BACKGROUND/OBJECTIVES: This is the first study to identify common genetic factors associated with the basal metabolic rate (BMR) and body mass index (BMI) in obese Korean women including overweight. This will be a basic study for future research of obese gene-BMR interaction. SUBJECTS/METHODS: The e...
BACKGROUND/OBJECTIVES: This is the first study to identify common genetic factors associated with the basal metabolic rate (BMR) and body mass index (BMI) in obese Korean women including overweight. This will be a basic study for future research of obese gene-BMR interaction. SUBJECTS/METHODS: The experimental design was 2 by 2 with variables of BMR and BMI. A genome-wide association study (GWAS) of single nucleotide polymorphisms (SNPs) was conducted in the overweight and obesity (BMI > $23kg/m^2$) compared to the normality, and in women with low BMR (< 1426.3 kcal/day) compared to high BMR. A total of 140 SNPs reached formal genome-wide statistical significance in this study (P < $1{\times}10^{-4}$). Surveys to estimate energy intake using 24-h recall method for three days and questionnaires for family history, a medical examination, and physical activities were conducted. RESULTS: We found that two NRG3 gene SNPs in the 10q23.1 chromosomal region were highly associated with BMR (rs10786764; $P=8.0{\times}10^{-7}$, rs1040675; $2.3{\times}10^{-6}$) and BMI (rs10786764; $P=2.5{\times}10^{-5}$, rs10786764; $6.57{\times}10^{-5}$). The other genes related to BMI (HSD52, TMA16, MARCH1, NRG1, NRXN3, and STK4) yielded P < $10{\times}10^{-4}$. Five new loci associated with BMR and BMI, including NRG3, OR8U8, BCL2L2-PABPN1, PABPN1, and SLC22A17 were identified in obese Korean women (P < $1{\times}10^{-4}$). In the questionnaire investigation, significant differences were found in the number of starvation periods per week, family history of stomach cancer, coffee intake, and trial of weight control in each group. CONCLUSION: We discovered several common BMR- and BMI-related genes using GWAS. Although most of these newly established loci were not previously associated with obesity, they may provide new insights into body weight regulation. Our findings of five common genes associated with BMR and BMI in Koreans will serve as a reference for replication and validation of future studies on the metabolic rate.
BACKGROUND/OBJECTIVES: This is the first study to identify common genetic factors associated with the basal metabolic rate (BMR) and body mass index (BMI) in obese Korean women including overweight. This will be a basic study for future research of obese gene-BMR interaction. SUBJECTS/METHODS: The experimental design was 2 by 2 with variables of BMR and BMI. A genome-wide association study (GWAS) of single nucleotide polymorphisms (SNPs) was conducted in the overweight and obesity (BMI > $23kg/m^2$) compared to the normality, and in women with low BMR (< 1426.3 kcal/day) compared to high BMR. A total of 140 SNPs reached formal genome-wide statistical significance in this study (P < $1{\times}10^{-4}$). Surveys to estimate energy intake using 24-h recall method for three days and questionnaires for family history, a medical examination, and physical activities were conducted. RESULTS: We found that two NRG3 gene SNPs in the 10q23.1 chromosomal region were highly associated with BMR (rs10786764; $P=8.0{\times}10^{-7}$, rs1040675; $2.3{\times}10^{-6}$) and BMI (rs10786764; $P=2.5{\times}10^{-5}$, rs10786764; $6.57{\times}10^{-5}$). The other genes related to BMI (HSD52, TMA16, MARCH1, NRG1, NRXN3, and STK4) yielded P < $10{\times}10^{-4}$. Five new loci associated with BMR and BMI, including NRG3, OR8U8, BCL2L2-PABPN1, PABPN1, and SLC22A17 were identified in obese Korean women (P < $1{\times}10^{-4}$). In the questionnaire investigation, significant differences were found in the number of starvation periods per week, family history of stomach cancer, coffee intake, and trial of weight control in each group. CONCLUSION: We discovered several common BMR- and BMI-related genes using GWAS. Although most of these newly established loci were not previously associated with obesity, they may provide new insights into body weight regulation. Our findings of five common genes associated with BMR and BMI in Koreans will serve as a reference for replication and validation of future studies on the metabolic rate.
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문제 정의
From the questionnaire investigation, differences in items including family history and food intake were observed between the low BMR and high BMR groups. These findings provide new insights into the genetic etiology of obesity in relation to BMR and BMI. Recently, common variations of fat mass and obesity-related genes, including FTO, MC4R, and TMEM18, have been consistently associated with obesity traits and BMI in GWAS [17-18].
제안 방법
Anthropometry was performed for weight, height, BMI, BMR, WC, hip, lean body mass, fat mass, percent of fat mass, and WHR. WC was measured midway between the lowest rib and the superior border of the iliac crest at the end of normal expiration using an inelastic measuring tape to the nearest 0.
) were inspected for the family history. Assessments of habitual diet intake, including the number of starvation periods per week, intake of fast-food, carbonated drink, coffee, snack, and dietary (food, health, nutritional) supplement, and number of times eating-out were performed. Environmental data, including weight control methods, degree of physical activity such as hard, normal, and light exercise were acquired through the questionnaires.
Assessments of habitual diet intake, including the number of starvation periods per week, intake of fast-food, carbonated drink, coffee, snack, and dietary (food, health, nutritional) supplement, and number of times eating-out were performed. Environmental data, including weight control methods, degree of physical activity such as hard, normal, and light exercise were acquired through the questionnaires. Dietary intakes with three days recall methods were collected and analyzed using Can Pro 4.
For the analysis of GWAS data, the subjects were divided into two groups: high BMR and low BMI (control group) vs. low BMR and high BMI (case group). Continuous variables were expressed as mean ± SD, and differences between groups were assessed using Student’s t-test.
In addition, all datasets were filtered to exclude samples or SNPs with > 5% missing values, variants with < 5% minor allele frequency, and samples deviating from the HWE, using PLINK, whole genome data analysis tool set.
Quantitative trait association analyses for BMR and BMI in the 77 overweight women (BMR 23 kg/m2) and normal-weight control subjects (BMRI > 1426.3 kcal/day and BMI < 23 kg/m2) were performed.
Six divisions of general questionnaires were conducted; general question, family history, nutritive conditions with eating habits, weight-control history, exercise and diet intakes with eating pattern. Questions about age, smoking status, and drinking status were included as general questions, and questions on hypertension, diabetes, myocardial infarction, angina, stroke, and cancer (stomach, lung, breast, etc.
This study was approved by the ethics committee of Sungshin Women’s University (SSWU IRB 2012-003). The study included completion of anthropometrics, questionnaires (family history, a medical examination, and physical activities), and dietary intakes. Written informed consent was obtained from all participants.
Table 1 shows the clinical characteristics of the study population. The subjects were divided into several groups: normal vs. overweight according to BMI and low vs. high BMR. The mean BMR value was 1452.
Using continuous variables, 118 SNPs in the whole chromosome including the NRG3 and PTPRD regions reached our current threshold for genome-wide significance (data not shown). The subjects were divided into two groups: high-BMR and low-BMI (control group) vs. low-BMR and high-BMI (case group). In the second analysis, 49 additional loci including rs1018484 in NRG3 and a locus (rs11228758) at chromosome 11 in the intron of olfactory receptor, family 8, subfamily U, member 8 (OR8U8; GenBank NW_003871073) reached genomewide significance (Tables 2 and 3).
Several GWAS on BMI, WC, WHR, extreme obesity phenotypes, and BMI-adjusted WHR in ethnic groups have been published; however, GWAS of BMR and BMI has not yet been confirmed in Korean women. To investigate the differences of the eating behavior and obesity-related life pattern between women with obesity and healthy control subjects, we conducted a survey using the 24-h recall method and a questionnaire.
대상 데이터
A total of 77 subjects were enrolled in the current study. Table 1 shows the clinical characteristics of the study population.
The study population consisted of 77 Korean female participants aged 18-34 years who were recruited between May and July 2012. This study was approved by the ethics committee of Sungshin Women’s University (SSWU IRB 2012-003).
데이터처리
Continuous variables were expressed as mean ± SD, and differences between groups were assessed using Student’s t-test.
이론/모형
BMR measurement was performed using a MedGem® metabolic analyzer (Microlife USA, Dunedin, FL), a handheld indirect calorimeter used for its accuracy and portability in clinical settings, which is becoming popular in research studies as a screening tool and a criterion measure of RMR.
For the data obtained from the chip, internal quality control measures were used: the QC call rate (Dynamic Model algorithm) always exceeded 86% and heterozygosity on the X chromosome correctly identified the gender of the individual. Genotype calling was performed using the Birdseed v2 algorithm.
성능/효과
A total of 140 SNPs reached formal genome-wide statistical significance in this study (P < 1 × 10-4).
A total of 77 participants who fulfilled all requirements were divided into four groups including high vs. low BMR according to median value of BMR, 1426.3 kcal/day, and low BMI (< 23 kg/m2) vs. high BMI (> 23 kg/m2).
However, only eight of these associations have been verified by follow-up GWAS using more complicated evaluations of adiposity. Among these eight, an SNP close to the FTO gene has been studied for discovery of its function, while the remaining seven SNPs adjacent to, or within, the NEGR1, TMEM18, ETV5, FLJ35779, LINGO2, SH2B1, and GIPR genes are less well reported than FTO, particularly in connection with obesity. Some reports did not demonstrate the putative mechanism associating the FLJ35779 and LINGO2 genes with obesity.
First, NRG3 gene SNP (rs10786764) in the 10q23.1 chromosomal region was highly associated with both BMR (P = 8.0 × 10-7) and BMI (P = 8.0 × 10-7), and NRG3 gene SNP (rs1040675), also a gene commonly associated with BMR and BMI even though it was not as strong as rs10786764 in the linkage disequilibrium (LD) plot (Fig. 2).
Five common genes (NRG3, OR8U8, BCL2L2- PABPN1, PABPN1, and SLC22A17) yielded P < 1 × 10-5 in the BMR and BMI groups.
005). From questions about the family history of gastric cancer, it was found that women in the high BMR have higher family history rates than subjects in the low BMR group (P = 0.013).
low-BMR and high-BMI (case group). In the second analysis, 49 additional loci including rs1018484 in NRG3 and a locus (rs11228758) at chromosome 11 in the intron of olfactory receptor, family 8, subfamily U, member 8 (OR8U8; GenBank NW_003871073) reached genomewide significance (Tables 2 and 3). A total of 140 SNPs reached formal genome-wide statistical significance in this study (P < 1 × 10-4).
The TNR, B3GNT2, FZD7, OR2Y1, MGAT1, NPAS3, PKD1L2, and SETBP1 genes showed weaker associations (P < 1 × 10-5) with BMR.
The five common genes associated with both BMR and BMI were NRG3, OR8U8, BCL2L2-PABPN1, PABPN1, and SLC22A17 (P < 1 × 10-4).
We performed systematic quality control steps on the raw genotype data and obtained 904,085 SNPs; SNPs with a minor allele frequency of < 1%, a call rate of < 95%, and a significant deviation from Hardy-Weinberg equilibrium in controls (P < 1 × 10-7) were excluded.
후속연구
However, some reports showed that although these novel family members have conserved sequence elements like the other OCT members, these proteins were unable to transport typical substrates as the SLC22 family, and another possible function of SLC22A17 was suggested [25]. The SLC22 family has not yet been associated with obesity and/or BMI; however, further studies and experiments are needed in order to test this novel hypothesis.
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