家庭成员，观察到D7S684和D7S661之间的高风险单倍型有断裂，这表明有可能从HP基因座中再排除8厘摩。加入这些扩展家庭成员后，在D7S684处重组分数为θ时，获得了最大成对优势对数分数为4.73。
HP与7q35的连锁代表了我们对该疾病遗传基础理解的重大进展。
