A survey of plasma proteins in approximately 1300 individuals by MALDI‐TOF MS resulted in identification of a structural polymorphism of apolipoprotein C1 (ApoC1) that was found only in persons of American Indian or Mexican ancestry. MS/MS analysis revealed that the alteration consisted of a T45S variation. The methyl group of T45 forms part of the lipid‐interacting surface of ApoC1. In agreement with an impact on lipid contact, the S45 variant was more susceptible to N‐terminal truncation by dipeptidylpeptidase IV in vitro than was the T45 variant. The S45 protein also displayed greater N‐terminal truncation (loss of Thr‐Pro) in vivo than the T45 variant. The S45 variant also showed preferential distribution to the very‐low‐density lipoprotein fraction than the T45 protein. These properties indicate a functional effect of the S45 variant and support a role for residue 45 in lipid contact and lipid specificity. Further studies are needed to determine the effects of the variant and its altered N‐terminal truncation on the metabolic functions of ApoC1.

Obesity and diabetes are serious health problems for Americans and especially for those with American Indian or Mexican ancestry. A preliminary survey by protein analysis rather than classical nucleic acid sequencing methods has suggested a correlation between a newly discovered T45S variant of apolipoprotein C1 (ApoC1), found only in persons with American Indian or Mexican ancestry, and elevated body mass index (BMI). American Indians with the S45 ApoC1 variant (n ¼ 36) had an average of 9% higher BMI than those who had only T45 ApoC1 (n ¼ 192, P ¼ 0.029). Elevated rates of diabetes were reported for parents of subjects with the S45 protein (P ¼ 0.006). In five gender-matched sibling pairs, persons with Mexican ancestry showed a 1.34-fold higher BMI for those with S45 ApoC1 (P ¼ 0.022). This protein may contribute to the elevated rates of diabetes in relevant ethnic groups and might be more common in isolated populations.