Strnad Pavel, Lienau Tim C, Tao Guo-Zhong, Lazzeroni Laura C, Stickel Felix, Schuppan Detlef, Omary M Bishr
Department of Medicine, Palo Alto VA Medical Center, Palo Alto, CA 94304, USA.
Hepatology. 2006 Jun;43(6):1354-63. doi: 10.1002/hep.21211.
Keratins 8 and 18 (K8/K18) protect the liver from various forms of injury. Studies of liver explants from a large cohort of U.S. patients showed that K8/K18 mutations confer a risk to developing end-stage liver diseases, though which diseases are preferentially involved is unknown. We tested the hypothesis that K8/K18 variants are associated with chronic hepatitis C (CHC) and that their presence correlates with progression of fibrosis. Genomic DNA was isolated from peripheral blood of a well-characterized German cohort of 329 patients with CHC infection. Exonic regions were PCR-amplified and analyzed using denaturing high-performance liquid chromatography and DNA sequencing. Our findings showed: (1) amino acid altering keratin heterozygous variants in 24 of 329 CHC patients (7.3%) and non-coding heterozygous variants in 26 patients (7.8%), and (2) 3 new exonic K8 variants (T26R/G55A/A359T); 6 novel non-coding variants and one K18 coding variant (K18 S230T; 2 patients). The most common variants were K8 R341H (10 patients), K8 G62C (6 patients) and K8 I63V (4 patients). A novel and exclusive association of an intronic KRT8 IVS7+10delC deletion in all 10 patients with K8 R341H was observed. Notably, there was a significant association of exonic, but not of intronic K8 variants with increased fibrosis. In conclusion, previously described and novel K8 variants are present in a German population and collectively associate with progression of fibrosis in CHC infection. The unique 100% segregation of the most common K8 variant, R341H, with an intronic deletion suggests that one of these two genetic changes might lead to the other.
角蛋白8和18（K8/K18）可保护肝脏免受各种形式的损伤。对一大群美国患者的肝脏外植体研究表明，K8/K18突变会增加患终末期肝病的风险，不过具体哪些疾病更容易受累尚不清楚。我们检验了这样一个假设，即K8/K18变体与慢性丙型肝炎（CHC）相关，且它们的存在与纤维化进展相关。从一个特征明确的德国队列中329例CHC感染患者的外周血中分离基因组DNA。对外显子区域进行PCR扩增，并使用变性高效液相色谱和DNA测序进行分析。我们的研究结果显示：（1）329例CHC患者中有24例（7.3%）存在改变氨基酸的角蛋白杂合变体，26例（7.8%）存在非编码杂合变体；（2）有3个新的外显子K8变体（T26R/G55A/A359T）；6个新的非编码变体和1个K18编码变体（K18 S230T；2例患者）。最常见的变体是K8 R341H（10例患者）、K8 G62C（6例患者）和K8 I63V（4例患者）。在所有10例携带K8 R341H的患者中均观察到一种新的、独特的内含子KRT8 IVS7+10delC缺失。值得注意的是，外显子K8变体与纤维化增加显著相关，而内含子K8变体则不然。总之，先前描述的和新的K8变体存在于德国人群中，并且共同与CHC感染中的纤维化进展相关。最常见的K8变体R341H与一个内含子缺失的独特100%分离表明，这两个基因变化中的一个可能会导致另一个。
