In the present case-control association studies, we evaluated the relationship of common SNPs with gout and their potential influence on CAD. The variants are located in nine different genetic regions, four of which are known and the remaining five loci were only recently identified to be associated with serum UA levels in a large meta-analysis of GWA studies 
. We were able to confirm significant association between gout and SNPs in two established genes, namely SLC2A9
(rs734553 and rs6855911) and ABCG2
(rs2231142). However, for markers in the other known and novel loci, no association with the clinical phenotype gout was found in our study. Moreover, our results indicate no relevant influence of the investigated polymorphisms on CAD susceptibility in our German MI Family Study.
The strongest association signal with gout was detected for intronic SNPs rs6855911 and rs734553 in the SLC2A9
gene, which is consistent with previous studies on gout and serum UA levels 
is coding for GLUT9, a high-capacity urate transporter, which is abundantly expressed in liver and kidney tissues 
. It is noteworthy that both SNPs located in SLC2A9
gene showed deviation from HWE in gout cases, which can in some degree support a true association 
In addition, we found a significant association between the exonic SNP rs2231142 in ABCG2
and gout, again supporting the results of a prior GWA on serum UA levels and gout 
. This is the only marker examined that leads to a missense mutation with an amino acid exchange from glutamine to lysine at position 141 in ABCG2 transporter and therefore could have a direct and causal influence on development of the disease 
. It is notable, however, that the effect of this variant on susceptibility to gout is only present in our male subcohort.
A recent meta-analysis documented an additional locus on chromosome 6p23-p21.3 encompassing three members of the solute carrier family 17 (SLC17A1, SLC17A3 and SLC17A4) to be associated with serum UA levels 
. Interestingly, their top marker rs1183201 in the SLC17A1
gene did not show significant association with the qualitative trait of gout in our study. Another SNP marker, rs1165205 in SLC17A3
, which is in strong LD with rs1183201 in SLC17A1
was previously found to be related to serum UA levels and also representing a risk factor for gout 
. A possible explanation for these discrepancies may lie in the different recruitment strategies of the study populations and the distinct definition of the phenotype “gout”. While Kolz et al. 
in their meta-analysis examined participants of European ancestry from 14 different study cohorts with widely varying initial inclusion criteria – potentially concealing a substructure which could lead to false positive results – our ascertainment approach was to recruit individuals with a strong familial history of CAD from all over Germany with a concomitant accumulation of cardiometabolic risk factors, such as gout. On the other hand, Deghan et al. 
included participants from three large population-based studies (Framingham cohort, Rotterdam cohort and the Atherosclerosis Risk in Communities (ARIC) study) with different definitions of gout in each of the study cohorts. It is important to notice, that the allele frequencies between Deghan et al. (rs1165205) 
, Kolz et al. 
and our present study (both rs1183201) did not differ substantially (47%, 48% and 48%, respectively).
The same might hold true for the other SNPs that were genotyped in our present study but showed no significant association with the phenotype gout. However, one has to emphasize that in our study, we explicitly investigated the role of SNP markers with clinically manifest gout or gouty arthritis, for which elevated serum UA levels are an important but not a mandatory risk factor 
. Therefore, differences in the pathophysiological pathways of the development of elevated serum UA levels and the ignition of the inflammatory process of gout or gouty arthritis may account for the distinct findings of our study. This is also reflected by the clinical observations that many patients with high serum UA levels never experience an attack of gout, whereas other people in the absence of hyperuricemia suffer from severe and recurrent flares of gouty arthritis 
. One can speculate that other pathophysiological mechanisms might be involved, or a complex interplay of genes and their variants lead to the manifestation of the disease. For example, the well-known URAT1 transporter, encoded by SLC22A12
gene, is involved in renal urate exchange 
, and a SLC22A12
polymorphism is also linked to serum UA levels 
. Therefore, this gene is a strong candidate for gout, but does not show significant association with the clinical phenotype in this and a previous study 
. Another possible explanation is the small effect size of some polymorphisms on serum UA levels that could directly impact susceptibility to gout. Our present study showed a high degree of association between gout and SNPs in ABCG2
, those polymorphisms that were reported to have highest effects on serum UA levels found in the previous meta-analysis (explaining 0.57% and 3.53% of variability, respectively) 
and that showed ORs for gout between 1.37 and 1.52 in our study. All other SNPs were significant on a genome-wide level, but explained less the variability of serum UA levels (below 0.2%) 
. Therefore, either power was not sufficient for detection of association between these SNPs and gout in the present study, or their relevance on the clinical phenotype gout is not evident.
Additionally, we found only weak epistatic interaction between SNPs in SLC2A9 and LRRC16A on gout, making a relevant additive effect of SNPs influencing serum UA levels on the qualitative trait unlikely. Potential confounders, such as different medications and prevalence of type 2 diabetes, smoking or BMI, did not influence the association results significantly. Taken together, it is obvious that SNPs with highest influence on serum UA levels could be directly linked to susceptibility to gout, whereas the relevance of less contributing polymorphisms is still arguable.
More complex functional studies are warranted in the future to elucidate the pathways with which the newly identified genes impact serum UA levels and development of gout.
Furthermore, the presence of hyperuricemia and gout has often been discussed to be a cardiovascular risk factor 
. We thus examined the SNPs being associated with elevated UA serum levels in our second case-control study consisting of CAD cases and controls from the general population. Here, we did not detect a direct genetic relationship between the tested SNPs and CAD. One possible explanation may be limited power: polymorphisms with a small effect on disease susceptibility require very large study samples to be detected. Therefore, we cannot rule out a causal link between the SNPs influencing serum UA levels and CAD. On the other hand, CAD is possibly a more heterogeneous disorder than gout, even on genetic level. For example, no genes known to influence serum UA levels were identified by recent GWA studies on CAD, but genetic loci involved in several different pathways were found 
There are limitations in our study design that have to be considered. First, we do not have measurement of serum UA levels in our cohort. Hence, we can not directly replicate the findings of Kolz et al. on serum UA levels 
. However, we did not aim in replication of serum UA level association but in expansion of these results to clinical manifestation of the phenotypes gout and CAD. Second, all phenotypes were assessed retrospectively from patient documentations and medical history readings. When gout was diagnosed by a physician according to ICD-9 code 274, the phenotype gout was considered as confirmed. In case of self-reported gout, additional intake of uricostatic or uricosuric medication was required to affirm the diagnosis of gout. We have follow-up data from more than 80% of our study participants and, therefore, validation of clinicial phenotypes is available. Third, the power to analyze gender effects in our study is limited. As previously described, association of serum UA levels depends to some degree on gender 
. Our findings on gender-specific association between male but not female gout patients and rs2231142 in ABCG2
gene are likely to be true positive results but some other gender effects may have been overlooked. Forth, assuming that gout is a risk factor for CAD, we expected to observe significantly more CAD patients in the gout sample than in gout-free controls. However, based on our initial ascertainment strategy where we retrospectively identified gout patients and gout-free controls from a MI/CAD study cohort, we did not find a significant coincidence of CAD and gout. On the other hand, in our CAD case-control sample we found that the clinical phenotype of gout seems to be associated with CAD.
In conclusion, we performed a comprehensive analysis on association with susceptibility to gout and CAD of recently published polymorphisms known to be linked with serum UA levels. Markers in SLC2A9 and ABCG2 genes are strongly associated with clinical manifestation of gout in the German MI Family Study. With the knowledge of a comprehensive number of genetic polymorphisms contributing to gout, genetic testing as a supportive diagnostic tool would be conceivable.