Jae Woong Sull, Sun Ha Jee Eulji University, Yonsei University Association of CDH13 Polymorphisms with Serum Adiponectin Levels in a Korean Population Jae Woong Sull, Sun Ha Jee Eulji University, Yonsei University

Background Adiponectin is associated with obesity and insulin resistance. Several genome-wide association studies of adiponectin levels have identified candidate genes, including the CDH13 gene. Rule of thumb - Gender Inequality Women become intoxicated more quickly than men, even when body weights are the same. There are three likely explanations for this fact. First, soon after consumption, alcohol rapidly spreads throughout the water in a drinker’s body, and men’s bodies have a greater percentage of water by volume. If a woman drinks the same amount as a man, the effect is similar to pouring the same amount of alcohol into a smaller pail of water. Women also have lower levels of activity in the alcohol-metabolizing enzyme, alcohol dehydrogenase, in the stomach. This means that more alcohol is metabolized in the stomachs of men before being absorbed into the bloodstream than in the stomachs of women. The end result is that more alcohol passes directly into the bloodstream of women. Finally, as a woman’s hormone levels vary during the course of her menstrual cycle, her blood alcohol concentration can vary dramatically with the same amount of alcohol intake.

We genotyped for 990 subjects with the Affymetrix Genome-wide Human SNP array 5.0. Serum adiponectin levels were measured. For statistical analysis, we used multivariate linear regression model using PLINK. In the model, we adjusted age, sex, and smoking status and we used additive model.

Significance of SNPs in CDH13 for all 3 cohorts The upper part of the plot shows the -log10 P value. Black, red, and white solid spots are  respectively of the discovery study, of 1st replication and of 2nd replication. The lower part of the plot shows the recombination rate across the region (blue) and the cumulative recombination rate measured away from the most highly associated SNP of rs3865188 (yellow). Positions of highly significant SNPs were upstream of CDH13.

Study Objective to examine the association of serum adiponectin levels (or hypoadiponectinemia) with SNPs in CDH13 gene considering fasting blood glucose levels and smoking status.

Study Population A total of 4,294 subjects were recruited from a Hospital, Korea. 2289 subjects were excluded due to missing BMI and adiponectin level data. Thus, the final population included 2,005 subjects. The institutional Review Board at Yonsei University

Definition of Hypoadiponectinemia Hypoadiponectinemia was defined as the lowest quartile of adiponectin (<4.27 for all subjects, <3.85 for Men, <6.01 for Women).

Genotyping The CDH13 gene SNPs were genotyped via the TaqMan reaction. Duplicate genotyping for 1–2.5% of all samples was carried out as a QC measure.

Statistical Analysis Most statistical analyses were performed using PLINK and SAS ver. 9.2 (SAS Institute, Cary, NC, USA). The multivariate linear regression models used in the study incorporated covariates (age and sex). Multiple logistic regression analysis was also performed.

Table 1. General characteristics of study population Subjects All Men Women N 2005 1412 593 Mean ± SD Age, year 50.6±9.8 50.6±9.7 50.8±9.6 Waist circumference, cm 83.4±9.0 86.5±7.7 76.9±8.2 Body mass index, kg/m2 24.2±2.9 24.8±2.8 23.0±2.9 Fasting blood sugar, mg/Dl 96.3±22.0 98.4±23.8 91.2±15.8 Adiponectin, μg/ml 7.59±4.97 6.51±4.15 10.15±5.76 Systolic blood pressure, mmHg 121.7±14.3 123.3±13.9 117.9±14.4 Diastolic blood pressure, mmHg 77.8±10.9 79.3±10.8 74.0±10.2 % Smoking status Ex 28.6 39.7 1.6 Current 27.3 37.3 3.0 Diabetes* 7.9 9.2 4.9 Family history of diabetes 15.9 15.2 17.5

Fasting blood sugar, mg/dL Table 2. Association between the rs4783244 single nucleotide polymorphism in the CDH13 gene and adiponectin levels based on a linear regression model Genotypes Phenotypes GG (N=1009) TG (N=820) TT (N=176) Effect (mg/dL) P-value* Mean±SD Adiponectin, μg/ml 8.52±5.3 6.81±4.4 5.86±4.0 1.511 <0.0001 Fasting blood sugar, mg/dL 96.6±22.2 95.2±20.2 99.4±28.0 -0.367 0.6218 Body mass index, kg/m2 24.2±3.0 24.2±2.8 24.5±3.1 -0.065 0.5033 Estimated effect size (β) and p-value in the multiple linear regression model considered age and sex in the additive model.

Hypoadiponectinemia * Table 3. Odds ratios of rs4783244 CDH13 genotypes for hypoadiponectinemiaa (n = 2,005) Normal Hypoadiponectinemia * Subjects Genotype N (%) OR (95% CIb) P-value All GG 836 (55.5) 173(34.7) 1.00 (reference) TG/TT 670 (44.5) 326(65.3) 2.44(1.97-3.03) <0.0001 Men 594 (56.0) 117(33.3) 467 (44.0) 234(66.7) 2.56(1.99-3.29) Women 245 (55.1) 53(35.8) 200 (44.9) 95(64.2) 2.19(1.49-3.22) a Adjusted for age and sex b CI, confidence interval * Hypoadiponectinemia was defined as the lowest quartile of adiponectin.

Hypoadiponectinemia* Table 4. Odds ratios (OR) of polymorphic rs4783244 CDH13 genotypes for hypoadiponectinemiaa in the population (n = 2,005) Normal Hypoadiponectinemia* Subjects Genotype N (%) OR (95% CIb) P-value FBS<110 GG 741(54.6) 147(36.1) 1.00 (reference) TG/TT 616(45.4) 260(63.9) 2.19(1.73-2.76) <0.0001 110≤FBS<126 49(67.1) 8(17.4) 24(32.9) 38(82.6) 10.96(4.31-27.88) FBS≥126 46(60.5) 18(39.1) 30(39.5) 28(60.9) 2.72(1.25-5.94) 0.0120 Family history of Diabetes (No) 693(54.1) 142(34.9) 587(45.9) 265(65.1) 2.26(1.79-2.87) Family history of Diabetes (Yes) 143(63.3) 31(33.7) 83(36.7) 61(66.3) 3.80(2.23-6.47) a Adjusted for age and sex b CI, confidence interval * Hypoadiponectinemia was defined as the lowest quartile of adiponectin.

Table 5. Odds ratios (OR) of polymorphic rs4783244 CDH13 genotypes for hypoadiponectinemiaa in Korean men (n = 1,412) Normal Hyponectinemia* Subjects Genotype N (%) OR (95% CIb) P-value Non smokers GG 144(58.3) 16(23.2) 1.00 (reference) TG/TT 103(41.7) 53(76.8) 4.67(2.52-8.63) <0.0001 Ex smokers 224(54.0) 43(32.8) 191(46.0) 88(67.2) 2.44(1.61-3.69) Current smokers 211(57.2) 56(38.9) 158(42.8) 88(61.1) 2.17(1.46-3.23) 0.0001 a Adjusted for age and sex b CI, confidence interval * Hypoadiponectinemia was defined as the lowest quartile of adiponectin.

Summary / Discussion In this study, SNPs in CDH13 gene were associated with hypoadiponectinemia, consistent with previous studies. In the present study, we found that CDH13 SNP had a stronger association with hypoadiponectinemia in subjects with impaired fasting glucose levels than Normal subjects

Conclusions The association of CDH13 gene SNP was stronger in nonsmokers than that in mokers. In conclusion, this study clearly demonstrates that genetic variants in CDH13 gene influence serum adiponectin levels in Korean adults.

Thank you !