The phosphodiesterase 8B gene rs4704397 is associated with thyroid function, risk of myocardial infarction, and body height: the Tromsø study.
OBJECTIVE
High serum thyrotropin (TSH) levels predict cardiovascular disease (CVD). Recently several single nucleotide polymorphisms (SNPs) associated with TSH levels have been identified, one of them being the rs4704397 SNP in the phosphodiesterase 8B (PDE8B) gene. If the relation between thyroid function and CVD is causal, one could also expect rs4704397 genotypes to predict CVD and possibly health in general.


METHODS
DNA was prepared and genotyping performed for rs4704397 in subjects who participated in the fourth survey of the Tromsø Study in 1994-1995 and who were registered with the endpoints myocardial infarction (MI), type 2 diabetes (T2DM), cancer, or death, as well as a randomly selected control group. Similarly, genotyping was performed in subjects who had participated in clinical trials where serum TSH, free T4 (fT4), and free T3 (fT3) were measured.


RESULTS
From the Tromsø Study, 8938 subjects without thyroid disease or thyroid medication were successfully genotyped for rs4704397. Among these, 2098 were registered with MI, 1025 with T2DM, 2748 with cancer, and 3592 had died. The minor homozygote genotype (A:A) had a median serum TSH level that was 0.29 mIU/L higher than in the major homozygote genotype (G:G). The A:A genotype had a significantly increased risk of MI as compared to the G:G genotype (1.14 [1.00-1.29], hazard ratio [confidence interval], Cox regression with adjustment for age, sex, and body mass index). No significant associations were seen with the other endpoints or CVD risk factors. Furthermore, subjects with the G:G genotype were significantly taller than subjects with the A:A genotype (mean difference 1.5 cm). In 584 subjects with serum TSH, fT4, and fT3 measurements, the subjects with the A:A genotype had significantly higher serum TSH and nonsignificantly lower serum fT3 (mean difference 0.15 pmol/L) levels than subjects with the G:G genotype.


CONCLUSIONS
rs4704397 is associated with thyroid function, risk of MI, and body height. However, confirmation in other cohorts is needed before firm conclusions can be drawn.
1 Tromsø Endocrine Research Group, University of Tromsø , Tromsø, Norway .
Rolf
R
Jorde
Henrik
H
Schirmer
Tom
T
Wilsgaard
Ragnar Martin
RM
Joakimsen
Ellisiv Bøgeberg
EB
Mathiesen
Inger
I
Njølstad
Maja-Lisa
ML
Løchen
Yngve
Y
Figenschau
Johan
J
Svartberg
Moira Strand
MS
Hutchinson
Marie
M
Kjærgaard
Lone
L
Jørgensen
Guri
G
Grimnes
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000235:genetics*; D000328:Adult; D000368:Aged; D001827:Body Height; D002318:Cardiovascular Diseases / Q000209:etiology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000209:etiology; D009369:Neoplasms / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D013959:Thyroid Diseases / Q000503:physiopathology; D013961:Thyroid Gland / Q000503:physiopathology*; D013974:Thyroxine / Q000097:blood; D014284:Triiodothyronine / Q000097:blood
D014284:Triiodothyronine; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C468781:PDE8B protein, human; D013974:Thyroxine