The results of this study did not support an assoiation between APOM and T2D suseptibility in Hong Kong Chinese. For a subset of SNPs, we presented evidence of association between APOM and disease duration as well as metabolic traits in T2D patients. Further characterization of rs707922, one of the metabolic trait-associated SNP at molecular level lead to the discoveries of a novel transcript APOM5 and its SNP-dependent effect on cellular cholesterol content.
The LD block formed among rs805264, rs707922, and rs707921 in our cohort agreed with the LD structure reported in the Northern Chinese 
. It is currently unknown whether this subset of SNPs is also associated with metabolic traits in Northern Chinese with T2D. Among the four common haplotypes constructed from rs805297, rs9404941, and rs707922, only homozygous haplotype C-T-T was significantly associated with higher TC, LDL-C and HbA1c levels in T2D patients. Given the established association between rs7070922 and plasma TC and LDL-C levels, these association results did not support additional effects of the haplotypes on serum cholesterol levels. Interestingly, the association between the homozygous haplotype C-T-T with HbA1c indicated the interaction among the three alleles to control systemic glucose level in T2D patients.
It would have been ideal if the previously reported association between SNP rs805296(T-778C) and T2D in Northern Chinese were reproduced in this Hong Kong Chinese population. Unfortunately, genotyping of this SNP failed to produce results in this study, precluding it being used for discussions attempting to reconcile the current findings with prior results. Although rs805296 is physically close to rs9404941, the existing information/data does not allow the relationship between SNP rs805296 and T2D/T2D metabolic traits to be predicted in our cohort.
It is noteworthy that the case-control study design adopted by the current and other studies tend to be limited by the heterogeneity of the prevalent cases with regards to T2D ascertainment, i.e., both those have developed T2D and those have survived in the setting of T2D were included as cases. Therefore, those ‘susceptible to’ the disease were not distinguished from those ‘survived’ the disease'. One possibility to circumvent such issue is to examine for similar duration of diabetes across studies being compared and test for difference in duration of T2D by SNP. Interestingly, while our results did not support an association between APOM
and T2D susceptibility, stratification of our cases by disease duration allowed us to detect an association between rs805297(C-1065A) and T2D duration. This result implied the possibility that relative to the rs805297-A carriers, the rs805297-C carriers better survived the diabetic condition over the long term and such possibility can be further tested. Interestingly, Zhao et al., recently reported a positive association between rs805297-A and the risk of stroke in Norhtern Chinese (OR
0.002) after adjusting for other risk factors including history of diabetes 
. Whether such association is present among the Southern Chinese requires further investigation. Nevertheless, losing rs805297-A carriers with T2D to stroke over time provides a plausible explanation for the observed higher frequency of rs805297-C allele in the T2D duration >10 years subgroup (relative to T2D duration ≤10 years subgroup).
Previous studies attempting to correlate plasma apoM and cholesterol levels have generated inconsistent results 
. In this study, rs707922 homozygous minor allele (TT) was associated with elevated TC and LDL-C as well as plasma apoM levels in diabetic cases (average BMI of 25.26). These observations are consistent with previously reported positive association between plasma apoM and plasma TC and LDL-C in overweight-obese individuals 
. Results presented by Han et al. from the study of a Northern Chinese cohort showed significant association between rs707922 T allele and increased risk of cerebral infraction (OR
0.000). In parallel they also confirmed hypercholesterolemia as an independent risk factor for cerebral infraction 
. These results implied the possibility that rs707922 is also a modifier of serum cholesterol in Northern Chinese. The association between rs707922 TT genotype and elevated serum total-/LDL- cholesterol levels in type 2 diabetes found in the current report deserves to be further substantiated in strict replicate studies.
The mechanism underlying the effects of rs707922 on plasma TC and LDL-C levels in diabetes remains elusive. Richter et al., reported HNF-1 alpha being a potent transcription activator of APOM 
. The decreased serum apoM level in maturity-onset diabetes of the young subjects as compared to the controls could be explained by the HNF-1 alpha mutations in these patients 
. Given the association between APOM
and metabolic traits found in this study, one may speculate that SNP rs707922 (G+1837T), in the capacity of an intronic SNP (reference to the APOM1
transcript), may modify APOM
expression through SNP-specific recruitment of transcription factors (i.e., PAX 6 showed an allele-specific interaction with rs707922 T by computer prediction as presented in Supplementary Figure S5
) and subsequently affect cellular cholesterol homeostasis in liver and possibly other tissues. More interestingly, we found that rs707922 can also assume the capacity as an exonic SNP (i.e., reference to the APOM5
transcript). While the function of APOM5
requires further elucidation, the high renal and hepatic expression levels of APOM1
indicated the possibility of these transcripts coordinate to regulate cholesterol homeostasis in these tissues. Such possibility is further supported by the results showing the activities of ectopically expressed APOM5
in modifying hepatic cell cholesterol content. With regards to systematic cholesterol homeostasis, we observed that homozygous rs707922-T allele associated with elevated total- and LDL-cholesterol levels. One possible mechanism of such elevation is through reducd hepatic and/or pheripheral clearance of circulating cholesterol. Consistent with this notion, our in vitro
data showed that hepatic cells over-expressing APOM5-T
transcript had lower cholesterol content relative to cells expressing the APOM5-G
In conclusion, the APOM SNP frequencies and the LD structure reported in this study of Hong Kong Chinese population will facilitate future population genetics studies. While our results did not support an association between APOM and T2D susceptibility in Hong Kong Chinese, subgroup analyses found SNP as well as haplotype associations between APOM and metabolic traits in T2D. Bioinformatics/molecular analyses revealed the cryptic nature of exon 5 responsible for the expression of a novel transcript APOM5, predominantly in liver and kidney. The activity of APOM5 on modifying cellular cholesterol content revealed another layer of regulation underlying the expression and function of APOM.