Hispanic populations, such as Mexicans, have been mainly ignored in large scale genetic studies for cardiovascular risk factors as well as other common diseases, although the Mexican population has an increased predisposition to several forms of dyslipidemias (low HDL-C and high TGs) and premature CAD.2-4
The current study evaluated whether 15 associations identified in recent Caucasian GWAS5-7
with HDL-C or TGs also confer risk in the Mexican population. Association at nominal level (P ≤ 0.05) was observed for 10 of the loci, of which half were also significant after adjusting for multiple comparisons. Importantly, we also demonstrate that two associated SNPs are more prevalent in the Mexican population, and thus may confer to the increased predisposition to these forms of dyslipidemia in Mexicans.
Mexicans descend from a recent mix of Amerindian and European ancestry which led to marked differences in allelic frequencies and patterns of LD across their genome.31,32
Our strongest association signal (P = 2.60 × 10-11
) was obtained for the minor allele of rs964184 near the APOA1/C3/A4/A5 cluster that is significantly more prevalent in Mexicans (27%) than in Caucasians (12%). The strength of this association even surpassed the stringent criteria for declaring genome-wide significance22
(P < 5 × 10-8
) with only 2,298 individuals studied. This finding clearly demonstrates that even if a variant has an effect in all ancestry groups, it might be more prevalent in one population. Furthermore, this finding suggests that depending on its frequency, the contribution of each locus to disease susceptibility may vary between populations, and hence the implications of SNPs to public health can differ between populations.
The association signals (P ≤ 0.05) were all for the same risk allele as in Caucasians5-7
except for rs10096633, downstream of the LPL gene, that was significant for the opposite allele as in Caucasians.6
Although the allele frequency of rs10096633 was not significantly different between Mexicans and Europeans (P = 0.8), we show that the LD structure surrounding rs10096633 varies between the two populations. This finding suggests that rs10096633 is not the causal variant and that given the altered LD, future studies in Mexicans could assist in fine-mapping the actual functional variant in this locus. Conversely, SNP rs964184 near the APOA1/C3/A4/A5 gene cluster may be the actual susceptibility variant, as in both populations this SNP is a singleton (all pairwise r2
< 0.7) and strongly associated with TGs despite the large difference in allele frequency. Nevertheless, deep resequencing in the rs964184 region is needed in order to conclude that this SNP is the sole signal.
Although the genes of the APOA1/C3/A4/A5 cluster (≥ 11 kb away) are the most plausible candidates in the region of rs964184, this variant resides in the 5′ UTR of a zinc finger protein (ZPR1) that may be involved in cell proliferation and signal transduction.36
Hence, functional studies are warranted to establish the actual causal gene and the consequences of this variant. Regarding the other significant (i.e. Bonferroni correction) variants, SNP rs4846914 resides in the first intron of GALNT2. There are several SNPs redundant to rs4846914 (r2
≥ 0.7) all located within the first intron. First introns are known to harbor many regulatory elements.37
Accordingly, all of these variants in LD should be tested for potential regulatory effect. Similarly, rs3764261 resides 2.5kb upstream of CETP. This SNP is in high LD with variants located 1-8 kb from the transcriptional start site of CETP. Thus, these variants and their haplotypes should also be investigated in functional studies. On the other hand, SNP rs1260326 is a missense variant (P446L) in GCKR, and recent in-vitro experiments have shown that this amino-acid substitution affects glucose and TG levels through increased GCK activity in the liver.13
To screen for association signals, we also used family-based association method that is robust to population admixture,33
such as in Mexicans.31,32
Furthermore, we examined whether the associations were influenced by global ancestry using European/Amerindian informative markers. To reduce sources of heterogeneity, both the dyslipidemic families and case/control study sample were recruited by the same dyslipidemia clinic. We recognize that differences in ascertainment criteria may have potentially caused heterogeneity. For instance the common allele of rs2083637 near the LPL gene was associated with HDL-C (P = 3.85 × 10-3
) in the case-control samples, as in Caucasians,7
while the opposite allele was implicated in the FCHL families (P = 2.65 × 10-2
), suggesting that a different variant(s) in LPL may be involved in FCHL.38
Nevertheless, we feel that a more reliable conformation was obtained by utilizing a variety of resources that includes dyslipidemic families with multiple affected individuals and unrelated hypertriglyceridemic case/control individuals.
As our sample size was not sufficiently powered for rare variants and small genetic effects (OR <1.3) we have not attempted to investigate confirmed associations with MAF less than 10% in the Mexican-American data of HapMap. Hence, given our relatively small sample size the remaining loci and those that did not replicate in this study will require comprehensive investigation using larger samples to exclude or verify their significance in Mexicans. Future GWAS in Mexicans should further assist in fine-mapping the causal variant(s) in these known loci as well as reveal novel susceptibility alleles.
In summary, this is the first study to present association signals of susceptibility variants from Caucasian GWAS for lipids in Mexicans. Furthermore, thus far all GWAS for lipids have examined study samples that were not ascertained for dyslipidemia. Hence, to the best of our knowledge this is also the first study to report the effect of these variants in dyslipidemic individuals.