Sarah Yang

The Healthy Twin Study, Korea Updates: Resources for Omics and Genome Epidemiology Studies

The Healthy Twin Study, Korea (HT) is an ongoing multi-center cohort study that was initiated in 2005, based on a nation-wide twin and family database. Since its inception, the HT has recruited 815 pairs of adult twins and a total of 3,690 individual twins and their families as of July 2012. Here we summarize updates since the previous report in 2006. Besides the increase in size, the HT has been enriched in several aspects: a biobank was constructed for ongoing and future omics studies; and genome-wide single nucleotide polymorphism markers (Affymetrix GeneChip version 6.0, 1 M probes) have been analyzed for 2,200 individuals, which enabled gene identification studies for measured phenotypes. In addition, longitudinal study protocols were established through the HT and a second wave survey was finished in 2010 with >70% follow-up rate. The parallel genome research projects were recently launched, which would expedite multi-omics studies maximizing the twin potentials such as metagenomics and epigenetics studies, and endow us with resources for recruiting more participants. We submit this report to share updates and research opportunities from the HT.

GWA meta-analysis of personality in Korean cohorts.

Personality is a determinant of behavior and lifestyle that is associated with health and human diseases. Despite the heritability of personality traits is well established, the understanding of the genetic contribution to personality trait variation is extremely limited. To identify genetic variants associated with each of the five dimensions of personality, we performed a genome-wide association (GWA) meta-analysis of three cohorts, followed by comparison of a family cohort. Personality traits were measured with the Revised NEO Personality Inventory for the five-factor model (FFM) of personality. We investigated the top five single-nucleotide polymorphisms (SNPs) for each trait, and revealed the most highly association with neuroticism and TACC2 (rs1010657, P=8.79 × 10−7), extraversion and PTPN12 (rs12537271, P=1.47 × 10−7), openness and IMPAD1 (rs16921695, P=5 × 10−8), agreeableness and RPS29 (rs8015351, P=1.27 × 10−6) and conscientiousness and LMO4 (rs912765, P=2.91 × 10−6). It had no SNP reached the GWA study threshold (P<5 × 10−8). When expanded the SNPs up to top 100, the correlation of PTPRD (rs1029089) and agreeableness was confirmed in Healthy Twin cohort with other 13 SNPs. This GWA meta-analysis on FFM personality traits is meaningful as it was the first on a non-Caucasian population targeted to FFM of personality traits.

Genetic and environmental influences on sodium intake determined by using half-day urine samples: the Healthy Twin Study

BACKGROUND Salt is essential in our diet, but excess intake is a well-established risk factor for hypertension. The presence and importance of genetic contributions to salt intake, however, are not well understood. OBJECTIVE The aim of this study was to examine whether a genetic predisposition and an environmental influence exist for sodium intake and salt habit. DESIGN In a twin-family cohort, half-day urine samples from 1204 individuals (133 pairs of monozygotic twins, 29 pairs of dizygotic twins, and 880 singletons) were collected to assess 24-h sodium intakes. Daily total sodium intake, sodium density per calorie (Na-D), and salt habit questions were analyzed with adjustment for other epidemiologic characteristics. We calculated heritability (h2) and intraclass correlations to examine the genetic and shared environmental contributions to total sodium intake traits. RESULTS The average sodium intake was 208.4 ± 107.0 mmol/d. Men had a higher absolute sodium intake (242.6 ± 117.4 mmol/d), but Na-D did not differ by sex. Moderate genetic influences existed (h2 = 0.31-0.34) for sodium intake and Na-D. We also found that sharing current residence rather than being a family member explained 22% of the variance in Na-D. CONCLUSION Our findings suggest that both genetic predisposition and shared environment contribute to sodium intakes and salt habits alike.

Genetic and environmental influences on adult human height across birth cohorts from 1886 to 1994

Human height variation is determined by genetic and environmental factors, but it remains unclear whether their influences differ across birth-year cohorts. We conducted an individual-based pooled analysis of 40 twin cohorts including 143,390 complete twin pairs born 1886–1994. Although genetic variance showed a generally increasing trend across the birth-year cohorts, heritability estimates (0.69-0.84 in men and 0.53-0.78 in women) did not present any clear pattern of secular changes. Comparing geographic-cultural regions (Europe, North America and Australia, and East Asia), total height variance was greatest in North America and Australia and lowest in East Asia, but no clear pattern in the heritability estimates across the birth-year cohorts emerged. Our findings do not support the hypothesis that heritability of height is lower in populations with low living standards than in affluent populations, nor that heritability of height will increase within a population as living standards improve. DOI: http://dx.doi.org/10.7554/eLife.20320.001

Twin's Birth-Order Differences in Height and Body Mass Index From Birth to Old Age: A Pooled Study of 26 Twin Cohorts Participating in the CODATwins Project

We analyzed birth order differences in means and variances of height and body mass index (BMI) in monozygotic (MZ) and dizygotic (DZ) twins from infancy to old age. The data were derived from the international CODATwins database. The total number of height and BMI measures from 0.5 to 79.5 years of age was 397,466. As expected, first-born twins had greater birth weight than second-born twins. With respect to height, first-born twins were slightly taller than second-born twins in childhood. After adjusting the results for birth weight, the birth order differences decreased and were no longer statistically significant. First-born twins had greater BMI than the second-born twins over childhood and adolescence. After adjusting the results for birth weight, birth order was still associated with BMI until 12 years of age. No interaction effect between birth order and zygosity was found. Only limited evidence was found that birth order influenced variances of height or BMI. The results were similar among boys and girls and also in MZ and DZ twins. Overall, the differences in height and BMI between first- and second-born twins were modest even in early childhood, while adjustment for birth weight reduced the birth order differences but did not remove them for BMI.

Twin's Birth-Order Differences in Height and Body Mass Index From Birth to Old Age: A Pooled Study of 26 Twin Cohorts Participating in the CODATwins Project.

We analyzed birth order differences in means and variances of height and body mass index (BMI) in monozygotic (MZ) and dizygotic (DZ) twins from infancy to old age. The data were derived from the international CODATwins database. The total number of height and BMI measures from 0.5 to 79.5 years of age was 397,466. As expected, first-born twins had greater birth weight than second-born twins. With respect to height, first-born twins were slightly taller than second-born twins in childhood. After adjusting the results for birth weight, the birth order differences decreased and were no longer statistically significant. First-born twins had greater BMI than the second-born twins over childhood and adolescence. After adjusting the results for birth weight, birth order was still associated with BMI until 12 years of age. No interaction effect between birth order and zygosity was found. Only limited evidence was found that birth order influenced variances of height or BMI. The results were similar among boys and girls and also in MZ and DZ twins. Overall, the differences in height and BMI between first- and second-born twins were modest even in early childhood, while adjustment for birth weight reduced the birth order differences but did not remove them for BMI.

Effects of alcohol consumption, ALDH2 rs671 polymorphism, and Helicobacter pylori infection on the gastric cancer risk in a Korean population

The effect of alcohol consumption on the risk of gastric cancer (GC) has not yet been fully elucidated, and an aldehyde dehydrogenase 2 (ALDH2) polymorphism, rs671, is a genetic variant that influences alcohol consumption in East Asians. Additionally, the discrepancy between the Helicobacter pylori (H. pylori) infection prevalence and GC incidence across Asian countries has not been explained. This study evaluated the effects of alcohol consumption and genetic susceptibility to defective acetaldehyde metabolism on the GC risk and their interactions with H. pylori infection. This study included 450 Korean GC cases and 1,050 controls recruited at the National Cancer Center. Data for 795 patients and 4,893 controls were used for further confirmation of the effect of rs671. Increased GC risks were evident for rs671 A allele carriers (odds ratio (OR), 1.23; 95% confidence interval (CI), 1.08-1.41) and H. pylori-infected individuals (OR, 7.07; 95% CI, 4.60-10.86), but no dose-response association with alcohol consumption was observed. Furthermore, the interactions between these factors were not significant. This study has demonstrated that alcohol consumption and rs671 should be considered simultaneously when assessing the GC risk. Additionally, alcohol-related factors were not found to interact with H. pylori infection, and further studies evaluating other environmental factors are required to explain the Asian enigma.

Effects of Soy Product Intake and Interleukin Genetic Polymorphisms on Early Gastric Cancer Risk in Korea: A Case-Control Study

Purpose The current study investigated whether the combined effects of soy intake and genetic polymorphisms of interleukin (IL) genes modify gastric cancer risk. Materials and Methods A total of 377 cases and 754 controls of Korean origin were included in the analysis. Soy consumption was assessed using a semi-quantitative food frequency questionnaire. Seven variants of IL10 (rs1800871), IL2 (rs2069763 and rs2069762), IL13 (rs6596090 and rs20541), and IL4R (rs7205663 and rs1805010) were genetically analyzed. To analyze the combined effect of soy intake and genetic polymorphisms, a low-intake group and high-intake group of each type of soy were categorized based on the intake level of the control group. Interactions between soy products and these genetic variants were analyzed by a likelihood ratio test, in which a multiplicative interaction term was added to the logistic regression model. Results A higher intake of nonfermented soy products was associated with a reduced cancer risk (odds ratio [OR], 0.62; 95% confidence interval [CI], 0.43 to 0.90), and the reduced risk was only apparent in males (OR, 0.44; 95% CI, 0.27 to 0.71). None of the IL genetic polymorphisms examined were independently associated with gastric cancer risk. Individuals with a minor allele of IL2 rs2069762 and a higher intake of nonfermented soy food had a decreased risk of gastric cancer (OR, 0.46; 95% CI, 0.31 to 0.68) compared to those with a lower intake (pinteraction=0.039). Conclusion Based on the genetic characteristics of the studied individuals, the interaction between IL2 rs2069762 and nonfermented soy intake may modify the risk of gastric cancer.

Genetic Influences on Macular Thickness in Koreans: The Healthy Twin Study

PURPOSE To estimate genetic influences accounting for macular thickness in the Korean population. METHODS Study subjects were 830 healthy Korean adults (117 monozygotic twin pairs and 523 family members) from the Healthy Twin study. Macular thickness was measured with optical coherence tomography for nine subfields including the fovea, four inner quadrants (within 1 to 3 mm of the center), and four outer quadrants (within 3 to 6 mm of the center). Quantitative genetic analyses were performed to estimate the heritability of macular thickness with respect to familial correlations. RESULTS Macular thickness varied by subfield and was thinnest at the fovea and thickest at the inner superior area. Heritability of macular thickness at each subfield was 0.76, 0.73, 0.70, 0.56, 0.67, 0.70, 0.73, 0.29, and 0.36 at the fovea, inner superior area, inner inferior area, inner nasal area, inner temporal area, outer superior area, outer inferior area, outer nasal area, and outer temporal area, respectively. CONCLUSIONS Genetic factors play a significant role in determining macular thickness in the Korean population.

Genetic variations in TAS 2 R3 and TAS 2 R4 bitterness receptors modify papillary carcinoma risk and thyroid function in Korean females

Type 2 taste receptors (T2Rs, TAS2Rs) mediate bitterness perception and are involved in diverse defence mechanisms in extraoral tissues. The thyrocyte-expressed T2Rs control thyroid hormone production, and this regulatory role may be associated with susceptibility to thyroid diseases. This study examined whether the variations in TAS2Rs modify the risk of papillary thyroid carcinoma (PTC) and whether such T2R-related PTC risk is associated with genetically modified thyroid function. We conducted a case-control study with 763 Korean females, including 250 PTC cases. Seventy-three single-nucleotide polymorphisms in 13 TAS2R genes and the pre-diagnosis levels of 4 thyroid-related functional markers [total triiodothyronine (TT3), free thyroxine, thyroid-stimulating hormone and thyroglobulin] were analysed. Individuals with TAS2R3/4 CC haplotype (rs2270009 and rs2234001) were at a lower risk for PTC than those with the remaining haplotypes (odds ratio = 0.59, 95% confidence interval: 0.36–0.97). Furthermore, TT3 levels were significantly reduced for TAS2R3/4 CC haplotype carriers compared with other haplotype carriers (p = 0.005). No other genetic variants exhibited critical associations with the PTC phenotype and biomarkers. In summary, genetic variations in T2R3/4 bitterness receptors may modify the PTC risk, and the genetically modified thyroid hormone level by those variations may be linked with the PTC-T2Rs association.