A GWAS on Helicobacter pylori strains points to genetic variants associated with gastric cancer risk

Elvire Berthenet, Koji Yahara, Kaisa Thorell, Ben Pascoe, Guillaume Meric, Jane M Mikhail, Lars Engstrand, Helena Enroth, Alain Burette, Francis Megraud, Christine Varon, John C Atherton, Sinead Smith, Thomas S Wilkinson, Matthew D Hitchings, Daniel Falush, Samuel K Sheppard

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

BACKGROUND: Helicobacter pylori are stomach-dwelling bacteria that are present in about 50% of the global population. Infection is asymptomatic in most cases, but it has been associated with gastritis, gastric ulcers and gastric cancer. Epidemiological evidence shows that progression to cancer depends upon the host and pathogen factors, but questions remain about why cancer phenotypes develop in a minority of infected people. Here, we use comparative genomics approaches to understand how genetic variation amongst bacterial strains influences disease progression.

RESULTS: We performed a genome-wide association study (GWAS) on 173 H. pylori isolates from the European population (hpEurope) with known disease aetiology, including 49 from individuals with gastric cancer. We identified SNPs and genes that differed in frequency between isolates from patients with gastric cancer and those with gastritis. The gastric cancer phenotype was associated with the presence of babA and genes in the cag pathogenicity island, one of the major virulence determinants of H. pylori, as well as non-synonymous variations in several less well-studied genes. We devised a simple risk score based on the risk level of associated elements present, which has the potential to identify strains that are likely to cause cancer but will require refinement and validation.

CONCLUSION: There are a number of challenges to applying GWAS to bacterial infections, including the difficulty of obtaining matched controls, multiple strain colonization and the possibility that causative strains may not be present when disease is detected. Our results demonstrate that bacterial factors have a sufficiently strong influence on disease progression that even a small-scale GWAS can identify them. Therefore, H. pylori GWAS can elucidate mechanistic pathways to disease and guide clinical treatment options, including for asymptomatic carriers.

Original languageEnglish
Article number84
Number of pages11
JournalBMC Biology
Volume16
Early online date2 Aug 2018
DOIs
Publication statusE-pub ahead of print - 2 Aug 2018

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stomach neoplasms
Helicobacter pylori
Genome-Wide Association Study
Stomach Neoplasms
cancer
genome
Genes
gastritis
Gastritis
disease course
neoplasms
minorities (people)
Disease Progression
pathogenicity islands
Phenotype
Genomic Islands
phenotype
Neoplasms
stomach ulcers
Asymptomatic Infections

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A GWAS on Helicobacter pylori strains points to genetic variants associated with gastric cancer risk. / Berthenet, Elvire; Yahara, Koji; Thorell, Kaisa; Pascoe, Ben; Meric, Guillaume; Mikhail, Jane M; Engstrand, Lars; Enroth, Helena; Burette, Alain; Megraud, Francis; Varon, Christine; Atherton, John C; Smith, Sinead; Wilkinson, Thomas S; Hitchings, Matthew D; Falush, Daniel; Sheppard, Samuel K.

In: BMC Biology, Vol. 16, 84, 02.08.2018.

Research output: Contribution to journalArticle

Berthenet, E, Yahara, K, Thorell, K, Pascoe, B, Meric, G, Mikhail, JM, Engstrand, L, Enroth, H, Burette, A, Megraud, F, Varon, C, Atherton, JC, Smith, S, Wilkinson, TS, Hitchings, MD, Falush, D & Sheppard, SK 2018, 'A GWAS on Helicobacter pylori strains points to genetic variants associated with gastric cancer risk', BMC Biology, vol. 16, 84. https://doi.org/10.1186/s12915-018-0550-3
Berthenet, Elvire ; Yahara, Koji ; Thorell, Kaisa ; Pascoe, Ben ; Meric, Guillaume ; Mikhail, Jane M ; Engstrand, Lars ; Enroth, Helena ; Burette, Alain ; Megraud, Francis ; Varon, Christine ; Atherton, John C ; Smith, Sinead ; Wilkinson, Thomas S ; Hitchings, Matthew D ; Falush, Daniel ; Sheppard, Samuel K. / A GWAS on Helicobacter pylori strains points to genetic variants associated with gastric cancer risk. In: BMC Biology. 2018 ; Vol. 16.
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abstract = "BACKGROUND: Helicobacter pylori are stomach-dwelling bacteria that are present in about 50{\%} of the global population. Infection is asymptomatic in most cases, but it has been associated with gastritis, gastric ulcers and gastric cancer. Epidemiological evidence shows that progression to cancer depends upon the host and pathogen factors, but questions remain about why cancer phenotypes develop in a minority of infected people. Here, we use comparative genomics approaches to understand how genetic variation amongst bacterial strains influences disease progression.RESULTS: We performed a genome-wide association study (GWAS) on 173 H. pylori isolates from the European population (hpEurope) with known disease aetiology, including 49 from individuals with gastric cancer. We identified SNPs and genes that differed in frequency between isolates from patients with gastric cancer and those with gastritis. The gastric cancer phenotype was associated with the presence of babA and genes in the cag pathogenicity island, one of the major virulence determinants of H. pylori, as well as non-synonymous variations in several less well-studied genes. We devised a simple risk score based on the risk level of associated elements present, which has the potential to identify strains that are likely to cause cancer but will require refinement and validation.CONCLUSION: There are a number of challenges to applying GWAS to bacterial infections, including the difficulty of obtaining matched controls, multiple strain colonization and the possibility that causative strains may not be present when disease is detected. Our results demonstrate that bacterial factors have a sufficiently strong influence on disease progression that even a small-scale GWAS can identify them. Therefore, H. pylori GWAS can elucidate mechanistic pathways to disease and guide clinical treatment options, including for asymptomatic carriers.",
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T1 - A GWAS on Helicobacter pylori strains points to genetic variants associated with gastric cancer risk

AU - Berthenet, Elvire

AU - Yahara, Koji

AU - Thorell, Kaisa

AU - Pascoe, Ben

AU - Meric, Guillaume

AU - Mikhail, Jane M

AU - Engstrand, Lars

AU - Enroth, Helena

AU - Burette, Alain

AU - Megraud, Francis

AU - Varon, Christine

AU - Atherton, John C

AU - Smith, Sinead

AU - Wilkinson, Thomas S

AU - Hitchings, Matthew D

AU - Falush, Daniel

AU - Sheppard, Samuel K

PY - 2018/8/2

Y1 - 2018/8/2

N2 - BACKGROUND: Helicobacter pylori are stomach-dwelling bacteria that are present in about 50% of the global population. Infection is asymptomatic in most cases, but it has been associated with gastritis, gastric ulcers and gastric cancer. Epidemiological evidence shows that progression to cancer depends upon the host and pathogen factors, but questions remain about why cancer phenotypes develop in a minority of infected people. Here, we use comparative genomics approaches to understand how genetic variation amongst bacterial strains influences disease progression.RESULTS: We performed a genome-wide association study (GWAS) on 173 H. pylori isolates from the European population (hpEurope) with known disease aetiology, including 49 from individuals with gastric cancer. We identified SNPs and genes that differed in frequency between isolates from patients with gastric cancer and those with gastritis. The gastric cancer phenotype was associated with the presence of babA and genes in the cag pathogenicity island, one of the major virulence determinants of H. pylori, as well as non-synonymous variations in several less well-studied genes. We devised a simple risk score based on the risk level of associated elements present, which has the potential to identify strains that are likely to cause cancer but will require refinement and validation.CONCLUSION: There are a number of challenges to applying GWAS to bacterial infections, including the difficulty of obtaining matched controls, multiple strain colonization and the possibility that causative strains may not be present when disease is detected. Our results demonstrate that bacterial factors have a sufficiently strong influence on disease progression that even a small-scale GWAS can identify them. Therefore, H. pylori GWAS can elucidate mechanistic pathways to disease and guide clinical treatment options, including for asymptomatic carriers.

AB - BACKGROUND: Helicobacter pylori are stomach-dwelling bacteria that are present in about 50% of the global population. Infection is asymptomatic in most cases, but it has been associated with gastritis, gastric ulcers and gastric cancer. Epidemiological evidence shows that progression to cancer depends upon the host and pathogen factors, but questions remain about why cancer phenotypes develop in a minority of infected people. Here, we use comparative genomics approaches to understand how genetic variation amongst bacterial strains influences disease progression.RESULTS: We performed a genome-wide association study (GWAS) on 173 H. pylori isolates from the European population (hpEurope) with known disease aetiology, including 49 from individuals with gastric cancer. We identified SNPs and genes that differed in frequency between isolates from patients with gastric cancer and those with gastritis. The gastric cancer phenotype was associated with the presence of babA and genes in the cag pathogenicity island, one of the major virulence determinants of H. pylori, as well as non-synonymous variations in several less well-studied genes. We devised a simple risk score based on the risk level of associated elements present, which has the potential to identify strains that are likely to cause cancer but will require refinement and validation.CONCLUSION: There are a number of challenges to applying GWAS to bacterial infections, including the difficulty of obtaining matched controls, multiple strain colonization and the possibility that causative strains may not be present when disease is detected. Our results demonstrate that bacterial factors have a sufficiently strong influence on disease progression that even a small-scale GWAS can identify them. Therefore, H. pylori GWAS can elucidate mechanistic pathways to disease and guide clinical treatment options, including for asymptomatic carriers.

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DO - 10.1186/s12915-018-0550-3

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VL - 16

JO - BMC Biology

JF - BMC Biology

SN - 1741-7007

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ER -