The Phosphodiesterase 8B Gene rs4704397 is Associated with Thyroid Function, Risk of Myocardial Infarction, and Body Height: The Tromsø Study

Abstract

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. Conclusion: 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.

Vitamin D Deficiency and Cardiovascular Disease: Potential Mechanisms and Novel Perspectives

“…Although Jorde et al (77) found no association between their investigated SNPs and myocardial infarction (among other outcomes), Levin et al (78) found that variations in the VDR gene may alter the association of 25(OH)D with major clinical outcomes, including myocardial infarction. While results of both studies were heavily supported by a large cohort size, their applicability to other populations is questionable on the basis that one study was confined to elderly white adults (78), whereas the other took place in Norway (77), the population of which does not possess a significantly lower 25(OH)D level compared to the rest of west Europe despite its latitude, and thus does not represent a vitamin D-depleted population. Nevertheless, it is abundantly clear that large-scale studies investigating different populations are warranted since SNPs in CYP2R1, CYP27B1 and DHCR7 have been associated with type 1 diabetes (79), warranting further investigations on diseases not covered by the previously conducted studies.…”

Once upon a Testis: The Tale of Cyclic Nucleotide Phosphodiesterase in Testicular Cancers

“…PDE8 is a highly selective cAMP hydrolyzing enzyme and consists of two genes, PDE8A and PDE8B that due to alternative splicing processes, generate five splice variants: PDE8A1-PDE8A5 and PDE8B1-PDE8B5 [117,118] (Figure 8). Both PDE8 genes are widely expressed in all steroidogenic cell types with PDE8A mostly expressed in the testis and T-cells and PDE8B mainly distributed in the brain and thyroid gland making PDE8 a key player in T-cell activation, thyroid hormones production, sperm and Leydig cell functions and cardiac functions [119,120]. Several studies investigated the role of PDE8 in the whole testis.…”

New aspects of an old dilemma: treatment of hypothyroidism with L-thyroxine combined with L-triiodothyronine

“…Recently, another SNP was identified which is associated with TSH levels, namely the rs4704397 SNP in the phosphodiesterase 8B (PDE8B) gene [32]. A large number of subjects (8938) of the Tromsø Study who were without thyroid disease or thyroid medication were successfully genotyped for rs4704397.…”