Genetic Predisposition to Elevated Serum Thyrotropin Is Associated with Exceptional Longevity

Gil Atzmon, Nir Barzilai, Martin I. Surks, and Ilan Gabriely

Division of Endocrinology, Departments of Medicine (G.A., N.B., M.I.S., I.G.), Genetics (G.A., N.B.), and Pathology (M.I.S.), Albert Einstein College of Medicine, Bronx, New York 10461

Context: Exceptional longevity is associated with raised serum TSH.

Objective: The aim of this study was to examine whether offspring of people with exceptional longevity have elevated serum TSH and whether specific single nucleotide polymorphisms (SNPs) in the TSH-B gene and TSH receptor (TSHR) gene are associated with this phenotype.

Design/Setting/Patients: We measured serum TSH and free T in Ashkenazi Jewish centenarians 4 (n(cid:1)232;medianage,97yr),theiroffspring(n(cid:1)366;medianage,69yr),andage-matchedcontrols without familial longevity (n   163; median age, 70 yr). We determined TSH heritability, its dis- tribution, and association with SNPs in the TSH-B and TSHR genes.

Results: Offspring had higher median serum TSH [1.68 mIU/liter (97.5% confidence interval, 0.65 to 4.79 mIU/liter)], compared to controls [1.50 mIU/liter (97.5% confidence interval, 0.63 to 3.93 mIU/liter); P   0.02], with estimated heritability of 0.33 (P   0.004). Allele frequency of two SNPs in the promoter/enhancer region of TSHR gene, associated with increased serum TSH, was higher in centenarians and their offspring compared to controls (rs10149689 G allele frequency, 0.57 and 0.53 vs. 0.48; P   0.001 and P   0.08; odds ratio, 1.56 and 1.22, respectively; and rs12050077 A allele frequency, 0.57 and 0.53 vs. 0.46; P   0.0001 and P   0.01; odds ratio, 1.68 and 1.32, respectively). LinkagedisequilibriumbetweenthetwoSNPswashigh(r2(cid:1)0.95),suggestinginteractionbetween them. Furthermore, GA haplotype frequency was significantly higher among centenarians and offspring compared to controls (0.57 and 0.53 vs. 0.46; P   0.0001 and P   0.01, respectively).

Conclusions: A heritable phenotype characterized by raised serum TSH is associated with human longevity. Carriers of rs12050077 and rs10149689 SNPs in the TSHR have higher serum TSH, possibly contributing to decreased thyroid function and longevity. (J Clin Endocrinol Metab 94: 4768–4775, 2009)

Several studies in humans suggest decreases in thyroid function with aging, which are considered to be in- dependent of antithyroid antibody levels or age-related comorbidities (1–3). Wehavepreviouslydemonstratedthat the increased TSH with aging reflects a progressive popula- tion shift to higher serum TSH with age that extends even to people who have achieved exceptional longevity (4–6). Because increased serum TSH concentrations may reflect decreased thyroid function, we hypothesized that excep- tional longevity may be associated with decreased thyroid

hormone secretion (6). Furthermore, we have recently reported a significant inverse correlation between se- rum TSH and free T (FT4) in Ashkenazi Jewish cente- 4 narians and younger Ashkenazi Jewish controls (6), suggesting a functional feedback in thyroid hormone regulation that results in a relative (subclinical) decrease in thyroid function.

These findings in humans are further supported by an- imal studies that demonstrate an inverse correlation be- tween extended life span and decreased thyroid function

Abbreviations:CI,Confidenceinterval;FT4,freeT ;OR,oddsratio;SNP,singlenucleotide 4 polymorphism; TSHR, TSH receptor.

Copyright © 2009 by The Endocrine Society doi: 10.1210/jc.2009-0808 Received April 15, 2009. Accepted August 27, 2009. First Published Online October 16, 2009

For editorial see page 4658

ications. Additionally, 10 participants in the control groups were excluded because their biological parents lived past 85 yr of age.

(7, 8), suggesting a causal relationship. The precise mech- anisms responsible for the effects of hypothyroidism on life span, however, have not been clarified, although mul- tiple actions of decreased thyroid hormone concentrations (including lowering the metabolic rate, lowering core body temperature and oxygen consumption, and reducing reactive oxygen species generation and oxidative damage) may play an important role in longevity (9–14).

We chose to study Ashkenazi Jews due to their known genetic homogeneity that is attributed to founder effects. The founders lived in the 16th to 17th centuries in eastern and central Europe. Although this population experienced isolation, inbreeding, and genetic drift, it has undergone rapid growth after immigration to the United States, beginning in the 18th century. In the past, the Ashkenazi population has served as a valuable genetic resource to discover the genetic bases of several Mendelian disorders as well as age-related diseases (21).

Hereditary and genetic influences on serum thyroid hor- mone and TSH concentrations have been reported in twin studies (15, 16) and in Mexican-American families (17). In addition, several recent reports show that polymorphisms in severalthyroidpathwaygenescouldinfluenceserumthyroid hormone and TSH concentrations (18–20).

Founder populations amplify certain gene variants while maintaining great stretches of uniformity in other DNA se- quences. Genes that are very close together exhibit extremely tight linkage (linkage disequilibrium), which is particularly pro- nounced in isolated populations. Numerous association studies have exploited the properties of linkage disequilibrium, geneti- cally uniform background in the isolated and founder popula- tions, such as the Finnish and Icelandic populations (22–24).

In this study, we hypothesized that the alterations in thyroid function seen in human longevity may have a ge- netic basis. Consequently, we examined thyroid function in offspring of individuals with exceptional longevity and searched for genetic markers that may be responsible for the specific pattern of thyroid function tests observed in this population.