Research Article: Independent associations of TOMM40 and APOE variants with body mass index

Date Published: November 21, 2018

Publisher: John Wiley and Sons Inc.

Author(s): Alexander M. Kulminski, Yury Loika, Irina Culminskaya, Jian Huang, Konstantin G. Arbeev, Olivia Bagley, Mary F. Feitosa, Joseph M. Zmuda, Kaare Christensen, Anatoliy I. Yashin.


The TOMM40‐APOE variants are known for their strong, antagonistic associations with Alzheimer’s disease and body weight. While a stronger role of the APOE than TOMM40 variants in Alzheimer’s disease was suggested, comparative contribution of the TOMM40‐APOE variants in the regulation of body weight remains elusive. We examined additive effects of rs2075650 and rs157580 TOMM40 variants and rs429358 and rs7412 APOE variants coding the ε2/ε3/ε4 polymorphism on body mass index (BMI) in age‐aggregated and age‐stratified cohort‐specific and cohort‐pooled analysis of 27,863 Caucasians aged 20–100 years from seven longitudinal studies. Minor alleles of rs2075650, rs429358, and rs7412 were individually associated with BMI (β = −1.29, p = 3.97 × 10−9; β = −1.38, p = 2.78 × 10−10; and β = 0.58, p = 3.04 × 10−2, respectively). Conditional analysis with rs2075650 and rs429358 identified independent BMI‐lowering associations for minor alleles (β = −0.63, p = 3.99 × 10−2 and β = −0.94, p = 2.17 × 10−3, respectively). Polygenic mega‐analysis identified additive effects of the rs2075650 and rs429358 heterozygotes (β = −1.68, p = 3.00 × 10−9), and the strongest BMI‐lowering association for the rs2075650 heterozygous and rs429358 minor allele homozygous carriers (β = −4.11, p = 2.78 × 10−3). Conditional analysis with four polymorphisms identified independent BMI‐lowering (rs2075650, rs157580, and rs429358) and BMI‐increasing (rs7412) associations of heterozygous genotypes with BMI. Age‐stratified conditional analysis revealed well‐powered support for a differential and independent association of the rs429358 heterozygote with BMI in younger and older individuals, β = 0.58, 95% confidence interval (CI) = −1.18, 2.35, p = 5.18 × 10−1 for 3,068 individuals aged ≤30 years and β = −4.28, CI = −5.65, −2.92, p = 7.71 × 10−10 for 6,052 individuals aged >80 years. TOMM40 and APOE variants are independently and additively associated with BMI. The APOE ε4‐coding rs429358 polymorphism is associated with BMI in older individuals but not in younger individuals.

Partial Text

Studies report that deviation from the normal body weight is associated with cognitive decline and development of dementia and Alzheimer’s disease (AD) (Emmerzaal, Kiliaan, & Gustafson, 2015). Despite these results are challenged in Fitzpatrick et al. (2009), they suggest that there might be common underlying biological mechanisms involved in regulation of body weight and cognitive function and/or AD pathology (Hinney et al., 2014). The relationship between body weight and cognitive function is complex as it may vary with age from a positive relationship between mid‐life obesity and AD to a negative relationship in late life (Emmerzaal et al., 2015).

Data on 27,863 participants were obtained from seven longitudinal cohort studies (ARIC, CHS, CARDIA, MESA, HRS, LLFS, and FHS) (see Section 4). Baseline measurements of BMI, the number of longitudinal measurements of BMI used in the analysis, and basic demographic information for the genotyped participants in each cohort and the pooled sample are presented in Supporting Information Table S1). Frequency distributions of genotypes for rs2075650, rs157580, rs429358, rs7412, and APOE ε2/ε3/ε4 (coded by rs429358 and rs7412, Supporting Information Table S2) polymorphisms are presented in Supporting Information Table S3. All polymorphisms were in Hardy–Weinberg equilibrium.

This study presents the results of the largest analysis so far of the associations of TOMM40 (rs2075650 and rs157580) and APOE (rs429358 and rs7412 coding the ε2/ε3/ε4 polymorphism) variants with BMI in seven cohorts of participants ranging in age from early reproductive age (about 20 years) to centenarians. These analyses leveraged longitudinal information on BMI assessed at different ages and addressed the impact of TOMM40 and APOE variants in the age‐aggregated and age‐stratified samples of older and younger individuals defined using varying cutoffs ranging from 30 years (i.e., people who were younger and older than 30 years at BMI assessment) to 90 years.

The authors declare that they have no conflict of interest.

A.M.K. conceived and designed the experiment and wrote the paper; Y.L. performed statistical analyses and contributed to drafting of the paper; I.C. prepared data and performed bioinformatics analysis; J.H., K.G.A., and O.B. prepared data; M.F.F. J.M.Z., K.C., and A.I.Y. contributed to discussion of the intermediate and final results and drafting the manuscript.




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