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Hot Topic: An Association Between a Leptin Single Nucleotide Polymorphism and Milk and Protein Yield

F. C. Buchanan^*, A. G. Van Kessel^*, C. Waldner, D. A. Christensen^*, B. Laarveld^* and S. M. Schmutz^*

^* Department of Animal and Poultry Science and
Department of Large Animal Clinical Sciences, University of Saskatchewan, Saskatoon, Canada

Corresponding author: F. C. Buchanan; e-mail: Buchanan{at}sask.usask.ca.

	ABSTRACT

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Allelic variation (C to T transition that results in an Arg25Cys) in the leptin gene has been associated with increased fat deposition in beef cattle. We report that this same genetic variant is also present in dairy breeds. Body fat reserves play an important role in sustaining high milk production in early lactation, when energy intake is limited. To test for an association between the leptin single nucleotide polymorphism and milk productivity, we genotyped 416 Holstein cows and compared lactation performance data using a mixed model. Animals homozygous for the T allele produced more milk (1.5 kg/d vs. CC animals) and had higher somatic cell count linear scores, without significantly affecting milk fat or protein percent over the entire lactation. The increase in milk yield is most prominent in the first 100 d of lactation (2.44 kg/d), declining to 1.74 kg/d between 101 and 200 d in lactation. The milk yield advantage, observed in cows homozygous for the T allele, could represent a major economic advantage to dairy producers.

Key Words: leptin gene • allelic variation • milk productivity • immune response

Abbreviation key: SNP = single nucleotide polymorphism

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Leptin is a hormone secreted predominantly from white adipose tissue and performs important roles in the control of BW, feed intake, immune function, and reproduction (Santos-Alvarez et al., 1999; Kadokawa et al., 2000; Block et al., 2001). The primary factors affecting plasma leptin levels include body fat mass and energy balance (Block et al., 2001). Before calving, increased body condition provides energy stores to support milk production. Nevertheless, during early lactation dairy cattle are in a negative energy balance. Leptin has also been shown to regulate the immune response (Santos-Alvarez et al., 1999), and a delay in the recovery of leptin secretion postpartum increases the delay to first ovulation in Holstein dairy cows (Kadokawa et al., 2000). We have previously shown that a C to T transition in exon 2 of leptin that encodes an Arg25Cys substitution (position four of the secreted peptide) is associated with body fat deposition in beef cattle (Buchanan et al., 2002). The T allele is associated with increased fat deposition and higher leptin mRNA levels in adipose tissue.

Using PCR-RFLP to distinguish the alleles (Buchanan et al., 2002), we genotyped individuals from six dairy breeds. The single nucleotide polymorphism (SNP) was present in all breeds examined (Table 1). Using DHI records for 416 Holstein cows and a total of 9584 observations (from 11 Saskatchewan herds; Table 2) associations between milk production, milk fat percentage, milk protein percentage, SCC linear score, and leptin genotype were analyzed. Many of the cows were not registered, and, therefore, sire-group information was not available. Data were analyzed using a mixed model (SAS v. 8.0 for Windows (PROC MIXED); SAS Institute, Cary, NC). The model included a random effect for cow nested within herd to account for the repeated test dates and lactations within cow and the clustering of observations at the herd level. A compound symmetry covariance structure was specified in which all observations within cows within each herd were assumed to be equally correlated. This choice of random effect and covariance structure produced the model with the best R². Initial analyses were examined by looking at the association between each individual production outcome (milk production, fat percent, protein percent, and linear score) and genotype (TT, TC, and CC). Genotype was analyzed as a fixed effect, with CC as the referent category. Potentially important covariates were then introduced for each outcome using a manual step-wise process to produce the final models for milk production, fat percentage, protein percentage, and, finally, SCC linear score. Additional covariates introduced into the model for milk production as fixed effects included milk fat percent, milk protein percent, DIM, lactation number, month the lactation started (for potential seasonal effects), and SSC linear score. Models for fat percent, protein percent, and SSC linear score included fixed effects for milk production, lactation number, month at the start of lactation and protein, fat, or SSC linear score as appropriate. The main-effects model in each case was assessed for first-order interactions where genotype and one or more covariates remained in the model with P < 0.05. Model diagnostics included visual examination of the raw and standardized residuals (SAS, 2000). The residuals were plotted against predicted values of each observation. Rankit plots and Wilk-Shapiro tests were used to assess the normality of the residuals (SAS, 2000).

An unpaired cysteine exists in chicken leptin, three amino acids from the N-terminus of the secreted protein. Dridi et al. (2000) suggest that after substituting this unpaired cysteine with serine that it does not alter bioactivity. However, a heterologous bioassay system was used to compare avian leptins (wild type and mutated) against mammalian receptors. In the in vivo assay reported, the serine form of leptin suppressed accumulated food intake in chickens more than the wild type but not significantly so. It is possible that, similar to our previous observation in beef cattle in which the T allele was associated with increased gene expression and fat deposition (Buchanan et al., 2002), animals homozygous for the T allele may have had increased body fat reserves. Further we speculate that TT animals have increased feed intake, but the effect of genotype on appetite in early lactation would be limited as cows are in a negative energy balance and leptin levels would be low (Kadokawa et al., 2000; Block et al., 2001). The mechanism of action may also be independent of changes in adipose tissue reserves. For example, Silva et al. (2002) demonstrated a direct inhibitory effect of leptin on proliferation of a mammary epithelial cell line (Mac T cells) in vitro. Liefers et al. (2002) using a different, intronic, SNP in the leptin gene also found an increase in milk and protein yield in Holsteins. However, in their population the favorable allele was very rare (only 1 of 613 homozygous) compared with the high frequency of the SNP reported in this study.

Higher SCC can be symptomatic of mastitis infection. However, we show an increase in milk yield and SSC linear score associated with the T allele. This may reflect a possible increase in mastitis incidence associated with higher milk yield or the role of leptin in modulating an immune response. Leptin has been shown to act as a proinflammatory cytokine, stimulating the proliferation and activation of peripheral blood leukocytes (Santos-Alvarez et al., 1999). Further investigation will be necessary to resolve the relationship between leptin genotype and SCC.

These results indicate that the leptin TT genotype is associated with increased milk and protein yield, without changing yield of milk fat. These observations are of economic interest. A more extensive study is under way in which issues of sire information and immune function are to be addressed. Although in this study we measured the effect of leptin genotype on production in Holsteins only, we have noted that all dairy breeds tested showed the presence of the favorable T allele. This preliminary study suggests that the leptin genotype may play an important role in regulating milk and protein yield.

	ACKNOWLEDGEMENTS

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This project received financial support from Dairy Farmers of Canada and the Natural Sciences and Engineering Research Council-Collaborative Research Development. Access to the 416 Holstein blood samples was provided through the Western Canadian Dairy Herd Improvement Services with permission of the 11 producers. Data records on these animals where provided with permission from Holstein Canada from the Canadian Dairy Network. Thanks to Max Rothschild for comments on the manuscript.

Received for publication March 25, 2003. Accepted for publication July 23, 2003.

	REFERENCES

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Block, S. S., W. R. Butler, R. A. Ehrhardt, A. W. Bell, M. E. Van Amburgh, and Y. R. Boisclair. 2001. Decreased concentration of plasma leptin in periparturient dairy cows is caused by negative energy balance. J. Endcrinol. 171:339–348.

Buchanan, F. C., C. J. Fitzsimmons, A. G. Van Kessel, T. D. Thue, D. C. Winkelman-Sim, and S. M. Schmutz. 2002. Association of a missense mutation in the bovine leptin gene with carcass fat content and leptin mRNA levels. Genet. Sel. Evol. 34:105–116.[Medline]

Dridi, S., N. Raver, E. E. Gussakovsky, M. Derouet, M. Picard, A. Gertler, and M. Taouis. 2000. Biological activities of recombinant chicken leptin C4S analog compared with unmodified leptins. Am. J. Physiol. Endocrinol. Metab. 279:116–123.

Liefers, S. C., M. F. W. te Pas, R. F. Veerkamp, and T. van der Lende. 2002. Associations between leptin gene polymorphisms and production, live weight, energy balance, feed intake, and fertility in Holstein heifers. J. Dairy Sci. 85:1633–1638.[Abstract]

Kadokawa, H., D. Blache, Y. Yamada, and G. B. Martin. 2000. Relationships between changes in plasma concentrations of leptin before and after parturition and the timing of first post-partum ovulation in high-producing Holstein dairy cows. Reprod. Fertil. Dev. 12:405–411.[Medline]

Santos-Alvarez, J., R. Goberna, and V. Sánchez-Margalet. 1999. Human leptin stimulates proliferation and activation of human circulating monocytes. Cell. Immunol. 194:6–11.[Medline]

SAS User’s Guide: Statistics, Version 8 Edition. 2000. SAS Inst., Inc., Cary, NC.

Silva, L. F. P., M. J. vandeHaar, M. S. Weber Nielsen, and G. W. Smith. 2002. Evidence for a local effect of leptin in the bovine mammary gland. J. Dairy Sci. 85:3177–3286.

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