The Māori and Pacific specific CREBRF variant and adult height

Background: The CREBRF missense variant (p.Arg457Gln) is paradoxically associated with lower risk of type 2 diabetes, yet higher body mass index (BMI). Here we sought to determine whether this CREBRF variant might be associated with adult height. Methods: Linear regression was used to analyse the association of the CREBRF minor (A) allele with height in 2286 Māori and Pacific adults living in Aotearoa/New Zealand. A potential type 2 diabetes index event was corrected to account for a bias that may be the cause of paradoxical association between the CREBRF diabetes-protective allele and higher BMI and height. Results: The CREBRF protective allele was associated with increased adult height (ß = 1.25 cm, P = 3.9 × 10⁻⁶), with the effect being more pronounced in males. The lower odds of diabetes remained similar when analyses were adjusted for height (OR = 0.67–0.65). We found no evidence of a diabetes index event bias to explain the paradoxical effect of CREBRF with either BMI or height and diabetes. The orthologous CREBRF p.Arg457Gln variant was created in knock-in mice to independently assess the effect of the variant, and length was found to be greater in male mice at 8 weeks of age. Conclusion: These data taken together indicate that CREBRF p.Arg457Gln is associated with taller stature in Māori and Pacific adults.