The Mucin-1 568 Adenosine to Guanine Polymorphism Influences Serum Krebs von den Lungen-6 levels

Abstract

Krebs von den Lungen (KL)-6 offers a new perspective as a disease marker in pulmonary diseases. The aim of this study was to analyze whether serum KL-6 levels are dependent on the functional adenosine to guanine mucin-1 (MUC1) gene polymorphism at nucleotide position 568 in a well-characterized white population. Polymorphisms were determined in 327 healthy, white individuals and 74 patients with sarcoidosis, using a PCR-sequence-specific primer assay. The serum KL-6 levels were measured by ELISA. Significant differences between serum KL-6 levels of healthy subjects who were grouped according to MUC1 568 genotype were observed (P<0.0001) (mean+/-SEM): AA (195.2+/-9.9 U/ml; 95% confidence interval [CI], 175.7-214.8), AG (246.0+/-8.6 U/ml; 95% CI, 229.0-263.1), and GG (302.6+/-11.8 U/ml; 95%CI, 279.3-326.0). In the patients with sarcoidosis, the results were (mean+/-SD): AA (550.1+/-411.7; 95% CI, 380.2-720.1), AG (716.3+/-452.4; 95% CI, 547.4-885.2), GG (1,151.0+/-1122; 95% CI, 610.1-1692.0); P=0.02. Comparison of the KL-6 levels in which the 568 genotype was ignored rendered 6 out of 74 (7.5%) misclassifications of "elevated" versus "normal" KL-6 levels or vice versa. In conclusion, the MUC1 568 A to G polymorphism may be of interest for diagnostic purposes because our study delivered in vivo evidence that it contributes to interindividual variations in KL-6 levels.

Randomized Phase II Trial of Letrozole plus Anti-MUC1 Antibody AS1402 in Hormone Receptor–Positive Locally Advanced or Metastatic Breast Cancer

“…The FcgRIIIa 158 V/V genotype and/or FcgRIIa 131 H/H genotype increases the affinity of the receptors for IgG and subsequent cell killing by immune cells (16) and correlates with higher response rates to monoclonal antibodies including rituximab and trastuzumab (17)(18)(19). A MUC1 polymorphism at nucleotide position 568 has been shown to have functional implications in human disease (20). Participants in this study were allotyped for FcgRIIIa 158, FcgRIIa 131, and MUC1 568 in an attempt to identify patient subsets particularly suited for therapy with AS1402.…”

Risk of gastric cancer is associated with the MUC1 568 A/G polymorphism

“…The forward primer 5'-CTA TGG GCA GAG AGA AGG AG-3' (primer 1), the reverse SSPs 5'-AGC TTG CAT GAC CAG AAC CC-3' (primer 2) and 5'-AGC TTG CAT GAC CAG AAC CT-3 ' (primer 3) were used in combination with the consensus forward primer, i.e. primer 1, leading to expected PCR product sizes of 233 bp (23). The total PCR reaction volume was 26 μl containing 2.6 μl of 10X PCR buffer, 1.024 μl of 2.5 mM dNTP mixture, 0.8 μl of each upstream and downstream primer at 10 pmol/μl, 0.6 U of rTaq DNA polymerase, 10 ng of the template DNA and an appropriate amount of ddH 2 O. PCR reaction was performed by predenaturing at 95˚C for 1 min, 5 cycles with 95˚C for 25 sec, 70˚C for 25 sec, 72˚C for 30 sec, then 21 cycles with 95˚C for 35 sec, 65˚C for 30 sec, 72˚C for 30 sec, and then, 4 cycles 95˚C for 50 sec, 55˚C for 60 sec, 72˚C for 90 sec (23,24).…”

“…primer 1, leading to expected PCR product sizes of 233 bp (23). The total PCR reaction volume was 26 μl containing 2.6 μl of 10X PCR buffer, 1.024 μl of 2.5 mM dNTP mixture, 0.8 μl of each upstream and downstream primer at 10 pmol/μl, 0.6 U of rTaq DNA polymerase, 10 ng of the template DNA and an appropriate amount of ddH 2 O. PCR reaction was performed by predenaturing at 95˚C for 1 min, 5 cycles with 95˚C for 25 sec, 70˚C for 25 sec, 72˚C for 30 sec, then 21 cycles with 95˚C for 35 sec, 65˚C for 30 sec, 72˚C for 30 sec, and then, 4 cycles 95˚C for 50 sec, 55˚C for 60 sec, 72˚C for 90 sec (23,24). Twelve μl of PCR product in 2% agarose gel was electrophoresized at 150 V for 30 min separation, then stained by ethidium bromide for 5 min and observed.…”

“…MUC1 is a transmembrane molecule with a large extracellular domain which contains a variable number of tandem repeats (VNTR) sequences of 20 amino acids. The MUC1 gene in 1q21-24 which encodes the MUC1 protein, is now known to have two exon polymorphisms, which have been reported as a VNTR polymorphism in exon 2 and its upstream as an A/G single nucleotide polymorphism (SNP) within exon 2 at 568 site (10,23,28). The Human Genome Project has reported (http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=4072037) the distribution frequencies from the people of representative countries and regions in MUC1 A/G polymorphism at 568 site.…”

“…Several cancer-related studies have reported an association between the MUC1 A/G polymorphism at 568 site and alterations in DNA and its encoding proteins have recently been linked with diseases. Janssen and colleagues reported this polymorphism had association with the KL-6 expression in the serum, which was MUC1 antibody in the lung and was an indicator of pulmonary fibrosis (23). Imbert and colleagues found that this polymorphism was associated with the dry eye syndrome, and MUC1 secreted by allele A carriers in the cornea and conjunctiva functioned in an inferior manner when compared to allele G carriers, which were more susceptible to dry eye syndrome (29,30).…”