A functional variant of the SIDT2 gene involved in cholesterol transport is associated with HDL-C levels and premature coronary artery disease

Low HDL-C is the most frequent dyslipidemia in Mexicans, but few studies have examined the underlying genetic basis. Moreover, few lipid-associated variants have been tested for coronary artery disease (CAD) in Hispanic populations. Here, we performed a GWAS for HDL-C levels in 2,183 Mexican individuals, identifying 7 loci , including three with genome-wide significance and containing the candidate genes CETP, ABCA1 and SIDT2 . The SIDT2 missense Val636Ile variant was associated with HDL-C levels for the first time, and this association was replicated in 3 independent cohorts ( P =5.5×10−21 in the conjoint analysis). The SIDT2 /Val636Ile variant is more frequent in Native American and derived populations than in other ethnic groups. This variant was also associated with increased ApoA1 and glycerophospholipid serum levels, decreased LDL-C and ApoB levels and a lower risk of premature CAD. Because SIDT2 was previously identified as a protein involved in sterol transport, we tested whether the SIDT2/Ile636 protein affected this function using an in vitro site-directed mutagenesis approach. The SIDT2/Ile636 protein showed increased uptake of the cholesterol analog dehydroergosterol, suggesting this variant is functional. Finally, liver transcriptome data from humans and the Hybrid Mouse Diversity Panel (HMDP) are consistent with the involvement of SIDT2 in lipid and lipoprotein metabolism. In conclusion, this is the first study assessing genetic variants contributing to HDL-C levels and coronary artery disease in the Mexican population. Our findings provide new insight into the genetic architecture of HDL-C and highlight SIDT2 as a new player in cholesterol and lipoprotein metabolism in humans. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by grants FOSISS-289699 and PEI-230129 from Mexican National Council for Science and Technology (CONACyT). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was conducted according to the principles expressed in the Declaration of Helsinki and was approved by the Ethics Committees of participant institutions. All adult participants provided written informed consent prior to inclusion in the study. For children, parents or guardians of each child signed the informed consent and children assented to participate. For Totonac and Nahua participants a translator was used as needed. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The datasets supporting the current study have not been deposited in a public repository because they are part of other studies in progress, but are available from the corresponding authors on reasonable request.