How are HLA-DQ2 and fatigue related?

HLA-DQ2 is a major genetic risk factor for celiac disease, an autoimmune condition triggered by gluten. Fatigue is a well-documented symptom of celiac disease, even in the absence of classic gastrointestinal issues. The evidence linking celiac disease to fatigue is human-strong: numerous studies show that untreated celiac disease can cause chronic exhaustion due to malabsorption, systemic inflammation, and nutrient deficiencies (e.g., iron, vitamin B12, folate). However, carrying HLA-DQ2 alone does not mean you have or will develop celiac disease. Only about 30% of HLA-DQ2 carriers develop celiac disease, and fatigue has many other potential causes. There is no direct causal evidence that HLA-DQ2 itself causes fatigue without celiac disease. Caveat: A DNA test for HLA-DQ2 is not diagnostic for celiac disease; if you experience fatigue, consult a physician for proper evaluation including serology and possibly duodenal biopsy. The evidence for the SNP is mechanistic (HLA-DQ2 presents gluten peptides), but its clinical relevance for fatigue is only in the context of celiac disease.