Independent associations of TOMM40 and APOE variants with body mass index

Abstract

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.

APOE Alleles and Diet in Brain Aging and Alzheimer’s Disease

“…This association is consistent with increased risk of AD with age in the general population and higher risk or underweight subjects to develop AD in old age (Joo et al, 2018). There are additive effects of rs2075650 and rs157580 TOMM40 variants and rs429358 and rs7412 APOE variants coding the ε2/ε3/ε4 polymorphism on BMI in age-aggregated and age-stratified cohortspecific and cohort pooled analysis of 27,863 Caucasians aged 20-100 years from seven longitudinal studies (Kulminski et al, 2019).…”

“…Recently, Kulminski et al (2019Kulminski et al ( , 2020 and Wolters et al (2019) documented new AD risk variants in 11 more genes in 19q13.3 (Table 3) Together with its AD-associated genes, the 19q13.3 locus includes more than 50 other genes with diverse functions (Table 3), including lipid metabolism and transport (ApoC1), inflammatory mediators (NFkB, PVRL2), reproductive hormones (luteinizing hormone), and transcription factors (NFkB, zinc finger). While many of these genes do not have reported AD associations, we include them because of the possibilities of co-regulation.…”

APOE – a genetic marker of comorbidity in subjects with morbid obesity

“…In a case-control study with 198 obese and normal-weight subjects, the prevalence of E4 was high in subjects with obesity [3]. In a review of pooled data from seven studies with 27,863 Caucasians, E4 was associated with reduced BMI in individuals above 60 years of age but not in younger [2]. This study gives no support for an abnormal distribution of the E alleles in subjects with morbid obesity but is too small for a valid conclusion.…”

“…The human APOE gene has three common allelic variants E2, E3, and E4 encoded on chromosome 19. Depending on the genetic variability, the gene has been ascribed significant positive and negative health effects such as longevity and shortened lifespan, neurological and psychosomatic disorders, cognitive decline and Alzheimer disease, altered lipoprotein profile, atherosclerosis and cardiovascular disease, type II diabetes, changes in the immune response, oxidative stress, quality of life, physical activity, and obesity [1][2][3][4]. At large, E4 has been ascribed unfavourable health outcomes and E2 healthpromoting effects [1,[5][6][7][8][9][10][11].…”

“…The associations between biomarkers and disease in subjects with obesity are, however, not always as expected, as exemplified by the protective effect of obesity on the outcome of cardiovascular disease (the obesity paradox) [15]. Except for a possible association between E4 and obesity, little is known about associations between APOE variability and morbidity in subjects with obesity [2,3].…”