Question
A 30-year-old man is being evaluated for a sleep disorder characterized by sudden irresistible sleep attacks during the day. Genetic testing reveals a strong association with a specific HLA subtype. Which of the following conditions is most closely linked with the HLA-DR2 antigen?
A. Ankylosing spondylitis
B. Rheumatoid arthritis
C. Gluten-sensitive enteropathy
D. Narcolepsy
E. Iron overload disorder
Answer
Narcolepsy
Detailed Explanation
HLA (Human Leukocyte Antigen) molecules are part of the immune system and are strongly associated with several autoimmune and neurological diseases.
- HLA-DR2 (Class II antigen) has a very strong association with narcolepsy, especially type 1 narcolepsy (with cataplexy).
- Up to ~98% of patients with narcolepsy carry HLA-DR2 (particularly DQB1*0602 allele).
- The condition is thought to involve autoimmune destruction of hypocretin (orexin)-producing neurons in the hypothalamus.
Now, why the other options are incorrect:
- Ankylosing spondylitis → strongly linked to HLA-B27
- Rheumatoid arthritis → associated with HLA-DR4
- Coeliac disease → associated with HLA-DQ2/DQ8
- Haemochromatosis → associated with HLA-A3 (and HFE gene mutations)
Cheat Sheet (High-Yield HLA Associations)
- HLA-B27 → Ankylosing spondylitis, reactive arthritis, uveitis
- HLA-DR2 → Narcolepsy, Goodpasture syndrome
- HLA-DR3 → SLE, Sjögren syndrome, PBC
- HLA-DR4 → Rheumatoid arthritis, Type 1 DM
- HLA-DQ2/DQ8 → Coeliac disease
- HLA-B51 → Behçet disease
- HLA-A3 → Haemochromatosis
Flashcards
Q1: Which HLA subtype is most strongly associated with narcolepsy?
A: HLA-DR2 (DQB1*0602)
Explanation: Seen in majority of narcolepsy patients; linked to autoimmune hypocretin neuron loss.
Q2: Which HLA is linked to ankylosing spondylitis?
A: HLA-B27
Explanation: Strongest genetic association among all HLA diseases.
Q3: Which HLA is associated with coeliac disease?
A: HLA-DQ2 and DQ8
Explanation: Required for disease development.
Q4: Which HLA is most associated with rheumatoid arthritis?
A: HLA-DR4
Explanation: Especially DRB1 gene variants.
Q5: Which HLA is linked to haemochromatosis?
A: HLA-A3
Explanation: Also associated with HFE gene mutation.
MCQs (Challenging)
MCQ 1
A patient with excessive daytime sleepiness and cataplexy is found to have a specific HLA association. Which is the most likely HLA subtype?
A. HLA-B27
B. HLA-DR2
C. HLA-DQ8
D. HLA-A3
Answer: B
Explanation: Narcolepsy is strongly associated with HLA-DR2.
MCQ 2
Which of the following disease–HLA associations is incorrect?
A. Ankylosing spondylitis – HLA-B27
B. Rheumatoid arthritis – HLA-DR4
C. Coeliac disease – HLA-DR2
D. Behçet disease – HLA-B51
Answer: C
Explanation: Coeliac disease is associated with HLA-DQ2/DQ8, not DR2.
MCQ 3
A patient develops pulmonary haemorrhage and rapidly progressive glomerulonephritis. Which HLA subtype is associated with this condition?
A. HLA-DR2
B. HLA-B27
C. HLA-DR4
D. HLA-DQ2
Answer: A
Explanation: Goodpasture syndrome is associated with HLA-DR2.
MCQ 4
Which HLA antigen is most strongly linked to Type 1 diabetes mellitus?
A. HLA-DR2
B. HLA-DR3
C. HLA-DR4
D. HLA-B51
Answer: C
Explanation: Type 1 DM is most strongly associated with DR4 (also DR3).
MCQ 5
Which of the following is FALSE regarding HLA associations?
A. HLA-B27 is linked to reactive arthritis
B. HLA-DR2 is linked to narcolepsy
C. HLA-A3 is linked to haemochromatosis
D. HLA-DQ8 is linked to rheumatoid arthritis
Answer: D
Explanation: Rheumatoid arthritis is associated with HLA-DR4, not DQ8.
MCQ 6
A genetically predisposed individual develops villous atrophy after gluten ingestion. Which HLA subtype is essential for this condition?
A. HLA-DR4
B. HLA-DQ2
C. HLA-B27
D. HLA-A3
Answer: B
Explanation: Coeliac disease requires HLA-DQ2 or DQ8.
Summary for Quick Exam Revision
HLA antigens are critical genetic markers linked to multiple autoimmune and systemic diseases, and remembering these associations is highly exam-relevant. HLA-DR2 is classically associated with narcolepsy and Goodpasture syndrome, with narcolepsy showing one of the strongest known HLA correlations due to autoimmune destruction of hypocretin neurons. HLA-B27 is the hallmark of seronegative spondyloarthropathies including ankylosing spondylitis and reactive arthritis. HLA-DR4 is strongly linked to rheumatoid arthritis and is also more strongly associated than DR3 in type 1 diabetes mellitus. Coeliac disease requires HLA-DQ2 or DQ8 for its pathogenesis. Behçet disease is associated with HLA-B51, while haemochromatosis is linked to HLA-A3 along with HFE gene mutations. A systematic approach to memorizing HLA associations—grouping by class I (A, B, C) and class II (DP, DQ, DR)—helps in rapid recall during exams. Among all, HLA-B27 and HLA-DR2 are particularly high-yield due to their strong disease correlations.