Future Nutrigenetics: In Search of the Missing Genetic Variation

Mariman, E.C.M.

doi:10.1159/000297212

Cited by 3 publications

(4 citation statements)

References 93 publications

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“…However, so far, no research has been done in this direction. On the other hand, inter-individual differences in food intake are undoubtedly influenced by genetic variation as for instance by polymorphisms of taste receptor genes and mutations in genes regulating feelings of hunger and satiety (Grimm and Steinle 2011;Mariman 2009). The latter refers to homozygous or compound heterozygous cases of early onset obesity, but evidence is accumulating that heterozygous mutations in those genes can influence food intake as well.…”

Section: Discussionmentioning

confidence: 99%

“…This led scientists to speculate on the nature of the missing variation such as CNVs and epigenetic influences. Based on our previous research on neural tube defects, we, as others, proposed a contribution of relatively rare genetic variants with a moderate-to-high biological effect (Mariman 2009;Manolio et al 2009). The low population frequency and incomplete penetrance of these variants prevent their identification by association and linkage studies.…”

Section: Introductionmentioning

confidence: 99%

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High frequency of rare variants with a moderate-to-high predicted biological effect in protocadherin genes of extremely obese

et al. 2014

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Relatively rare variants with a moderate-to-high biological effect may contribute to the genetic predisposition of common disorders. To investigate this for obesity, we performed exome sequencing for 30 young (mean age: 29.7 years) extremely obese Caucasian subjects (mean body mass index: 51.1 kg/m(2); m/f = 11/29). Rare variants with a moderate-to-high predicted biological effect were assembled and subjected to functional clustering analysis. It showed that the 55 clustered protocadherin genes on chromosome 5q31 have a significantly (P = 0.002) higher frequency of rare variants than a set of 325 reference genes. Since the protocadherin genes are expressed in the hypothalamus, we tested another 167 genes related to the function of the hypothalamus, but in those genes, the frequency of rare variants was not different from that of the reference genes. To verify the relation of variation in the protocadherin genes with extreme obesity, we analyzed data from more than 4,000 European Americans present on the Exome Variant Server, representing a sample of the general population. The significant enrichment of rare variants in the protocadherin genes was only observed with the group of extremely obese individuals but not in the "general population", indicating an association between rare variants in the protocadherin cluster genes and extreme obesity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

High frequency of rare variants with a moderate-to-high predicted biological effect in protocadherin genes of extremely obese

et al. 2014

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“…Usually these variants have a low population frequency, have a high predicted or proven impact on protein function, and comply with a recessive mode of inheritance. Such variants have been found most frequently in the gene for MC4R, but also in other genes including the gene for the leptin receptor (LEPR) and single-minded family bHLH transcription factor 1 (SIM1) (22). Interestingly, it has been suggested that heterozygous variants with a predicted high impact on protein function may also confer risk for obesity.…”

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confidence: 99%

“…In addition to rare variants, common variants have been identified by genome-wide association studies (GWAS) to mark risk loci for body mass index (BMI) or BMI-related phenotypes. Much of the variation resides in genes that are functionally related to the hypothalamus (14,22).…”

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confidence: 99%

Extreme obesity is associated with variation in genes related to the circadian rhythm of food intake and hypothalamic signaling

Mariman

Bouwman

Aller

et al. 2015

Physiological Genomics

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The hypothalamus is important for regulation of energy intake. Mutations in genes involved in the function of the hypothalamus can lead to early-onset severe obesity. To look further into this, we have followed a strategy that allowed us to identify rare and common gene variants as candidates for the background of extreme obesity from a relatively small cohort. For that we focused on subjects with a well-selected phenotype and on a defined gene set and used a rich source of genetic data with stringent cut-off values. A list of 166 genes functionally related to the hypothalamus was generated. In those genes complete exome sequence data from 30 extreme obese subjects (60 genomes) were screened for novel rare indel, nonsense, and missense variants with a predicted negative impact on protein function. In addition, (moderately) common variants in those genes were analyzed for allelic association using the general population as reference (false discovery rate<0.05). Six novel rare deleterious missense variants were found in the genes for BAIAP3, NBEA, PRRC2A, RYR1, SIM1, and TRH, and a novel indel variant in LEPR. Common variants in the six genes for MBOAT4, NPC1, NPW, NUCB2, PER1, and PRRC2A showed significant allelic association with extreme obesity. Our findings underscore the complexity of the genetic background of extreme obesity involving rare and common variants of genes from defined metabolic and physiologic processes, in particular regulation of the circadian rhythm of food intake and hypothalamic signaling.

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Genetic Predictors of ≥5% Weight Loss by Multidisciplinary Advice to Severely Obese Subjects

Aller¹,

Mariman²,

Bouwman³

et al. 2017

Lifestyle Genomics

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Background:Weight loss success is determined by genetic factors, which may differ according to treatment strategy. Methods: From a multidisciplinary obesity treatment program involving dietary advice, psychological counseling, and increased physical activity, 587 subjects (68% female; 46.1 ± 12.4 years; BMI 39.9 ± 6.3) were recruited. At baseline, a blood sample was drawn for DNA isolation. Genotypes were determined for 30 polymorphisms in 25 candidate genes. The association between genotypes and weight loss was assessed after 3 months (short-term) and after 12 months of treatment (long-term). Weight loss was categorized as ≥ 5% or <5% of initial weight. Results: The G/G genotype of PLIN1 (rs2289487) and PLIN1 (rs2304795), the T/T genotype of PLIN1 (rs1052700), and the C/C genotype of MMP2 predicted ≥ 5% weight loss in the first 3 months. The C/G-G/G genotype of PPARγ (rs1801282) and the T/C genotype of TIMP4 (rs3755724) predicted ≥ 5% weight loss after 12 months. Subjects with the combination of PPARγ (rs1801282) C/G-G/G and TIMP4 (rs3755724) T/C lost even more weight. Conclusion: Polymorphisms in genes related to regulation of fat storage and structural adaptation of the adipocytes are predictors for weight loss success with different genes being relevant for short-term and long-term weight loss success.

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Future Nutrigenetics: In Search of the Missing Genetic Variation

Cited by 3 publications

References 93 publications

High frequency of rare variants with a moderate-to-high predicted biological effect in protocadherin genes of extremely obese

High frequency of rare variants with a moderate-to-high predicted biological effect in protocadherin genes of extremely obese

Extreme obesity is associated with variation in genes related to the circadian rhythm of food intake and hypothalamic signaling

Genetic Predictors of ≥5% Weight Loss by Multidisciplinary Advice to Severely Obese Subjects

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