Association between antibiotic use during early life and early-onset colorectal cancer risk overall and according to polygenic risk and FUT2 genotypes.

Early-onset colorectal cancer (EOCRC) has been increasing worldwide. Potential risk factors may have occurred in childhood or adolescence. We investigated the associations between early-life factors and EOCRC risk, with a particular focus on long-term or recurrent antibiotic use (LRAU) and its interaction with genetic factors. Data on the UK Biobank participants recruited between 2006 and 2010 and followed up to February 2022 were used. We used logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) of the associations between LRAU during early life and EOCRC risk overall and by polygenic risk score (constructed by 127 CRC-related genetic variants) and Fucosyltransferase 2 (FUT2), a gut microbiota regulatory gene. We also assessed the associations for early-onset colorectal adenomas, as precursor lesion of CRC, to examine the effect of LRAU during early-life and genetic factors on colorectal carcinogenesis. A total of 113 256 participants were included in the analysis, with 165 EOCRC cases and 719 EOCRA cases. LRAU was nominally associated with increased risk of early-onset CRC (OR = 1.48, 95% CI = 1.01-2.17, P = .046) and adenomas (OR = 1.40, 95% CI = 1.17-1.68, P < .001). When stratified by genetic polymorphisms of FUT2, LRAU appeared to confer a comparatively greater risk for early-onset adenomas among participants with rs281377 TT genotype (OR = 1.10, 95% CI = 0.79-1.52, P = .587, for CC genotype; OR = 1.75, 95% CI = 1.16-2.64, P = .008, for TT genotype; Pinteraction = .089). Our study suggested that LRAU during early life is associated with increased risk of early-onset CRC and adenomas, and the association for adenomas is predominant among individuals with rs281377 TT/CT genotype. Further studies investigating how LRAU contributes together with genetic factors to modify EOCRC risk, particularly concerning the microbiome-related pathway underlying colorectal carcinogenesis, are warranted.

Helicobacter pylori and Inflammatory Bowel Disease: An Unresolved Enigma.

The article describes the hypothesis that there may be a noncausal relationship between Helicobacter pylori infection and inflammatory bowel disease (IBD) that is related to the host mucin glycan fucosylation status in the gastrointestinal tract. The proposed hypothesis may explain why IBD is less prevalent in patients with H. pylori, and no increased risk of IBD is seen after H. pylori eradication therapy, as was shown in the study by Tanner et al.

Association of fucosyltransferase 2 gene with norovirus infection: A systematic review and meta-analysis.

BACKGROUND: Norovirus is a leading cause of viral gastroenteritis outbreaks worldwide. Histo-blood group antigens (HBGAs) are important host attachment factors in susceptibility to norovirus. In this study, the association of FUT2 gene, which participates in the biosynthesis of HBGAs, with norovirus infection has been investigated. METHODS: All relevant studies on the associations of FUT2 gene with norovirus were retrieved from PubMed, Web of Science, Embase, and Cochrane Library databases. Odds ratios (ORs) and 95% confidence interval (CI) were used to analyze the extracted data. I2 statistic, sensitivity analysis and publication bias analysis were used to confirm the findings. Subgroup analyses were performed for races, genotypes, development degree of the countries, publication years, age and setting when heterogeneity was recorded. RESULTS: Twenty studies including 4066 participants were included for the meta-analysis. This analysis showed that there is a significant association between FUT2 gene and norovirus infection (OR = 3.02, 95%CI = 2.00-4.55, P < 0.001). Additionally, the ORs of norovirus infection among Chinese (OR = 4.49, 95%CI = 2.37-8.50, P < 0.001) were higher than those among Caucasian (OR = 3.23, 95%CI = 2.20-4.74, P < 0.001). CONCLUSIONS: The meta-analysis suggested that FUT2 gene is associated with susceptibility to norovirus infection.

Divergence in phenotyping and genotyping analysis of the Lewis histo-blood group system.

OBJECTIVES: This study evaluated the red blood cell (RBC) Lewis phenotypes by simple haemagglutination technique and molecular genotyping in healthy individuals. BACKGROUND: The expression of Lewis antigen on RBCs is dependent on the interaction of FUT3 and FUT2 genes. Complexity of the genetic control of Lewis antigen expression and the error-prone nature of Lewis phenotyping result in non-genuine RBC Lewis phenotypes, which could be misleading. MATERIALS AND METHODS: ABO blood group and RBC Lewis phenotypes were determined by conventional haemagglutination tube techniques. FUT2 and FUT3 genotypes were analysed by polymerase chain reaction and direct DNA sequencing. The RBC Lewis phenotypes were also inferred from the FUT2 and FUT3 genotyping results. RESULTS: The frequencies of RBC Lewis phenotypes typed by the conventional tube test were Le(a+b-) 19.63%, Le(a-b+) 49.32% and Le(a-b-) 31.05%, whereas the frequencies inferred from the FUT2 and FUT3 genotypes were Le(a+b-) 20.09%, Le(a-b+), 59.82%; Le(a-b-), 17.81%; and Le(a+b+), 5 (2.28%). The Le(a+b+) phenotype was not detected by the tube test, and a significant difference was observed in the frequencies of the determined Le(a-b-) and Le(a-b+) phenotypes. CONCLUSION: The phenotyping and genotyping of Lewis blood group system reveal a high rate of discordance in the frequencies of Lewis phenotypes among the healthy individuals.

Estimation of genetic variation in the Secretor and Lewis genes in Iranian hospitalized children.

BACKGROUND: The Secretor (FUT2) and lewis gene (FUT3) are in charge of the construction of histo-blood group antigens, which act as a receptor for some Pathogenes. This study aimed to estimate the prevalence of five significant single nucleotide polymorphisms (SNPs) in Iranian children. METHODS: In this cross-sectional study, 102 blood samples collected from hospitalized children. The FUT2 gene region was amplified and sequenced to explore rs1047781 and rs601338, and the FUT3 gene region was amplified to explore rs28362459, rs812936, rs778986 SNPs. RESULTS: In FUT2 gene, Se358,428 that produces Se phenotype with 63% (0.53 - 0.72) prevalence, was the most common genotype. For FUT3 gene Le59,202,314 with 80% prevalence was most common genotype (0.71 - 0.87). CONCLUSION: This study genotyped Secretor and Lewis genes and designated SNPs' distinct distribution in Iran, and clarified at-risk groups for certain diseases.

Can the FUT 2 Gene Variant Have an Effect on the Body Weight of Patients Undergoing Bariatric Surgery?-Preliminary, Exploratory Study.

BACKGROUND: The FUT2 gene (Se gene) encoding the enzyme α-1,2-L-fucosyltransferase 2 seems to have a significant effect on the number and type of bacteria colonizing the intestines. METHODS: In a group of 19 patients after bariatric surgery, the polymorphism (rs601338) of FUT2 gene was analyzed in combination with body mass reduction, intestinal microbiome (16S RNA sequencing), and short chain fatty acids (SCFA) measurements in stools. RESULTS: Among the secretors (Se/Se polymorphism of the FUT2 gene rs601338, carriers of GG variant), correlations between waist-hip ratio (WHR) and propionate content and an increase in Prevotella, Escherichia, Shigella, and Bacteroides were observed. On the other hand-in non-secretors (carriers of GA and AA variants)-higher abundance of Enterobacteriaceae, Ruminococcaceae, Enterobacteriaceae, Clostridiales was recorded. CONCLUSIONS: The increased concentrations of propionate observed among the GG variants of FUT 2 may be used as an additional source of energy for the patient and may have a higher risk of increasing the WHR than carriers of the other variants (GA and AA).

Can the FUT2 Non-secretor Phenotype Associated With Gut Microbiota Increase the Children Susceptibility for Type 1 Diabetes? A Mini Review.

The global toll of type 1 diabetes (T1D) has steadily increased over the last decades. It is now widely acknowledged that T1D pathophysiology is more complex than expected. Indeed, a multifaceted interplay between genetic, metabolic, inflammatory and environmental factors exists that leads to heterogeneous clinical manifestations across individuals. Children with non-secretor phenotype and those affected by T1D share low abundance of bifidobacteria, low content of short-chain fatty acids, intestinal phosphatase alkaline and a high incidence of inflammatory bowel diseases. In this context, host-gut microbiota dyad may represent a relevant contributor to T1D development and progression due to its crucial role in shaping host immunity and susceptibility to autoimmune conditions. The FUT2 gene is responsible for the composition and functional properties of glycans in mucosal tissues and bodily secretions, including human milk. FUT2 polymorphisms may profoundly influence gut microbiota composition and host susceptibility to viral infections and chronic inflammatory disease. In this minireview, the possible interplay between mothers' phenotype, host FUT2 genetic background and gut microbiota composition will be discussed in perspective of the T1D onset. The study of FUT2-gut microbiota interaction may add a new piece on the puzzling T1D etiology and unveil novel targets of intervention to contrast T1D development and progression. Dietary interventions, including the intake of α-(1, 2)-fucosyl oligosaccharides in formula milk and the use of specific prebiotics and probiotics, could be hypothesized.

FUT3 and FUT2 genotyping and glycoconjugate profile Lewisb as a protective factor to Toxoplasma gondii infection.

The interaction between the ABO, FUT2 and FUT3 genes results in the synthesis of different glycoconjugates profiles expressed in gastrointestinal tract. Moreover, the protozoan Toxoplasma gondii, which causes toxoplasmosis, utilizes this organ as an infection route. We analyzed the frequencies of the different glycoconjugate profiles which were determined by phenotyping ABO and genotyping the status secretor (FUT2; substitution G428A) and Lewis (FUT3; substitution T202C and C314T) histo-blood systems, assessed by PCR-RFLP and PCR-SSP, respectively. A total of 244 pregnant women (G1: Seropositive; G2: Seronegative) for IgG T. gondii antibodies were enrolled. IgG anti-T. gondii antibodies were determined by ELISA. G1 was composed of 158 (64.8%) sample and G2 by 86 (36.2%). The glycoconjugate profile was accessed in 151 seropositive and 85 seronegative samples by the combination of ABO and Lewis phenotyping as well as FUT2 and FUT3 genotyping. In G1, 36 (22.8%) presented the glycoconjugate profile ALeb, 5 (3.3%) A, 13 (8.6) BLeb, 1 (0.6%) B, 41 (27.1%) Leb, 13(8.6%) H, 38(25.2%) Lea and 4 (2.6%) Lec. G2 was composed of 13 (15.3%) of ALeb, 15 (17.6%) BLeb, 1 (1.2%) B, 42 (49,4%) Leb and 14 (16.5) Lea. H and Lec glycoconjugate profiles were not found in G2. The frequencies of the glycoconjugates profiles Leb (p = 0.001) and H (p = 0.005) were significantly different compared between G1 and G2. The glycoconjugate profile H inferred from the ABO phenotyping and FUT3 and FUT2 genotyping is associated with infection by T. gondii in pregnant women and the Leb profile appears to protect the infection by this parasite.

Association analysis of the SNP (rs345476947) in the FUT2 gene with the production and reproductive traits in pigs.

The FUT2 gene was considered as an important candidate for pathogenic infections, while the potential associations between this gene and the production and reproductive traits of pigs have not been explored. In this study, we detected the genetic variants of porcine FUT2 gene and analyzed the associations of the polymorphisms with FUT2 mRNA expression and production and reproductive traits (age at 100 kg, backfat thickness at 100 kg, eye muscle thickness, the number of newborn piglets, the number of weaned piglets, and birth weight) in 100 Large White sows. One single nucleotide polymorphism (SNP) (rs345476947, C→T) in the intron of FUT2 and three genotypes (TT, CT and CC) were determined. Association analysis revealed significant associations between this SNP with the number of newborn piglets and weaned piglets. Furthermore, individuals with the TT genotype had significantly higher numbers of newborn piglets and weaned piglets than those with the CC genotype (P < 0.05). Quantitative PCR analysis showed that FUT2 expression in individuals with CC genotype was significantly higher than those with TT and CT genotypes in the liver and lymph gland (P < 0.05) and higher than that of CT in the spleen, kidney, and duodenum (P < 0.05). These findings indicated that the TT genotype may be a favorable genotype for the reproductive traits of pigs. Our study revealed the genetic variants of the FUT2 gene and identified a promising candidate SNP (rs345476947) associated with the reproductive traits, which has the potential to be applied in selective breeding of pigs.

Comprehensive mutation screening for 10 genes in Chinese patients suffering very early onset inflammatory bowel disease.

AIM: To perform sequencing analysis in patients with very early-onset inflammatory bowel disease (VEO-IBD) to determine the genetic basis for VEO-IBD in Chinese pediatric patients. METHODS: A total of 13 Chinese pediatric patients with VEO-IBD were diagnosed from May 2012 and August 2014. The relevant clinical characteristics of these patients were analyzed. Then DNA in the peripheral blood from patients was extracted. Next generation sequencing (NGS) based on an Illumina-Miseq platform was used to analyze the exons in the coding regions of 10 candidate genes: IL-10, IL-10RA, IL-10RB, NOD2, FUT2, IL23R, GPR35, GPR65, TNFSF15, and ADAM30. The Sanger sequencing was used to verify the variations detected in NGS. RESULTS: Out of the 13 pediatric patients, ten were diagnosed with Crohn's disease, and three diagnosed with ulcerative colitis. Mutations in IL-10RA and IL-10RB were detected in five patients. There were four patients who had single nucleotide polymorphisms associated with IBD. Two patients had IL-10RA and FUT2 polymorphisms, and two patients had IL-10RB and FUT2 polymorphisms. Gene variations were not found in the rest four patients. Children with mutations had lower percentile body weight (1.0% vs 27.5%, P = 0.002) and hemoglobin (87.4 g/L vs 108.5 g/L, P = 0.040) when compared with children without mutations. Although the age of onset was earlier, height was shorter, and the response to treatment was poorer in the mutation group, there was no significant difference in these factors between groups. CONCLUSION: IL-10RA and IL-10RB mutations are common in Chinese children with VEO-IBD. Patients with mutations have an earlier disease onset, lower body weight and hemoglobin, and poorer prognosis.

Expression of key glycosphingolipid biosynthesis-globo series pathway genes in Escherichia coli F18-resistant and Escherichia coli F18-sensitive piglets.

A pioneering study showed that the glycosphingolipid biosynthesis-globo series pathway genes (FUT1, FUT2, ST3GAL1, HEXA, HEXB, B3GALNT1 and NAGA) may play an important regulatory role in resistance to Escherichia coli F18 in piglets. Therefore, we analysed differential gene expression in 11 tissues of two populations of piglets sensitive and resistant respectively to E. coli F18 and the correlation of differential gene expression in duodenal and jejunal tissues. We found that the mRNA expression of the seven genes was relatively high in spleen, liver, lung, kidney, stomach and intestinal tract; the levels in thymus and lymph nodes were lower, with the lowest levels in heart and muscle. FUT2 gene expression in the duodenum and jejunum of the resistant population was significantly lower than that in the sensitive group (P < 0.01). ST3GAL1 gene expression was also significantly lower in the duodenum of the resistant population than in the sensitive group (P < 0.05). No significant differences were observed among the remaining genes. The expression level of FUT1 was extremely significantly positively correlated with FUT2 and B3GALNT1 expression (P < 0.01) and also had a significant positive correlation with NAGA expression (P < 0.05). The expression level of FUT2 had extremely significant positive correlations with FUT1, ST3GAL1 and B3GALNT1 (P < 0.01). These results suggest that FUT2 plays an important role in E. coli F18 resistance in piglets. FUT1, ST3GAL1, B3GALNT1 and NAGA may also participate in the mechanism of resistance to E. coli F18.

Lewis histo-blood group system phenotyping and genotyping reveal divergence in the association of Le(a-b-) phenotype and type 1 diabetes.

BACKGROUND AND OBJECTIVES: The red blood cell Le(a-b-) phenotype was proposed as risk factor for type 1 diabetes, but contradictory results were published elsewhere. This study re-examined the potential association between Lewis histo-blood group system and type 1 diabetes. MATERIAL AND METHODS: Patients and controls of both sexes, Caucasians and non-Caucasians, matched by sex, geographical origin and ethnicity were evaluated. The red blood cell Lewis phenotypes were identified by gel column agglutination and also inferred from the FUT2 and FUT3 genotyping. RESULTS: The Le(a-b-) phenotype was prevalent in patients with type 1 diabetes, and the Le(a-b+) phenotype was prevalent in controls when both were determined by gel columns agglutination. No differences were observed in the frequencies of the Le(a-b-) phenotype inferred from the FUT2 and FUT3 genotyping between patients and controls. CONCLUSIONS: The Lewis red blood cell phenotyping and genotyping reveal divergence in the association of Le(a-b-) phenotype and type 1 diabetes.

Evaluation of the Genotypes of the Lewis Blood Group in a Korean Population Using Direct Sequencing

BACKGROUND: The FUT2 and FUT3 genes determine the Lewis phenotype of red blood cells (RBCs). Recently, the Lewis genes, the secretor genes, and several mutations that cause Lewis negative and nonsecretor phenotypes have been identified. The purpose of this study was to analyze the gene frequency of FUT2 and FUT3 in a Korean population by comparing the use of the direct sequencing method to the use of the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method for mutation detection in the FUT2 and FUT3 genes. METHODS: RBCs and peripheral blood leukocytes were obtained from 225 apparently healthy volunteers to determine the phenotype and genotype of the FUT2 and FUT3 genes. Lewis phenotypes were determined on K3EDTA-stablized fresh blood samples using the column agglutination method. Lewis blood group genotyping was performed by use of the direct sequencing method. For the detection of T59G, C357T, and A385T mutations, the PCR-RFLP method was performed. RESULTS: The frequencies of the Lewis blood group phenotype were 12.4% for Le(a+b-), 70.7% for Le(a-b+), 11.1% for Le(a-b-) and 5.8% for Le(a+b+), respectively. Direct Sequencing of the FUT2 gene identified 92.2% C357T, 56.9% A385T, 0.4% G244A mutations and 1.8% del396. Direct Sequencing of the FUT3 gene identified 46.9% T59G, 30.4% G508A, 1.1% T202C, 1.1% C314T, 0.7% A1029G, 3.0% T1067A and 13.3% G1242A mutations. The PCR-RFLP method results were discordant in nine cases (1 case for C357T, 4 cases for A385T and 2 cases for T59G) as compared to the direct sequencing method results. CONCLUSION: We have determined the frequencies of FUT2 and FUT3 gene mutations in a Korean population. The use of the direct sequencing method was more accurate than the use of the PCR-RFLP method for the determination of the genotype of the FUT2 and FUT3 genes.

Evaluation of the RBC Lewis Blood Group Phenotypes and Genotypes of the FUT3 and FUT2 Gene / 대한진단검사의학회지

BACKGROUND: The Lewis and secretor gene determine the Lewis phenoytpe. Conventional Lewis blood grouping is difficult because of the presence of nongenuine Lewis negative individuals. Recently, the Lewis gene (FUT3), the secretor gene (FUT2), and several mutations that cause the Lewis negative and the nonsecretor phenotypes were identified. The purpose of this study was to compare Lewis phenotypes determined by commercially available three pairs of monoclonal antibodies with the Lewis and secretor genotypes. METHODS: RBCs for phenotyping and peripheral blood leukocytes for genotyping of FUT3 and FUT2 gene were obtained from 184 apparently healthy volunteers. Lewis phenotypes were determined on K3EDTA-stablized fresh blood samples using three pairs of commercially available monoclonal antibodies, one of which was the column agglutination method and the others were the tube agglutination methods. Lewis blood group genotyping was performed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to detect T59G, G428A, C357T, and A385T mutations. RESULTS: The frequencies of the Lewis blood group phenotype were Le(a+b-) 15.0%, Le(a-b+) 65.8%, Le(a-b-) 14.8%, and Le(a+b+) 4.3%, respectively. The Lewis blood group phenotypes determined by three pairs of monoclonal antibodies were 93.5%, 93.5% and 89.1% in accordance with the genotypes. The frequencies of Le, le, Se and se alleles were 64.4%, 35.6%, 48.6%, and 51.4% and we have newly detected 4 cases with only one A385T mutation. All of the Le(a+b+) phenotype cases have both C357T, and A385T homozygotic mutations. CONCLUSIONS: The PCR method may be effectively used for the genotyping of the FUT3 and FUT2 genes and offers an attractive alternative to Lewis phenotyping using hemagglutination method.

Study on the FUT2 gene structure of Xinjiang Uighur people of China / 中国输血杂志

Objective To study the Secretor gene (FUT2) molecular structure of Uighur population in Xinjiang area,China. Methods DNA was extracted from 40 Uygur unrelated donors' blood and sequence analysis of FUT2 genes was performed. Results Four mutations in the FUT2 genes of Uighur donors have been identified. The frequencies of mutations were 71.25% for 357T, 28.75% for 357C,77.50% for 385A,22.50% for 385T,70% for 428G,30% for 428A,72.50% for 739G and 27.50% for 739A. Conclusion Based on the characteristics of FUT2 gene structure of Xinjiang Uighur,it cauld be thought that there are some relationships between Xinjiang Uighur, Taiwanese of China and Caucasiany.

Molecular genetics analysis and frequency survey of H deficient phenotype / 中国输血杂志

Objective To survey the frequency of H deficient phenotype in blood donor population and analyze the serological and genetic characteristics of these individuals.Methods The H deficient phenotype was screened with anti-H monoclonal antibody.The ABO type was screened with serological method and with sequence specific primer polymerase chain reaction(PCR-SSP).FUT1 and FUT2 gene sequences were analyzed with direct sequencing of PCR products and gene cloning products.Result Of 85 390 blood donors,ten individuals were identified to be para-Bombay phenotype.Four h alleles were found in 14 para-Bombay phenotype individuals,h1(nt547-552?ag),h2(nt880-882?tt),h3(nt658c→t),and h_(new-2)(nt328g→a).The FUT1 genotypes of these para-Bombay individuals were h1/h1(6 individuals),h1/h2(7 individuals) and h3/h_(new2)(1 individual),and the frequency of 4 allele were 67.85%(h1),25%(h2),3.57%(h3),and 3.57%(h_(new-2)),respectively.FUT2 gene was analyzed in 12 para-Bombay phenotype individuals,and a mutation of nt357c→t was detected in all FUT2 gene,another mutation of nt716g→a were heterozygous in 5 individuals with h1/h2 genotype.No null FUT2 gene was detected.In serological analysis,all atypical anti-A or anti-B antibody of 14 para-Bombay individuals were inactive at 37℃,7 individuals had active anti-H antibody at 37℃.Conclusion The frequency of H deficient phenotype in Fujian population is about 1:8 500.The h1 and h2 alleles are predominant in Fujian H deficient individuals on h1-Se~(357) and h2-Se~(357,716) haplotype background.

Mutational analysis of FUT1 and FUT2 genes in para-Bombay individuals / 中国输血杂志

Objective To study the mutation of FUT1 and FUT2 genes in para-Bombay individual.Methods Direct DNA sequencing of FUT1 and FUT2 gene coding region were analyzed in two individuals with para-Bombay phenotype.Results One individual lost one of the three AG repeats located at nucleotides 547~552 of the FUT1 gene, whereas two of the three T repeats located at nucleotides 880~882 were deleted in the other.Conclusion Two frame-shift mutations of FUT1 gene are responsible for the H antigen deficiency

A study of FUT2 gene point mutation in the Chinese Han Population / 中国输血杂志

Objective To study the point mutation of FUT2 gene in Chinese Han population.Methods Using direct sequencing,molecular cloning techniques and the comparing with the gene sequence reportedby Kelly, the FUT2 gene structures of 41Chinese Han individuals have were studied.Results The G428A mutations of FUT2 gene was not found,but the A385T and C357T mutations were found in the 41 Chinese Han individuals.Among the 41 individuals,24 had A385T mutation and 17 had no A385T mutation.The neutral mutation C357T was found in all 41individuals.Conclusion The G428A point mutation of FUT2 which is commonly found in non secretor of Africans and Caucasian was not found in Chinese population.There are A385T and C357T point mutations which were found in 41 Chinese Han individuals.The present stady shows the difference between Chinese and Caucasian,and other non secretor mutations will be revealed by further investigation