medwireNews: Ancestral differences in the impact genetic variants have on glycated hemoglobin (HbA1c) can substantially affect the performance of HbA1c as a diagnostic test for type 2 diabetes, results of a large trans-ethnic genome-wide meta-analysis show.
Specifically, the newly identified G202A variant in the glucose-6-phosphate dehydrogenase gene (G6PD), which can shorten red blood cell lifespan, and thus lower HbA1c levels regardless of blood glucose level, is associated with substantial reductions in HbA1c in African Americans.
James Meigs (Harvard Medical School, Boston, Massachusetts, USA) and colleagues estimated that these reductions could lead to approximately 2% of African–American adults with type 2 diabetes remaining undiagnosed when screened with HbA1c.
Meigs and team performed genome-wide association meta-analyses in up to 159,940 individuals without diabetes from 82 cohorts of European, African, East Asian, and South Asian ancestry.
They identified 60 common genetic variants – including 42 that were novel – associated with HbA1c. Of these, 19 were glycemic variants, implicated in glycemic control, and 22 were erythrocytic variants, involved in erythrocytic biology, and the remainder were of unclassified biology.
When the researchers combined groups of these variants to investigate whether they could predict diabetes incidence in 33,241 individuals from five longitudinal cohorts, they found that each additional HbA1c-raising allele implicated in glycemic control increased the risk for type 2 diabetes by a significant 5% during a 10-year follow-up period.
By contrast, the erythrocytic variants were not associated with increased risk for type 2 diabetes overall, and were associated with a reduced risk in Europeans and African Americans after adjusting for HbA1c (5% reduction per allele).
“Thus, the influence of erythrocytic HbA1c variants may partly explain why some individuals with the same HbA1c may have different risks of future [type 2 diabetes],” Meigs and co-authors remark.
Next, the team showed that erythrocytic variants in aggregate had only minor effects on the diagnostic accuracy of HbA1c in Europeans and Asians.
Whereas, in African Americans, the X-linked G6PD G202A erythrocytic variant was associated with an absolute decrease in HbA1c of 0.81% in men with the T versus C allele, and an absolute decrease of 0.68% in women homozygous for the TT versus CC allele.
The researchers calculated that, at the observed allele frequency of 11.0%, an additional 2.2% of African Americans with HbA1c below 6.5% could be diagnosed with type 2 diabetes if genotype-specific HbA1c thresholds of 5.7% for T in men, and 5.8% for TT and 6.2% for TC in women, were used.
This suggests that “0.65 million adults with [type 2 diabetes] would remain undiagnosed when screened by a single HbA1c measurement if this genetic information were not taken into account,” Meigs et al write in PLOS Medicine.
They add: “We therefore recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose [type 2 diabetes] in populations of African ancestry or groups where G6PD deficiency is common, and screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency.”
By Laura Cowen
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