Choline metabolites: gene by diet interactions

This review highlights recent advances in our understanding of the interactions between genetic polymorphisms in genes that metabolize choline and the dietary requirements of choline and how these interactions relate to human health and disease

Expanding role of gut microbiota in lipid metabolism

This review highlights recent advances in the emerging role that gut microbiota play in modulating metabolic phenotypes, with a particular focus on lipid metabolism

Genetic-related and carbohydrate-related factors affecting liver fat accumulation

Purpose of review To summarize recent findings that have examined dietary, genetic and gene-diet interactions that contribute to fat accumulation in the liver during growth and development, with particular focus on contributions relating to dietary carbohydrate and sugar consumption. In addition, this review highlights how some of these contributions to liver fat vary across the population in terms of ethnic-specific effects. Recent findings Dietary carbohydrate, and especially sugars contribute to increased liver fat accumulation due to the lipogenic potential of fructose during liver metabolism. In addition, recent genome-wide studies have identified several polymorphisms that contribute to increased liver fat accumulation, with some of these genes relating to dietary carbohydrate and sugar consumption. In particular, the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene, which is highly prevalent in Hispanics, contributes to excessive liver fat beginning at a young age, especially in the context of high sugar consumption. Summary Dietary sugar contributes to liver fat accumulation, with this being explained by de-novo lipogenesis from fructose in the liver. Certain genetic factors, including PNPLA3, glucokinase regulatory protein and APOC3 contribute to increased liver fat accumulation, with these effects being manifested at an early age. Hispanics in particular are at elevated risk for liver fat accumulation because of the higher frequency of genetic variants such as PNPLA3 and glucokinase regulatory protein as well as an interaction between the PNPLA3 and dietary sugar

The Genetic Architecture of Noise-Induced Hearing Loss: Evidence for a Gene-by-Environment Interaction.

The discovery of environmentally specific genetic effects is crucial to the understanding of complex traits, such as susceptibility to noise-induced hearing loss (NIHL). We describe the first genome-wide association study (GWAS) for NIHL in a large and well-characterized population of inbred mouse strains, known as the Hybrid Mouse Diversity Panel (HMDP). We recorded auditory brainstem response (ABR) thresholds both pre and post 2-hr exposure to 10-kHz octave band noise at 108 dB sound pressure level in 5-6-wk-old female mice from the HMDP (4-5 mice/strain). From the observation that NIHL susceptibility varied among the strains, we performed a GWAS with correction for population structure and mapped a locus on chromosome 6 that was statistically significantly associated with two adjacent frequencies. We then used a "genetical genomics" approach that included the analysis of cochlear eQTLs to identify candidate genes within the GWAS QTL. In order to validate the gene-by-environment interaction, we compared the effects of the postnoise exposure locus with that from the same unexposed strains. The most significant SNP at chromosome 6 (rs37517079) was associated with noise susceptibility, but was not significant at the same frequencies in our unexposed study. These findings demonstrate that the genetic architecture of NIHL is distinct from that of unexposed hearing levels and provide strong evidence for gene-by-environment interactions in NIHL

Salsalate treatment improves glycemia without altering adipose tissue in nondiabetic obese hispanics.

ObjectiveSalsalate treatment has well-known effects on improving glycemia, and the objective of this study was to examine whether the mechanism of this effect was related to changes in adipose tissue.MethodsA randomized double-blind and placebo-controlled trial in obese Hispanics (18-35 years) was conducted. The intervention consisted of 4 g day(-1) of salsalate (n = 11) versus placebo (n = 13) for 4 weeks. Outcome measures included glycemia, adiposity, ectopic fat, and adipose tissue gene expression and inflammation.ResultsIn those receiving salsalate, plasma fasting glucose decreased by 3.4% (P < 0.01), free fatty acids decreased by 42.5% (P = 0.06), and adiponectin increased by 27.7% (P < 0.01). Salsalate increased insulin AUC by 38% (P = 0.01) and HOMA-B by 47.2% (P < 0.01) while estimates of insulin sensitivity/resistance were unaffected. These metabolic improvements occurred without changes in total, abdominal, visceral, or liver fat. Plasma markers of inflammation/immune activation were unchanged following salsalate. Salsalate had no effects on adipose tissue including adipocyte size, presence of crown-like structures, or gene expression of adipokines, immune cell markers, or cytokines downstream of NF-κB with the exception of downregulation of IL-1β (P < 0.01).ConclusionsFindings suggest that metabolic improvements in response to salsalate occurred without alterations in adiposity, ectopic fat, or adipose tissue gene expression and inflammation

Inflammatory Gene Variants in the Tsimane, An Indigenous Bolivian Population With a High Infectious Load

The Tsimane of lowland Bolivia are an indigenous forager-farmer population living under conditions resembling pre-industrial European populations, with high infectious morbidity, high infection and inflammation, and shortened life expectancy. Analysis of 917 persons ages 5 to 60+ showed that allele frequencies of 9 SNPs examined in the apolipoprotein E (apoE), C-reactive protein (CRP), and interleukin-6 (IL-6) genes differed from some European, African, and north Asian-derived populations. The apoE2 allele was absent, whereas four SNPs related to CRP and IL-6 were monomorphic: CRP (rs1800947, rs3093061, and rs3093062) and IL-6 (rs1800795). No significant differences in apoE, CRP, and IL-6 variants across age were found CRP levels were higher in carriers of two CRP proinflammatory SNPs, whereas they were lower in carriers of apoE4. Taken together, the evidence for (1) different allele frequencies between the Tsimane and other populations and (2) the correlations of CRP and apoE alleles with blood CRP may suggest that these variants are under selection in response to a high infection environment

Prevalence of common disease-associated variants in Asian Indians

<p>Abstract</p> <p>Background</p> <p>Asian Indians display a high prevalence of diseases linked to changes in diet and environment that have arisen as their lifestyle has become more westernized. Using 1200 genome-wide polymorphisms in 432 individuals from 15 Indian language groups, we have recently shown that: (i) Indians constitute a distinct population-genetic cluster, and (ii) despite the geographic and linguistic diversity of the groups they exhibit a relatively low level of genetic heterogeneity.</p> <p>Results</p> <p>We investigated the prevalence of common polymorphisms that have been associated with diseases, such as atherosclerosis (<it>ALOX5</it>), hypertension (<it>CYP3A5</it>, <it>AGT</it>, <it>GNB3</it>), diabetes (<it>CAPN10</it>, <it>TCF7L2</it>, <it>PTPN22</it>), prostate cancer (DG8S737, rs1447295), Hirschsprung disease (<it>RET</it>), and age-related macular degeneration (<it>CFH</it>, <it>LOC387715</it>). In addition, we examined polymorphisms associated with skin pigmentation (<it>SLC24A5</it>) and with the ability to taste phenylthiocarbamide (<it>TAS2R38</it>). All polymorphisms were studied in a cohort of 576 India-born Asian Indians sampled in the United States. This sample consisted of individuals whose mother tongue is one of 14 of the 22 "official" languages recognized in India as well as individuals whose mother tongue is Parsi, a cultural group that has resided in India for over 1000 years. Analysis of the data revealed that allele frequency differences between the different Indian language groups were small, and interestingly the variant alleles of <it>ALOX5 </it>g.8322G>A and g.50778G>A, and <it>PTPN22 </it>g.36677C>T were present only in a subset of the Indian language groups. Furthermore, a latitudinal cline was identified both for the allele frequencies of the SNPs associated with hypertension (<it>CYP3A5</it>, <it>AGT</it>, <it>GNB3</it>), as well as for those associated with the ability to taste phenylthiocarbamide (<it>TAS2R38</it>).</p> <p>Conclusion</p> <p>Although caution is warranted due to the fact that this US-sampled Indian cohort may not represent a random sample from India, our results will hopefully assist in the design of future studies that investigate the genetic causes of these diseases in India. Our results also support the inclusion of the Indian population in disease-related genetic studies, as it exhibits unique genotype as well as phenotype characteristics that may yield new insights into the underlying causes of common diseases that are not available in other populations.</p

Noise exposure and distortion product otoacoustic emission suprathreshold amplitudes : a genome-wide association study

Background: Although several candidate-gene association studies have been conducted to investigate noise-induced hearing loss (NIHL) in humans, most are underpowered, unreplicated, and account for only a fraction of the genetic risk. Mouse genome-wide association studies (GWASs) have revolutionized the field of genetics and have led to the discovery of hundreds of genes involved in complex traits. The hybrid mouse diversity panel (HMDP) is a collection of classic inbred and recombinant inbred strains whose genomes have been either genotyped at high resolution or sequenced. To further investigate the genetics of NIHL, we report the first GWAS based on distortion product otoacoustic emission (DPOAE) measurements and the HMDP. Methods: A total of 102 strains (n = 635) from the HMDP were evaluated based on DPOAE suprathreshold amplitudes before and after noise exposure. DPOAE amplitude variation was set at 60 and 70 dB SPL of the primary tones for each frequency separately (8, 11.3, 16, 22.6, and 32 kHz). These values provided an indirect assessment of outer hair cell integrity. Six-week-old mice were exposed for 2 h to 10 kHz octave-band noise at 108 dB SPL. To perform local expression quantitative trait locus (eQTL) analysis, gene expression microarray profiles were generated using cochlear RNA from 64 hybrid mouse strains (n = 3 arrays per strain). Results: Several new loci were identified and positional candidate-genes associated with NIHL were prioritized, especially after noise exposure (1 locus at baseline and 5 loci after exposure). A total of 35 candidate genes in these 6 loci were identified with at least 1 probe whose expression was regulated by a significant cis-eQTL in the cochlea. After careful analysis of the candidate genes based on cochlear gene expression, 2 candidate genes were prioritized: Eya1 (baseline) and Efr3a (post-exposure). Discussion and Conclusion: For the first time, an association analysis with correction for population structure was used to map several loci for hearing traits in inbred strains of mice based on DPOAE suprathreshold amplitudes before and after noise exposure. Our results identified a number of novel loci and candidate genes for susceptibility to NIHL, especially the Eya1 and Efr3a genes. Our findings validate the power of the HMDP for detecting NIHL susceptibility genes