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FUT2 nonfunctional variant: a "missing link" between genes and environment in type 1 diabetes?

Yang P, Li HL, Wang CY - Diabetes (2011)

View Article: PubMed Central - PubMed

Affiliation: Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

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Recent worldwide epidemiological studies demonstrate that the incidence for type 1 diabetes in most regions has been increasing by 2–5% and that type 1 diabetes prevalence in the U.S. is approximately 1 in 300 by the age of 18... The famous “hygiene hypothesis” has been frequently used to explain the rapid increase and discrepancy of type 1 diabetes incidence... It is believed that our increasingly hygienic environment, resulting from improvements in health care delivery and sanitation, has decreased the frequency of childhood infections, perhaps resulting in concomitant alterations in the gut microbiome, leading to a modulation of the developing immune system in genetically predisposed individuals and favoring the development of autoimmunity... Individuals that are homozygous for any nonfunctional FUT2 allele fail to present ABO antigens in secretions and on the intestinal mucosa (called nonsecretors or se individuals), while those subjects carrying at least one functional FUT2 allele can express ABO on secretions (called secretors or Se individuals)... It is noteworthy that the FUT2 nonsecretor phenotype has been noted to be associated with alterations in the gut microbiome, with recent studies demonstrating that it confers genetic susceptibility to Crohn’s disease... Keeping these facts in mind, Smyth et al. conducted a genetic study for the FUT2 nonsecretor allele in type 1 diabetes susceptibility using 8,344 type 1 diabetic case subjects, 10,008 control subjects, and 3,360 type 1 diabetic families... To determine whether rs601338 is the only causative variant within this chromosomal region, they combined the rs601338 genotype data with another dataset containing 116 single nucleotide polymorphisms flanking this region and originating from a genome-wide association study, followed by a stepwise regression analysis in 3,419 case and 3,524 control subjects—an analysis that failed to obtain convincing evidence supporting independent effects in Chr19q-13.33 region... Failure to secrete ABO blood group antigens on the intestinal mucosa has been noted to alter the gut microbiome associated with resistance to a variety of infectious diseases... The microbiome may also be modulated by dietary compounds and host (i.e., genetic) factors from the early days of life... In line with this notion, the FUT2 se allele was found to be selected under evolutionary pressure... This natural selection on the one hand is beneficial for humans against bacterial, fungi and viral infections, but on the other hand may affect gastric mucosa glycosylation, an essential process for the adherence of microorganisms to the mucosal epithelial cells and the mucus layer lining the gastric epithelium... As a consequence, it reshapes microbiome composition in the gut, potentially contributing to decreased antigenic stimulation in early life in the modern society, which would predispose those individuals with increased risk to the development of autoimmune responses against β-cell self-antigens (Fig. 1).

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A model for the potential implication of interactions between the FUT2 nonsecretor status and the gut microbiome in the pathogenesis of type 1 diabetes (T1D). The FUT2 nonsecretor (se) allele was naturally selected under evolutionary pressure to protect hosts against bacterial, fungi, and viral infections by altering the profile of mucosa glycosation, which then prevents the adherence of microorganisms to the mucosal epithelial cells and the mucus layer lining the gastric epithelium. While this protective effect is beneficial for host defense, it also imbalances the microbiome in the gut associated with decreased antigenic stimulation to the immune system in early life of subjects in the modern society, which would predispose those individuals homozygous for the nonsecretor allele with increased risk to the development of type 1 diabetes. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 1: A model for the potential implication of interactions between the FUT2 nonsecretor status and the gut microbiome in the pathogenesis of type 1 diabetes (T1D). The FUT2 nonsecretor (se) allele was naturally selected under evolutionary pressure to protect hosts against bacterial, fungi, and viral infections by altering the profile of mucosa glycosation, which then prevents the adherence of microorganisms to the mucosal epithelial cells and the mucus layer lining the gastric epithelium. While this protective effect is beneficial for host defense, it also imbalances the microbiome in the gut associated with decreased antigenic stimulation to the immune system in early life of subjects in the modern society, which would predispose those individuals homozygous for the nonsecretor allele with increased risk to the development of type 1 diabetes. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: This said, the FUT2 gene represents an ideal candidate that bridges genetic susceptibility and alterations in the gut microbiome to modulate the immune system in early life (Fig. 1). FUT2 is located on Chr19q-13.33 and encodes the α(1,2) fucosyltransferase responsible for the synthesis of H antigen, which is the precursor of the ABO histo-blood group antigens in body fluids and on the surface of the intestinal mucosa. Individuals that are homozygous for any nonfunctional FUT2 allele fail to present ABO antigens in secretions and on the intestinal mucosa (called nonsecretors or se individuals), while those subjects carrying at least one functional FUT2 allele can express ABO on secretions (called secretors or Se individuals) (9). It is noteworthy that the FUT2 nonsecretor phenotype has been noted to be associated with alterations in the gut microbiome (10), with recent studies demonstrating that it confers genetic susceptibility to Crohn’s disease (11,12). Keeping these facts in mind, Smyth et al. (13) conducted a genetic study for the FUT2 nonsecretor allele in type 1 diabetes susceptibility using 8,344 type 1 diabetic case subjects, 10,008 control subjects, and 3,360 type 1 diabetic families. They genotyped the nonfunctional allele se428 (single nucleotide polymorphism rs601338, A>G) that is unique to subjects of European origin, which encodes a stop codon at position 143 (X143 W). They demonstrated convincing evidence supporting a recessive association between type 1 diabetes and rs601338. Specifically, in the case/control dataset, the odds ratio for the homozygous nonfunctional allele A/A against A/G and G/G was 1.29 (95% CI 1.20–1.37; P = 7.3 × 10−14). Similarly, the familial dataset demonstrated a relative risk of 1.22 (95% CI 1.12–1.32; P = 6.8 × 10−6) for A/A against A/G and G/G. The evidence was further strengthened by combining the two datasets (P = 4.3 × 10−18). To determine whether rs601338 is the only causative variant within this chromosomal region, they combined the rs601338 genotype data with another dataset containing 116 single nucleotide polymorphisms flanking this region and originating from a genome-wide association study (14), followed by a stepwise regression analysis in 3,419 case and 3,524 control subjects—an analysis that failed to obtain convincing evidence supporting independent effects in Chr19q-13.33 region.


FUT2 nonfunctional variant: a "missing link" between genes and environment in type 1 diabetes?

Yang P, Li HL, Wang CY - Diabetes (2011)

A model for the potential implication of interactions between the FUT2 nonsecretor status and the gut microbiome in the pathogenesis of type 1 diabetes (T1D). The FUT2 nonsecretor (se) allele was naturally selected under evolutionary pressure to protect hosts against bacterial, fungi, and viral infections by altering the profile of mucosa glycosation, which then prevents the adherence of microorganisms to the mucosal epithelial cells and the mucus layer lining the gastric epithelium. While this protective effect is beneficial for host defense, it also imbalances the microbiome in the gut associated with decreased antigenic stimulation to the immune system in early life of subjects in the modern society, which would predispose those individuals homozygous for the nonsecretor allele with increased risk to the development of type 1 diabetes. (A high-quality digital representation of this figure is available in the online issue.)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198105&req=5

Figure 1: A model for the potential implication of interactions between the FUT2 nonsecretor status and the gut microbiome in the pathogenesis of type 1 diabetes (T1D). The FUT2 nonsecretor (se) allele was naturally selected under evolutionary pressure to protect hosts against bacterial, fungi, and viral infections by altering the profile of mucosa glycosation, which then prevents the adherence of microorganisms to the mucosal epithelial cells and the mucus layer lining the gastric epithelium. While this protective effect is beneficial for host defense, it also imbalances the microbiome in the gut associated with decreased antigenic stimulation to the immune system in early life of subjects in the modern society, which would predispose those individuals homozygous for the nonsecretor allele with increased risk to the development of type 1 diabetes. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: This said, the FUT2 gene represents an ideal candidate that bridges genetic susceptibility and alterations in the gut microbiome to modulate the immune system in early life (Fig. 1). FUT2 is located on Chr19q-13.33 and encodes the α(1,2) fucosyltransferase responsible for the synthesis of H antigen, which is the precursor of the ABO histo-blood group antigens in body fluids and on the surface of the intestinal mucosa. Individuals that are homozygous for any nonfunctional FUT2 allele fail to present ABO antigens in secretions and on the intestinal mucosa (called nonsecretors or se individuals), while those subjects carrying at least one functional FUT2 allele can express ABO on secretions (called secretors or Se individuals) (9). It is noteworthy that the FUT2 nonsecretor phenotype has been noted to be associated with alterations in the gut microbiome (10), with recent studies demonstrating that it confers genetic susceptibility to Crohn’s disease (11,12). Keeping these facts in mind, Smyth et al. (13) conducted a genetic study for the FUT2 nonsecretor allele in type 1 diabetes susceptibility using 8,344 type 1 diabetic case subjects, 10,008 control subjects, and 3,360 type 1 diabetic families. They genotyped the nonfunctional allele se428 (single nucleotide polymorphism rs601338, A>G) that is unique to subjects of European origin, which encodes a stop codon at position 143 (X143 W). They demonstrated convincing evidence supporting a recessive association between type 1 diabetes and rs601338. Specifically, in the case/control dataset, the odds ratio for the homozygous nonfunctional allele A/A against A/G and G/G was 1.29 (95% CI 1.20–1.37; P = 7.3 × 10−14). Similarly, the familial dataset demonstrated a relative risk of 1.22 (95% CI 1.12–1.32; P = 6.8 × 10−6) for A/A against A/G and G/G. The evidence was further strengthened by combining the two datasets (P = 4.3 × 10−18). To determine whether rs601338 is the only causative variant within this chromosomal region, they combined the rs601338 genotype data with another dataset containing 116 single nucleotide polymorphisms flanking this region and originating from a genome-wide association study (14), followed by a stepwise regression analysis in 3,419 case and 3,524 control subjects—an analysis that failed to obtain convincing evidence supporting independent effects in Chr19q-13.33 region.

View Article: PubMed Central - PubMed

Affiliation: Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Recent worldwide epidemiological studies demonstrate that the incidence for type 1 diabetes in most regions has been increasing by 2–5% and that type 1 diabetes prevalence in the U.S. is approximately 1 in 300 by the age of 18... The famous “hygiene hypothesis” has been frequently used to explain the rapid increase and discrepancy of type 1 diabetes incidence... It is believed that our increasingly hygienic environment, resulting from improvements in health care delivery and sanitation, has decreased the frequency of childhood infections, perhaps resulting in concomitant alterations in the gut microbiome, leading to a modulation of the developing immune system in genetically predisposed individuals and favoring the development of autoimmunity... Individuals that are homozygous for any nonfunctional FUT2 allele fail to present ABO antigens in secretions and on the intestinal mucosa (called nonsecretors or se individuals), while those subjects carrying at least one functional FUT2 allele can express ABO on secretions (called secretors or Se individuals)... It is noteworthy that the FUT2 nonsecretor phenotype has been noted to be associated with alterations in the gut microbiome, with recent studies demonstrating that it confers genetic susceptibility to Crohn’s disease... Keeping these facts in mind, Smyth et al. conducted a genetic study for the FUT2 nonsecretor allele in type 1 diabetes susceptibility using 8,344 type 1 diabetic case subjects, 10,008 control subjects, and 3,360 type 1 diabetic families... To determine whether rs601338 is the only causative variant within this chromosomal region, they combined the rs601338 genotype data with another dataset containing 116 single nucleotide polymorphisms flanking this region and originating from a genome-wide association study, followed by a stepwise regression analysis in 3,419 case and 3,524 control subjects—an analysis that failed to obtain convincing evidence supporting independent effects in Chr19q-13.33 region... Failure to secrete ABO blood group antigens on the intestinal mucosa has been noted to alter the gut microbiome associated with resistance to a variety of infectious diseases... The microbiome may also be modulated by dietary compounds and host (i.e., genetic) factors from the early days of life... In line with this notion, the FUT2 se allele was found to be selected under evolutionary pressure... This natural selection on the one hand is beneficial for humans against bacterial, fungi and viral infections, but on the other hand may affect gastric mucosa glycosylation, an essential process for the adherence of microorganisms to the mucosal epithelial cells and the mucus layer lining the gastric epithelium... As a consequence, it reshapes microbiome composition in the gut, potentially contributing to decreased antigenic stimulation in early life in the modern society, which would predispose those individuals with increased risk to the development of autoimmune responses against β-cell self-antigens (Fig. 1).

Show MeSH
Related in: MedlinePlus