Genetic Proxies for Helicobacter pylori Serology Are Dominated by HLA Class II Haplotype Structure: Implications for Reported Associations with Neurodegenerative Disease

Genetic variants that predict anti-Helicobacter pylori immunoglobulin G (IgG) seropositivity lie almost entirely within the major histocompatibility complex (MHC), which also carries established risk loci for several diseases. Mendelian randomisation studies using such variants have reported causal effects of H. pylori infection on neurodegenerative disease, although the phenotype indexed is anti-H. pylori IgG seropositivity, not infection itself. We evaluated 22 candidate variants from a Japanese genome-wide study of anti-H. pylori IgG antibody titre in two-sample Mendelian randomisation analyses across five prespecified genomic proxy sets; the number retained varied by outcome. Higher genetically predicted anti-H. pylori IgG seropositivity was associated with lower Alzheimer’s disease risk (odds ratio 0.83, 95% confidence interval 0.73 to 0.95). The association was absent once MHC variants were removed (0.94, 0.78 to 1.12), was strongest using HLA class II variants alone (0.73, 0.59 to 0.91), and traced to two variants near HLA-DRB1 and HLA-DQA1. Those proxies did not predict peptic ulcer disease in an ancestry-matched Japanese study (1.02, 0.92 to 1.13), differing from Parkinson’s disease (0.73, 0.55 to 0.97; difference p = 0.029). Colocalisation did not support a shared causal variant for the serological and disease signals, selected proxy associations were attenuated after conditioning on leading class II variants, and the haplotypes tagged by the proxies differed between European and East Asian reference panels, indicating limited cross-ancestry transferability. The behaviour of these proxies is dominated by HLA class II haplotype structure, and they are therefore unsuitable for inferring a protective effect of H. pylori infection on neurodegenerative disease from IgG seropositivity.