Haplotype Structures Covering the UGT1A Gene and Ethnic Differences

As the importance of haplotype analysis in pharmacogenetic studies has been recognized, the analysis of UGT1A genes, particularly the 1A1 segment, has been conducted for irinotecan-pharmacogenetics in several ethnic populations. The first haplotype analysis of the UGT1A1 enhancer (PBREM)/promoter region was conducted by Innocenti et al. using hepatic samples from 55 Caucasians and 37 African-Americans (37). This

Table l

UGTlA Genetic Variations Described in this Chapter

Allelesa

Region

Nucleotide change Amino acid Phenotype change

Enzymatic activity in vitro in vivo

Reference No.

to vi to

Exon 1 Exon 5 Exon 1

Promoter

A(TA)nTAA Promoter

A(TA)nTAA Promoter

A(TA)nTAA PBREM

PBREM

211 G>A

1456T>G

686C>A

-3279T>G

G71R CN2, Gilbert Reduced

Y486D CN2 Reduced

P229Q Gilbert

Gilbert

Gilbert

Reduced or

No change Reduced

Increased

Reduced

Reduced

Reduced Unknown

28 16

to vi

UGT1A7 *2 Exon 1

UGT1A9 *1b(*22)b Promoter

Exon 1 Exon 1 Intron Exon 1

387T>G/391C>A N129K/R131K

387T>G/391C>A/ N129K/R131K/

622T>C W208R

622T>C W208R

98T>C 766 G>A I399C>T 605C>T

M33T D256N

T202I

Reduced or

No change Reduced

Reduced Increased

Reduced Reduced

Reduced

No change,

Increased or 44, 45, 51 Reduced

35 45

Increased a UGT Alleles Nomemclature (http://www.pharmacogenomics.pha.ulaval.ca/sgc/ugt_alleles/site/pharmacogenomics; as of August 15, 2007). b Original names are described in paretheses.

PBREM, phenobarbital-responsive enhancer module; Gilbert, Gilbert syndrome; CN2, Crigler-Najjar syndrome type II.

study revealed a close linkage between the (TA)7 polymorphism (*28), -3279T>G(*60) and-3156 G>A.

The frequencies of the 10 haplotypes identified in the study differed between the two ethnic groups (Fig. 3). Haplotype analysis of UGT1A1 in 195 Japanese subjects defined four haplotype groups in the 1A1 segment according to the *1, *60, *6, and *28 marker alleles (38) (Fig. 3). Close linkages among -3279T>G (*60), -3156 G>A and (TA)7 (*28) were also observed in the Japanese subjects (haplotype *28b), but the TA repeat variations were less frequent than in Caucasians and African-Americans (38). This study also revealed that the *6 allele [211 G>A (G71R)], specific for East Asians, was independent of the *28 allele, while the *27 allele [686C>A(P229Q)], another rare non-synonymous variation in Asians, was completely linked to the *28 allele; therefore, this haplotype was designated as a *28 group member (*28c).

Haplotypes with the *60 allele (-3279T>G) in the absence of the *28 allele were defined as the *60 haplotype group (Fig. 3). Racial differences in the occurrence of UGT1A1 haplotypes were investigated among Caucasians, African-Americans, and Japanese for each 150 subjects (39). The *6 haplotype was detected only in the Japanese, while the frequencies of the *28 group in Caucasians and African-Americans were 3.9-and 4.5-fold higher, respectively, than in the Japanese population. The other TA variant haplotypes, *36b [including (TA)5] and *37b [including (TA)8], were observed only in Caucasians and African-Americans (Fig. 3).

Regarding the haplotypes covering exons 25 (Block C), the haplotypes harboring three linked SNPs in the 3'-UTR (1813C>T, 1941 C>G and 2042 C>G) were originally identified in the Japanese population and named *IB (38). The frequency of *IB was much higher in African-Americans (18.3%) and Caucasians (15.7%) subjects than in the Japanese (9.7%) (39).

Comprehensive haplotype analysis throughout the UGT1A gene complex was conducted for 196 Japanese subjects (40), and the combinatorial haplotypes among 1A9, 1A7 and 1A1 were estimated. This study revealed close linkages between 1A9*1b(*22) [-118(T)10] and 1A7*1; between 1A7*2 and the 1A1*60 haplotype (without the *28 allele); and between 1A7*3 and 1A1*6 or 1A1*28 in the Japanese population. The five major combinatorial haplotypes (1A9-1A7-1A1) consisted of *1b(*22)-*1-*1, *1-*3-*6, *1-*2-*60, *1b(*22)-*1-*28 and *1-*3-*28 at frequencies of 58%, 13%, 11%, 6%, and 6%, respectively (Table 2A). An investigation of the haplotype structure among the 1A9, 1A7 and 1A1 polymorphisms in 81 Korean cancer patients found comparable structures between the two Asian populations (40,41).

Linkages among the functional polymorphisms across the UGT1A segments were also shown in Caucasians and other ethnic populations. Kohle et al. investigated the linkages among the polymorphisms of 1A7, 1A6, and 1A1 for 100 Caucasians and 50 Egyptians, and reported a close linkage between the UGT1A1*28 [(TA)7] and UGT1A7*3 alleles (42). The frequencies of the combinatorial haplotype 1A7*3-1A1*28 were 28.5% in Caucasians and 21.8% in Egyptians. Perfect linkage of the low-activity 1A7 alleles (1A7*2 and 1A7*3) with the 1A9*1 allele [-118(T)9], and vice versa 1A7*1 with 1A9*1b(*22) [-118(T)10], were also found in a group of 66 cancer patients consisting of 55 Caucasians (43).

In this study, the frequencies of the combinatorial haplotypes of 1A9*1 [-118(T)9]-1A7*2, 1A9*1 [-118(T)9]-1A7*3, and 1A9*1b(*22) [-118(T)10]-1A7*1 were 25.8%, to

Region

PB REM

Promoter (TATA box)

Exon 1

Nucleotide change Amino acid chanqe

-3279 T>G

(TA)5

(TA)7

(TA}8

211G>A G71R

6860A P223Q

Marker allelea

'60

*36

•28

•37

'6

1

*1a

*60a

*28

'28b °

*28cc

•28d

16b

*37b

*6

•6a

*6d

Haplotype frequency11

Caucasian

African American

Japanese

(N=5S)8

(N=147) '

(N=37)°

(N=149)'

(N=195)s

(N=150)'

0.530

0.451

0.150

0.150

0.582

0.610

0.090

0.135

0.330

0.296

0.136

0.145

0.360

0,389

0.350

0.446

0.121

0.097

NDh

0.000

NDh

0.000

0.005

0.003

O.OOO

0.000

0.000

0.000

0.005

0.000

0.010

0,017

0.040

0.044

0.000

0.000

0.010

0.007

0.120

0.065

0.000

0.000

NDh

O.OOO

ND h

O.OOO

0.151

0.141

ND*

O.OOO

NDh

0.000

O.OOO

0.003

Fig. 3. UGT1A1 haplotype frequencies in three ethnic populations. (a) UGT allele nomenclature (http://www.pharmacogenomics.pha.ulaval.ca/sgc/ ugt_alleles/site/pharmacogenomics; as of August 15, 2007). (b) Definition by Kaniwa et al. (2005) (39). (c) The *28b and *28c haplotypes harbor -3156 G> A in addition to -3279 T>G. (d) Data in the literature were used to determine frequencies according to the haplotype definition of Kaniwa et al. (2005) (39). (e) Innocenti et al. (2002) (37). One subject with *36b was excluded from the haplotype analysis. (f) Kaniwa et al. (2005) (39). (g) Sai et al. (2004) (38). (h) 211 G>A (G71R) and 686C>C (P229Q) were not genotyped. N: The number of subjects is described in parentheses.

Table 2

Combinatorial Haplotypes Among UGT1A1, 1A7 and 1A9

(A) Combinatorial haplotypes of 1A9, 1A7 and 1A1: (B) Combinatorial haplotypes of 1A9 and 1A1:

Comparison between Koreans and Japanese Comparison between Caucasians and Asians

Combinatorial haplotype Haplotype frequency a Combinatorial haplotype Haplotype frequencya

1A9 - 1A7 - 1A1 Koreanb Japanesec 1A9 - 1A1 Caucasiand Asiand

*1b(*22/ - *1 - *1 47.5 58.3 *1b(*22) - *1 36.8 45.3

6 other combinations *60 2.4 1.4 *1b(*22) *60 1.1 1.0

*1b(*22) - *1 - *28 4.9 7.3 5.6 12.5 *1b(*22) - *28 1.5 34.0 6.7 11.0

other combinations *28 1.8 1.1

N: The number of subjects is described in parentheses.

a Data in the literature were used to determine frequencies according to the haplotype definition of Saeki et al. (2006) (40). b Hanetal. (2006) (41). c Saeki et al. (2006) (40). d Innocenti et al. (2005) (44).

e A mixed population that included 110 Chinese, 20 Tiwanese and 10 Japanese. f 1A9*1bwas originally named 1A9*22.

31.1%, and 43.2%, respectively. Innocenti et al. investigated the combinatorial haplotypes for 1A9 and 1A1 in 132 Caucasians and 150 Asians, and showed the distinct haplotype structures among two ethnic groups (44). The most common three haplotypes were 1A9*1b (*22)[-118(T)10]-1A1*1 (36.8%), 1A9*1[-118(T)9]-1A1*28b (32.5%) and 1A9*1 [-118(T)9]-1A1*1 (19.0%) in Caucasians, and 1A9*1b(*22) [-118(T)10]-1A1*1 (45.3%), 1A9*1[-118(T)9]-1A1*60 (22.3%) and 1A9*1 [-118(T)9]-1A1*6 (12.7%) in Asians. (Table 2B).

Girard et al. also characterized 1A9-1A1 haplotype structures in 42 Caucasians and identified a novel 1A9 intronic (3'-flanking) tagging variation, 1A9 I399C>T (IVS1+399C>T), with a frequency of 49% (45). Maitland et al. re-sequenced evolu-tionally conserved UGT1A segments (a total of 47.1 kb) for 24 African-American, 24 European-American and 24 Asians, and analyzed linkage disequilibrium among the hepatically expressed UGT1A segments (1A1, 1A6, and 1A9). This study also clearly demonstrated large ethnic variability in allele frequencies and linkages of genetic variations in these regions, emphasizing the importance of consideration for inter-population difference in phenotype-genotype association studies (46).

Haplotype analyses across the UGT1A gene have revealed close linkages among the functional polymorphisms of 1A9, 1A7, and 1A1, and that their combinatorial haplotype structures vary by ethnicity. The data so far reported demonstrate that most 1A7*3-containing haplotypes are linked to 1A1*28 in Caucasians and to either 1A1*6 or 1A1*28 in East Asians. The reported findings also indicate that observations based on the 1A9 or 1A7 polymorphisms might reflect phenotypes of the 1A1 genotypes, and that the distinction between the effects of 1A1 and 1A9 or 1A7 polymorphisms may be difficult. Thus, information on haplotype structures covering these 1A segments in each ethnic population is integral for precise evaluation and selection of genetic markers for irinotecan therapy.

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