There were no significant differences in allelic or genotype frequencies of the 30 FTO
SNPs between the obese and non-obese groups in the Malaysian Malay population. Recent studies have pointed out that the SNPs in the FTO
gene contribute to obesity and obesity-related traits in various populations around the globe (1
). Single-marker analysis revealed that rs17817288 was significantly associated with LDL-C levels (P = 0.001) in Malaysian Malays. A recent study (22
) showed that, as a transcriptional coactivator, FTO
might play an important role in the transcriptional regulation of adipogenesis and suggested that FTO
might be involved in the regulation of fat development and maintenance. Therefore, we speculated that the FTO
rs17817288 SNP may have an effect on adipogenesis in Malaysian Malays, which is consistent with findings by Wu et al. (22
) concerning the functional effects of the FTO
gene. The FTO
rs9939609 SNP was chosen as representative of FTO
SNPs in the present study because this locus was highlighted in many studies as having the strongest effect on obesity; it was also the key signal identified in the GWAS (1
). A meta-analysis reported that 21 of 29 studies have shown a significant association between obesity and rs9939609 (5
). However, this SNP had no effect on obesity in the Malaysian Malay population.
A meta-analysis reported that the minor allele frequency (MAF) for rs9939609 varies across the global population. The MAF of the FTO
rs9939609 polymorphism was lower (0.31) in the Malaysian Malay population compared to the previously reported range of 0.38 to 0.46 in European populations (1
). For example, the MAF was 0.31 to 0.37 in Hispanics, 0.34 to 0.44 in Caucasians, 0.17 in South Americans, 0.36 in Africans, 0.11 to 0.20 in Asians, 0.25 in Singaporean Malays, 0.13 in Singaporean Chinese, and 0.42 in Singaporean Indians (5
). In addition, the MAF for rs1421085, rs1558902, rs17817449, rs3751812, rs9939609, and rs8050136 was similar across these six SNPs. The MAF for the SNPs is 0.31.
We investigated the LD structure of the FTO
SNPs in Malaysian Malays. Linkage analysis showed 57 regions with complete LD in the FTO
gene. Our results showed that 15 of the 30 FTO
SNPs (50%) are in high LD (D ≥ 0.88) with rs9939609. This indicates that the FTO
SNPs in the first intron of the FTO
gene are high in LD in Malaysian Malays. In our samples, three SNPs, rs9935401, rs16945088, and rs10852521 (D' = 1.0), were in complete LD with rs9939609. In the HapMap sample of Utah residents with ancestry from northern and western Europe (CEU), the three SNPs rs10852521, rs16945088, and rs9935401 are in complete LD (D' = 1.0) with rs9939609, as observed in our sample of Malaysian Malays. In contrast, in the HapMap sample of Yoruba in Ibadan, Nigeria (YRI), the rs9939609 at rs10852521 is not in strong LD (D' = 0.48). Complete LD (D = 1.0) with rs9939609 at rs16945088 and at rs17817449 has been shown in HapMap samples of African ancestry in Southwest USA (ASW); Utah residents with northern and western European ancestry (CEU); Han Chinese in Beijing, China (CHB); Chinese in Metropolitan Denver, Colorado (CHD); Gujarati Indians in Houston, Texas (GIH); Japanese in Tokyo, Japan (JPT); Luhya in Webuye, Kenya (LWK); Mexican ancestry in Los Angeles, California (MEX); Tuscans in Italy (TSI), and Yoruba in Ibadan, Nigeria (YRI). A similar LD strength was observed in our samples of Malaysian Malays. Interestingly, results from HapMap samples show that rs9939609 is in complete LD with rs10852521 with samples from Asia (JPT, CHD, and CHB), which was also replicated in our samples of Malaysian Malays. In contrast, the strength of LD of rs9939609 at rs10852521 is reduced in samples of African ancestry such as YRI, ASW, LWK, and Maasai in Kinyawa, Kenya (MKK; D > 0.35) (31
The Singaporean Genome Variation Project analyzed the LD in 98 Singaporean Malays (MAS) with the Affymetric Genome-Wide Human SNP Array and the Illumina Human1M single-sample BeadChip genotyping platforms (29
). In our study, we found that the LD pattern of all regions with complete LD in Malaysian Malays was similar to the MAS samples except for rs17218700 and rs7190492. The LD of rs17218700 with rs7190492 was lower in the MAS samples (D' = 0.74) compared with those in our study. By using the Sequenom MassARRAY®
iPLEX platform with a much larger sample size (N = 587), we found that the LD pattern from our own data for Malaysian Malays is very similar to that of the MAS samples. Therefore, we can predict a similar pattern of LD in the FTO
gene ancestry of Malays in Southeast Asia because of the genetic homogeneity. Further studies will be needed to address this pattern in Malays in other parts of Southeast Asia.
Differences exist in the LD structure of the FTO
gene in diverse ethnic populations (5
). For example, previous studies have shown that the degree of LD in a population with African ancestry is lower than that in European populations (32
). Recent studies have reported that the genetic variability in the FTO
gene that is in high LD are associated with a risk of obesity in Spanish (33
) and African Americans (27
). Our study showed novel patterns of LD in the FTO
gene ancestry of Malaysian Malays.
Most FTO haplotypes were found to have frequencies of more than 5% in Malaysian Malays. We identified major haplotypes in people of Malaysian Malay ancestry that may also be present in Malays in other parts of Southeast Asia. Studies of different populations will be needed, however, to confirm this finding. The haplotypes in block 1 and block 2 of the FTO gene were not associated with obesity in Malaysian Malays.
Previous studies on the association of the FTO
gene with obesity included between 240 and 5380 subjects from populations across the globe (5
). Although the sample investigated in the present study was of moderate size in comparison with other studies, this study was sufficiently powered with the population of Malaysian Malays. Since the participants of this study are middle-aged and elderly individuals, these findings cannot be generally extrapolated to children and adolescents in Malaysia. This study was conducted in Malaysian Malays, and we cannot generalize these findings to overall Malaysian populations such as Chinese, Indians and other ethnic groups in Malaysia. Therefore, large-scale genetic association studies on FTO
should be carried out in future in other ethnic groups within the Malaysian population.
To the best of our knowledge, this is the first study on genetic variants in the FTO gene in Malaysian Malays. We conclude that the genetic variations in the FTO gene are in high LD in this ethnic group. Two haplotype blocks of FTO were identified, neither of which confers an increased risk for obesity in this population. We detected the association of rs17817288 with LDL-C, and this SNP may be involved in lipid metabolism in Malaysian Malays. Replication of this association in larger samples and in functional molecular studies will further increase the validity of this association and the causative relationship between the FTO variant and LDL-C.