TTR T119M genotype associated with a 20% (19 nmol/L) increase in mean plasma levels of total thyroxine in heterozy- gotes versus noncarriers. Mean total thyroxine levels were 114 nmol/L and 95 nmol/L, respectively (Figure 2; P<0.0001). In contrast, genotype did not associate with other measures of thyroid function, that is, thyroid stimulating hormone, triiod- thyronine or triiodthyronine uptake test, an indirect measure , of the amount of thyroxine bound to thyroid-binding globu- lin, (Figure 2; P=0.56–0.63), or with plasma levels of albu- min (Table I in the online-only Data Supplement; P=0.89). In plasma, thyroid-binding globulin normally binds 70% to 80% of thyroxine, transthyretin binds 10% to 15%, and the rest is bound to albumin.3,24 Hence, these data suggest that T119M heterozygotes have increased total thyroxine levels attribut- able to an increased binding of thyroxine to transthyretin, but normal thyroid function. Results were similar after adjusting for age and sex by linear regression analysis (β-coefficient=18, corresponding to a mean increase in thyroxine of 18 nmol/L in heterozygotes versus noncarriers, P<0.0001; remaining

TTR T119M Genotype and Life Expectancy

In T119M heterozygotes versus noncarriers, median age at death was increased for all causes of death by 5 years (P=0.04), for death from vascular disease by 7 years (P=0.01), and for death from cerebrovascular disease by 10 years (P=0.03); age at death from nonvascular disease did not differ by genotype (P=0.61; Figure 5, left and middle). Furthermore, median age at death after diagnosis of vascular disease was increased by 7 years in heterozygotes versus noncarriers (P=0.002; Figure 5, right). Finally, median age at diagnosis of all vascular diseases and cardiovascular disease was increased by 7 and 8 years, respectively (Figure III in the online-only Data Supplement; P=0.05 and P=0.02), while the data suggested a similar trend for median age at diagnosis of cerebrovascular disease (P=0.59). Results were similar, but slightly attenuated, after adjusting for sex by linear regression analysis (P values for age at death, 0.01– 0.62; P values for age at disease, 0.06–0.75; data not shown).

TTR T119M Genotype and Risk of Vascular and Cerebrovascular Disease

Discussion

During a mean follow-up of 32 years (range, 0–34 years), the multifactorially adjusted (adjusted for age, sex, total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, body mass index, hypertension, diabetes mellitus, smoking, physical activity, lipid-lowering therapy, high-sensitivity C-reactive protein, and fibrinogen) hazard ratios for T119M heterozygotes versus noncarriers were 0.70 (95% confidence interval, 0.51–0.97; P=0.03) for all vascular disease, 0.85 (0.59–1.23; P=0.39) for cardiovascular disease, 0.45 (0.25–0.81; P=0.008) for cerebrovascular disease, 0.47 (0.25–0.88; P=0.02) for ischemic cerebrovascular disease, and

Our results were obtained in 2 similar prospective studies of the general population comprising 68 602 participants, includ- ing 321 heterozygotes for TTR T119M and 10 636 individuals with incident vascular disease.

The principal findings of this study are the following: (1) One in 200 individuals (0.47%) in a white general population is heterozygous for TTR T119M, a variant known to stabilize transthyretin tetramers and to increase binding of thyroxine in vitro; (2) T119M is associated with increases in transthyretin and total thyroxine levels in heterozygotes versus noncarriers,

P=0.63(nwsuoW oY Bulyejnus plosAyL25° ©a =e 10Ee ooP<0.00015 %q 2SY aQg a<fe.0 eo.SY. ~(squn Auesque)ys9}-aye}dN sulUOJAU}POIL |oO Sxy 8tlO “2.CO,7sc(7/JowWu) SUIUOIAUIPOILLCC CTCC CT

Figure 2. Plasma levels of thyroxine, thyroid stimulating hor- mone, triiodthyronine, and triiodthyronine uptake test in T119M heterozygotes vs noncarriers. Values are mean±standard error of the mean. CC indicates noncarriers; CT, T119M heterozy- gotes; and mIU/L, milli international units per liter. P values by Mann–Whitney U test.

providing direct evidence for the stabilizing function of this variant in the general population in vivo; (3) Genetic stabiliza- tion of transthyretin tetramers in T119M heterozygotes versus noncarriers is associated with reduced risk of vascular disease, mainly cerebrovascular disease; (4) T119M heterozygotes

have increased life expectancy overall and in those who die from vascular and cerebrovascular disease, increased life expectancy after diagnosis of vascular disease and increased age at diagnosis of vascular disease compared with noncarri- ers. These novel findings need to be confirmed in independent

No.of No.of Adjusted for ageAdjusted Hazard Ratio  Genotype Subjects Events and sex P-value multifactorially (95% Cl)All vascular cc 68,209 10,599 ’ 0.04 ? 1.0disease CT 319 37 0.70 (0.51-0.97)Cardiovascular cc 68,229 7,064 @ 0.44 ° 1.0disease CT 320 29 hen . heH 0.85 (0.59-1.23)Cerebrovascular CC 68,261 4,872 ° 0.008 @ 1.0disease CT 320 11 eH . eH 0.45 (0.25-0.81)Ischemic cerebro- CC 68,278 4,161 @ 0.02 ° 1.0vascular disease CT 321 10 eH : — 0.47 (0.25-0.88)Hemorrhagic CC 68,279 += 650 ° 0.24 ¢ 1.0stroke cT 321 1 ° 4 © 4 0.31 (0.04-2.22)t T T T 1 t T T T 1 0.1 0.2 0.4 1 2 4Hazard Ratio (95% Cl) 010204 14 2 4Hazard Ratio (95% Cl)P-value0.030.390.0080.020.24

Figure 3. Risk of all vascular disease, cardiovascular disease, cerebrovascular disease, ischemic cerebrovascular disease, and hemor- ragic stroke as a function of T119M genotype. CC indicates noncarriers; CI, confidence interval; and CT, T119M heterozygotes.