3.1. Single-locus analysis in the MADT Cohort

From this GLM model, considering age, gender and BMI as covariates, the global score statistic in the MADT Cohort was 9.54 (p = 0.410). The analysis of the scores associated with each haplotype indicated that the haplotype AAAG was significantly

Table 2 reports for each UCP3 SNP the test statistics for the different genetic models (dominant, additive and recessive) obtained in the MADT Cohort with the relevant p-values.

 

Fig. 1. LD structures of UCP3 SNPs in the 1905 (a) and MADT (B) Cohort.

Table 2

Results of the F association tests between the analyzed polymorphisms (risk allele in parenthesis) and the hand grip max

SNP Additive model Dominant model Recessive model F pc max Fa b p b F b p F b p b b b rs647126 (A) 488.75 0.740 0.035 488.78 1.116 0.034 486.01 0.773 0.215 488.78 0.075 rs1685354 (G) 484.85 (cid:4)0.223 0.578 484.78 0.238 0.626 490.28 (cid:4)2.528 0.014 490.28 0.029 rs3781907 (G) 486.78 (cid:4)0.577 0.124 485.87 (cid:4)0.579 0.237 486.39 (cid:4)1.159 0.163 486.78 0.230 rs11235972 (A) 485.37 (cid:4)0.364 0.354 484.87 (cid:4)0.281 0.566 485.79 (cid:4)1.099 0.253 485.79 0.451

a F-statistics under the additive, dominant and recessive models. b p-values of the regression coefficients associated with the analyzed polymorphism under the three genetic models. c p-valueadjustedformultipletestingofdifferentgeneticmodels(basedon10,000randompermutations),obtainedusingtheapproachproposedbyLettreetal.,2007(see 2).

Table 3

Estimation of haplotype frequencies in the UCP3 SNPs and association with hand grip performance in MADT Cohort.

Haplotype rs647126 rs1685354 rs3781907 rs11235972 Freq.a Score pb GAGA G A G A 0.21491 (cid:4)1.33136 0.182 AAGG A A G G 0.05587 (cid:4)1.23035 0.208 GAGG G A G G 0.01512 (cid:4)0.60371 0.558 GGAG G G A G 0.25016 (cid:4)0.60117 0.549 GAAG G A A G 0.04281 (cid:4)0.58967 0.546 GAAA G A A A 0.02988 (cid:4)0.44337 0.655 GGGG G G G G 0.00715 0.08633 0.930 AAGA A A G A 0.01973 1.23184 0.218 AAAG A A A G 0.35878 2.33717 0.019

a Estimated haplotype frequency. b Monte-Carlo p-value from 106 replications.

associated with higher HG scores (p = 0.019). Consistently with the single locus analysis, we found that SNP combinations including significant alleles resulted in significantly different haplotypic effects on the HG performances.

From this GLM model, considering gender and BMI as covariates, the global score statistic was 19.76 (p = 0.090). The data reported in Table 5 indicates that haplotypes GAGA, GAAA, GGAG and GGGG were significantly associated with the HG performance in this sample. In particular, haplotypes GAGA (p = 0.008) and GAAA (p = 0.068) points to be associated with lower HG scores, while haplotypes GGAG (p = 0.051) and GGGG (p = 0.029) were associated to higher scores. Also in this case we found that SNP combinations directly including alleles showing significant single-locus associations resulted in significantly different haplotype effects on the HG performances.

Table 4 reports for each UCP3 SNP the test statistics for the different genetic models with the relevant p-values as obtained in the 1905 Cohort.

The table clearly shows that the rs11235972 and rs1685354 variations had significant effects on the HG performance. In fact, as it regards for the rs11235972 variation, subjects carrying the A allele (dominant model) showed lower HG scores than those homozygotes for the G allele (p < 0.001), whereas for the rs1685354 variation, the comparison of the F statistics makes the additive model the most plausible, indicating that carrying the G allele positively influenced the HG scores in an additive manner.

3.5. Survival analysis

Table 6 reports the estimated parameters of the fitted AFT models in the 1905 Cohort, including sex and the different SNPs as covariates.

In Table 6 a positive coefficient indicates that an increment of the respective factor is associated with higher survival chances; conversely for negative coefficients. After 10 years, a significant effect on survival chances was observed for rs11235972 and rs3781907 (p = 0.029 and p = 0.050, respectively). In particular, since in these models each SNP was coded as 0,1 or 2 according to the count of the minor (less frequent) allele in the genotype,

Table 5 reports the estimation of the haplotype frequencies of the combined UCP3 SNPs and their association with the HG performance in the 1905 Cohort.

Table 4

Results of the F association tests with respect to the analyzed polymorphisms (risk allele in parenthesis) in the 1905 Cohort. max

SNP Additive model Dominant model Recessive model F pc max Fa b p b F b p F b p b b b rs647126 (A) 201.54 0.153 0.542 201.44 (cid:4)0.161 0.670 202.71 0.692 0.116 202.71 0.225 rs1685354 (G) 204.54 0.648 0.016 203.62 0.699 0.043 203.41 1.236 0.054 204.55 0.037 rs3781907 (G) 202.98 (cid:4)0.454 0.086 203.28 (cid:4)0.643 0.062 201.55 (cid:4)0.370 0.531 203.28 0.120 rs11235972 (A) 206.60 (cid:4)0.844 0.002 207.47 (cid:4)1.139 < 0.001 201.92 (cid:4)0.685 0.305 207.47 0.002

a F-statistics under the additive, dominant and recessive models. b p-values of the regression coefficients associated with the analyzed polymorphism under the three .genetic models. c p-value adjusted for multiple testing of different genetic models (based on 10,000 random permutations), obtained using the approach proposed by Lettre et al. (2007) (see Section 2).

Table 5

Estimation of haplotype frequencies in the UCP3 SNPs and association with hand grip performance in 1905 Cohort.