To determine whether medications taken by participants may affect TSH concentration, we applied a linear regression model where serum TSH levels served as a dependent variable, and various medications taken by our study subjects served as independent variables; no significant effect of any medication was detected. Furthermore, stepwise regression of a mixed model, where the probability to enter was 0.25 and the probability to leave was 0.05, demonstrated that none of the medications had any significant effect on serum TSH. Drug categories and the percentage of subjects using the drugs are listed in Table 2, as well as the percentage of subjects taking one or more drugs.

Heritability Analysis The phenotypic variance represents a combination of genetic (additive) variance, environmental variance, and the covariance between these17 Serum FT4 (ng/dl)

TABLE 2. Percentage of subjects taking drugs from various categories and percentage of subjects using medication(s)

% of total Drug categories 
Blood pressure 35.43 
Heart disease 21.40 
Diabetes mellitus 5.56 
Dyslipidemia 27.30 
Depression 13.44 
Sleep medications 10.21 
Aspirin 20.83 
Anticoagulants 0.75 

No. of drugs taken by the same person 
0 32.69 
1 26.06 
2 20.58 
3 12.95 
4 6.06 
5 1.41 
6 0.17 
7 0.08 

FIG. 3. The correlation between serum TSH and FT4 concentrations in all groups (A) and in controls (B). Serum TSH in offspring (mIU/L) vs O Ba aN @ 

Serum TSH in proband (mIU/L)r=0.32p=0.007  

Frequencies for these SNPs were not significantly different between offspring and centenarians. Linkage disequilibrium between the two SNPs was high (r2>0.95), suggesting interaction between them. The frequency of GA haplotype was significantly greater among both Ashkenazi Jewish centenarians and their offspring compared with controls (0.57 and 0.53 vs. 0.46; P<0.0001 and P<0.01, respectively). With adjustment for gender, we found that the median TSH in those who had rs10149689 (G allele) and rs12050077 (A allele) was significantly higher than those who had neither of the alleles [median (97.5% CI), 1.42 (0.56 to 3.33) vs. 1.68 (0.63 to 6.06) mIU/liter in controls, P=0.02; and 1.49 (0.46 to 3.74) vs. 1.70 (0.68 to 5.38) mIU/liter, P=0.049 in offspring]. Similarly, the median TSH level in the combined groups (control and offspring) associated with GA haplotype was significantly higher compared with the individuals without the GA [median (97.5% CI), 1.78 (0.59 to 7.01) vs.1.54 (0.50 to 5.29) mIU/liter; P=0.04]. 

FIG. 4. Heritability analysis of serum TSH in Ashkenazi Jewish centenarians (probands) and their offspring.

We found a moderate degree of heritability (h2=0.32; P=0.007) for serum TSH in Ashkenazi Jewish centenarians and their offspring (Fig. 4). To examine further the role of genetic factors, we performed a case-control genetic analysis of TSH and TSHR variants (4 and 2, respectively). The SNPs were part of a larger group of SNPs in an independent dataset comprised of individuals from the same genetic origin.

Although the SNPs in the TSH-B dataset did not show significant changes between cases and controls, the SNPs in the TSHR did show significant differences.

Thus, we chose to examine those SNPs using a different technology and an independent dataset.

The allelic frequency for SNPs in the TSHR gene was significantly different comparing Ashkenazi Jewish centenarians and controls [rs10149689 G allele frequency, 0.57 vs. 0.48; P<0.001, odds ratio (OR), 1.56 and (rs12050077 A allele frequency, 0.57 vs. 0.46; P<0.0001; OR 1.68). Allelic frequency also differed between the offspring and controls (rs10149689 G allele frequency, 0.53 vs. 0.48; P=0.08; OR 1.22; and rs12050077 A allele frequency, 0.53 vs. 0.46; P=0.01; OR 1.32; Fig. 5).

Carriers of the favorable allele in the combined groups (offspring and control) have higher TSH levels [median (97.5% CI), 1.70 (0.59 to 5.34) vs.1.45 (0.50 to 3.99) mIU/liter; P=0.005], suggesting that the high prevalence of the TSHR SNPs is associated with higher serum TSH levels.